Immunodeficiency 53

Mendelian MONDO:0054696 Pathograph 38 Show in embeddings browser Combined immunodeficiency Inborn error of immunity

Immunodeficiency 53 is the autosomal recessive combined immunodeficiency caused by biallelic loss-of-function or severely hypomorphic variants in RELB, the transcription factor of the alternative (non-canonical) NF-kappaB pathway. RelB is required in hematopoietic cells for T cell maturation, Th17 differentiation and B cell class switching, and in thymic stromal cells for the development of AIRE-expressing medullary thymic epithelial cells. Patients therefore combine opportunistic viral, bacterial and fungal infections (including chronic mucocutaneous candidiasis) with neutralizing autoantibodies against type I interferons, which can arise even after hematopoietic stem cell transplantation because the thymic stromal defect is not corrected. The three siblings homozygous for the amorphic Y397* allele presented in early infancy, but a patient with another amorphic allele was diagnosed with combined immunodeficiency only at 12 years. In one sibship with the hypomorphic P364L allele, progressive autoimmunity of the liver, gut, lung and skin dominated the second decade.

Ask OpenScientist

Ask a research question about Immunodeficiency 53. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
10
Pathophys.
31
Phenotypes
2
Hypotheses
3
Gaps
38
Pathograph
1
Genes
2
Medical Actions
1
Models
1
Deep Research
🏷

Classifications

IUIS Category
combined immunodeficiency
👪

Inheritance

1
Autosomal recessive HP:0000007
Patients are homozygous or compound heterozygous for RELB variants. Heterozygous parents and siblings are unaffected, and their plasma lacks autoantibodies against type I interferons.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:39231201 SUPPORT Human Clinical
"Familial segregation was, therefore, consistent with AR inheritance and complete clinical penetrance"
Segregation of the homozygous frameshift in P1's family, with heterozygous parents and siblings healthy.
PMID:37938781 SUPPORT Human Clinical
"By contrast, no AAN-I-IFNs were detected in patients with autosomal-recessive BAFFR or X-linked CD40L deficiency, or in the plasma from heterozygous relatives of patients with autosomal-recessive RELB deficiency (n = 8)"
Heterozygous carriers lack the autoantibody phenotype, consistent with recessive inheritance.
◈

Mechanistic Hypotheses

2
Organ autoimmunity from defective mTEC-dependent central tolerance
mtec_central_tolerance_autoimmunity ALTERNATIVE
Evidence balance 1 support
The liver, lung and skin autoimmunity of partial RelB deficiency arises from the same thymic stromal defect that causes anti-type I IFN autoantibodies: too few AIRE-expressing mTECs to delete organ-reactive T cells. The supporting argument is resemblance to mice lacking Relb only in mTECs.
Pathograph links
Defective Medullary Thymic Epithelial Cell Maturation -> Organ-Infiltrating Autoimmunity INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:39231201 SUPPORT INDIRECT Human Clinical
"By contrast, the liver, lung, and skin-related autoimmunity reported in two patients with AR partial RelB deficiency (25) closely mimics the T cell infiltration of organs in mice with a conditional Relb-KO in mTECs (67), providing additional evidence for the mTEC-intrinsic essential role of..."
States this hypothesis. The patients' clinical picture is human data, but the causal argument rests on resemblance to an mTEC-conditional Relb knockout mouse, which is model-organism evidence.
Organ autoimmunity from loss of RelB restraint on RelA
rela_derepression_autoimmunity ALTERNATIVE
Evidence balance 1 support
Residual but unstable RelB in P364L patients fails to restrain RelA-driven pro-inflammatory transcription, and this hyper-inflammatory state drives the organ autoimmunity. This would explain why organ autoimmunity is seen in the P364L sibship but not in complete deficiency.
Pathograph links
Impaired Alternative NF-kappaB Pathway Activation -> Derepressed RelA-Driven Inflammatory Gene Expression INDIRECT UNKNOWN INTERMEDIATES
Derepressed RelA-Driven Inflammatory Gene Expression -> Organ-Infiltrating Autoimmunity INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:36402602 SUPPORT INDIRECT In Vitro
"Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function."
The fibroblast transcriptional finding the hypothesis rests on.
?

Discussions and Knowledge Gaps

3
Is the organ autoimmunity of partial RelB deficiency caused by the thymic stromal tolerance defect, by loss of RelB restraint on RelA, or both?
CONTROVERSY OPEN relb_organ_autoimmunity_mechanism
Attached to
pathophysiology#Organ-Infiltrating Autoimmunity mechanistic_hypotheses#mtec_central_tolerance_autoimmunity mechanistic_hypotheses#rela_derepression_autoimmunity
Sharfe et al. (2022) attribute the autoimmunity to RelA derepression measured in fibroblasts. Le Voyer et al. (2024) attribute it to the mTEC defect, by analogy with mTEC-specific Relb knockout mice. Neither was tested in the patients' T cells or tissues. The two hypotheses also leave open why complete deficiency spares the organs. A thymic account predicts that organ autoimmunity persists after HSCT; a hematopoietic RelA account predicts it resolves. No partial-deficiency patient with organ autoimmunity has been transplanted.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"It would therefore be interesting to determine whether this procedure can also correct organ-related autoimmunity in patients with AR partial RelB deficiency."
The authors name the untested HSCT outcome.
Why does germline Relb loss cause lethal multiorgan inflammation in mice but only anti-type I IFN autoantibodies in human complete deficiency?
HUMAN MODEL MISMATCH OPEN relb_mouse_human_autoimmunity_mismatch
Attached to
animal_models#Mouse pathophysiology#Organ-Infiltrating Autoimmunity
The mouse knockout is the main experimental basis for RelB's role in tolerance and inflammation, but its autoimmune phenotype is far more severe than the human one. Mouse findings about inflammation should not be transferred to patients without human data.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"The autoimmune phenotype observed in P1 and P2, restricted to the development of auto-Abs against type I IFNs, sharply contrasts with that of Relb-KO mice, which die from overwhelming T lymphocyte-dependent multiple-organ inflammation at the age of 2 to 6 wk"
States the mismatch directly.
Can the thymic stromal defect be corrected, so that transplanted patients stop producing anti-type I IFN autoantibodies?
KNOWLEDGE GAP OPEN relb_thymic_stromal_defect_after_hsct
Attached to
pathophysiology#Defective Medullary Thymic Epithelial Cell Maturation treatments#Hematopoietic Stem Cell Transplantation
HSCT restores lymphocyte function but leaves patients at risk of severe viral disease from persistent anti-type I IFN autoantibodies. Thymus implantation and TEC regeneration have been suggested but not tried.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"They also suggest that therapeutic options for correcting the thymic stromal defect in these patients, such as thymic implantation or stem-cell-based TEC regeneration, are worth considering"
The authors propose untested stromal-directed therapies.
⚙

Pathophysiology

10
Biallelic RELB Loss of Function
Biallelic RELB variants either abolish RelB protein (the Q72fs frameshift and Y397* nonsense alleles are amorphic) or encode a protein with strongly reduced transcriptional activity (Q135dup, E145K, P364L are hypomorphic). The P364L protein is also unstable and expressed at very low levels.
RELB hgnc:9956 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RELB (hgnc:9956). hgnc:9956 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
RelB DNA-binding transcription factor activity GO:0003700 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased RelB DNA-binding transcription factor activity, annotated with DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology.
Downstream
Impaired Alternative NF-kappaB Pathway Activation
Show evidence (3 references)
PMID:39231201 SUPPORT In Vitro
"These data suggest that Q72fs and Y397* are amorphic, whereas Q135dup, P364L, and E145K, are strongly hypomorphic."
Overexpression and reporter assays classify the patient alleles as null or strongly hypomorphic.
PMID:36402602 SUPPORT In Vitro
"The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation."
Shows that the P364L hypomorph acts through low protein abundance with residual function.
PMID:33791233 SUPPORT Human Clinical
"Reverse transcription-polymerase chain reaction and Western blot analysis showed that the expression of RelB in the patient was lower than that in the healthy controls at mRNA and protein levels."
Reduced RelB expression in the patient homozygous for the Q135dup in-frame insertion.
Impaired Alternative NF-kappaB Pathway Activation
Without functional RelB, p52/RelB heterodimers cannot drive target-gene induction after lymphotoxin or TWEAK stimulation. NFKB2 and VCAM1 induction is impaired, while p100 processing to p52 and canonical NF-kappaB responses to TNF and IL-1beta are intact.
Organ autoimmunity from loss of RelB restraint on RelA
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
non-canonical NF-kappaB signal transduction GO:0038061 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased non-canonical NF-kappaB signal transduction (GO:0038061). GO:0038061 is a biological process from the Gene Ontology.
Downstream
Defective Medullary Thymic Epithelial Cell Maturation
Impaired Thymopoiesis and T Cell Maturation
Impaired Th17 Differentiation
B Cell-Intrinsic Failure of Class Switching and Antibody Secretion
Derepressed RelA-Driven Inflammatory Gene Expression Organ autoimmunity from loss of RelB restraint on RelA
Show evidence (2 references)
PMID:39231201 SUPPORT In Vitro
"The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients."
Direct measurement of the alternative-pathway defect in patient fibroblasts.
PMID:39231201 SUPPORT In Vitro
"By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1β via the canonical NF-κB pathway remains intact."
Shows the defect is confined to the alternative pathway.
Defective Medullary Thymic Epithelial Cell Maturation
The human thymus in RelB deficiency is hypoplastic and has a poorly formed medulla. mTEC specification is not fully blocked, but differentiation into AIRE-expressing and post-AIRE mTECs fails. This is a stromal defect, so hematopoietic stem cell transplantation does not correct it.
Organ autoimmunity from defective mTEC-dependent central tolerance
medullary thymic epithelial cell CL:0002365 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves medullary thymic epithelial cell (CL:0002365). CL:0002365 is a cell type from the Cell Ontology.
thymus development GO:0048538 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased thymus development (GO:0048538). GO:0048538 is a biological process from the Gene Ontology.
Animal models
Relb knockout mouse Mouse recapitulates
Downstream
Hypoplasia of the thymus
Failure of Central Tolerance to Type I Interferons
Organ-Infiltrating Autoimmunity Organ autoimmunity from defective mTEC-dependent central tolerance
Show evidence (2 references)
PMID:37938781 SUPPORT Human Clinical
"These findings suggest that RELB deficiency does not completely block mTEC specification but, rather, prevents differentiation into AIRE-expressing and post-AIRE mTECs."
Thymic biopsy from a patient with complete RELB deficiency.
PMID:41608125 SUPPORT REVIEW SYNTHESIS Other
"AR RelB deficiency results in an abnormal thymic architecture, characterized by a poorly formed medulla"
Review synthesis of the thymic pathology across reported patients.
Failure of Central Tolerance to Type I Interferons
Without AIRE-expressing mTECs, T cells reactive to type I interferons are not deleted in the thymus. In proteome-wide autoantibody screening, type I interferons were the most enriched autoantigens in RelB-deficient patients.
central tolerance induction to self antigen GO:0002509 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased central tolerance induction to self antigen (GO:0002509). GO:0002509 is a biological process from the Gene Ontology.
Downstream
Neutralizing Autoantibodies Against Type I Interferons
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"Overall, these data suggest that RelB is essential for thymic T cell tolerance to type I IFNs."
Conclusion from autoantigen profiling of two patients' plasma.
Neutralizing Autoantibodies Against Type I Interferons
Seven of eight tested patients with partial or complete RELB deficiency carry autoantibodies that neutralize IFN-alpha and IFN-omega. They can arise after hematopoietic stem cell transplantation: P1 had none before transplantation and developed them five years after. They are absent from heterozygous relatives. No HPO term exists for this finding, so it is recorded as a mechanism node rather than a phenotype.
Downstream
Severe varicella zoster infection
Show evidence (2 references)
PMID:37938781 SUPPORT Human Clinical
"AAN-I-IFNs were also detected in patients with autosomal-recessive RELB deficiency (n = 7 out of 8: four patients with partial and three with complete deficiency)."
Frequency of anti-type I IFN autoantibodies in the RELB-deficient cohort.
PMID:39231201 SUPPORT Human Clinical
"Consistent with the critical mTEC-intrinsic role of p52/RelB heterodimers in establishing tolerance to type I IFNs, HSCT did not prevent the development of thymic stromal cell-dependent autoimmunity in P1, who developed auto-Abs against type I IFNs after transplantation."
The autoantibodies arose after HSCT, consistent with a stromal rather than hematopoietic origin.
Impaired Thymopoiesis and T Cell Maturation
Patients have low TRECs and few recent thymic emigrants, low naive CD4+ and CD8+ T cells with expanded effector memory cells, skewed TCR repertoires with clonal expansion, and depressed T cell proliferation to mitogens. In partial deficiency, naive T cells decline with age. HSCT corrects the T cell-related infections, so part of the defect is hematopoietic-intrinsic.
naive CD4-positive T cell CL:0000895 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves naive CD4-positive T cell, annotated with naive thymus-derived CD4-positive, alpha-beta T cell (CL:0000895). CL:0000895 is a cell type from the Cell Ontology. naive CD8-positive T cell CL:0000900 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves naive CD8-positive T cell, annotated with naive thymus-derived CD8-positive, alpha-beta T cell (CL:0000900). CL:0000900 is a cell type from the Cell Ontology.
T cell differentiation in thymus GO:0033077 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell differentiation in thymus (GO:0033077). GO:0033077 is a biological process from the Gene Ontology.
Downstream
Decreased naive T cell proportion
Decreased total CD4+ T cell count
Abnormally low T cell receptor excision circle level
Decreased mitogen-induced T-cell proliferation
Cryptococcal meningitis
Unusual warts
Unusual JC virus infection
Unusual Talaromyces marneffei infection
Show evidence (3 references)
PMID:39231201 SUPPORT Human Clinical
"Overall, these results suggest that partial or complete forms of AR RelB deficiency caused inadequate thymopoiesis, defects of T lymphocyte development, maturation, and differentiation."
Summary of the immunophenotyping of two patients.
PMID:26385063 SUPPORT Human Clinical
"We show that the thymus in this patient is dysplastic and consequently new thymus emigrants are rare and there is an accumulation of CD45 RO(+) T cells with an increase in CD62L(+) central memory cells."
Same finding in the original complete-deficiency kindred.
PMID:36402602 SUPPORT Human Clinical
"This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+ cells."
Progressive loss of naive T cells in the partial-deficiency sibship.
Impaired Th17 Differentiation
Naive CD4+ T cells fail to differentiate into IL-17A/F- and IL-22-producing memory cells. Th17 proportions are low ex vivo, and IL-17A/F production stayed low six months after HSCT although no fungal infection recurred.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
T-helper 17 cell differentiation GO:0072539 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T-helper 17 cell differentiation (GO:0072539). GO:0072539 is a biological process from the Gene Ontology.
Downstream
Decreased Th17 T cell proportion
Chronic mucocutaneous candidiasis
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"Like patients with STAT1 GOF (39, 40), P1 had low proportions of IL-17A-, IL-17F-, and IL-22- producing, but not of IFN-γ-producing, memory CD4+ T cells ex vivo"
Ex vivo measurement of the selective Th17 cytokine defect.
B Cell-Intrinsic Failure of Class Switching and Antibody Secretion
RelB-deficient naive B cells proliferate and upregulate activation markers normally but barely secrete IgM and cannot switch to IgG or IgA after CD40L plus IL-21 stimulation. Class-switched memory B cells are almost absent. These defects were corrected by HSCT.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. class switched memory B cell CL:0000972 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves class switched memory B cell (CL:0000972). CL:0000972 is a cell type from the Cell Ontology.
isotype switching GO:0045190 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased isotype switching (GO:0045190). GO:0045190 is a biological process from the Gene Ontology.
Downstream
Decreased class-switched memory B cell proportion
Decreased total B cell count
Hypogammaglobulinemia
Decreased specific antibody response to vaccination
Recurrent respiratory infections
Recurrent pneumonia
Recurrent otitis media
Show evidence (2 references)
PMID:39231201 SUPPORT In Vitro
"Moreover, their naïve B cells cannot differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells is strongly impaired in vitro."
In vitro differentiation assay on patient naive B cells.
PMID:26385063 SUPPORT Human Clinical
"In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies."
Same B cell arrest in the original complete-deficiency kindred.
Derepressed RelA-Driven Inflammatory Gene Expression
In fibroblasts from patients homozygous for the hypomorphic P364L allele, stimulation induces a cluster of hyper-expressed pro-inflammatory transcripts. The authors read this as loss of RelB's inhibitory effect on RelA and propose it as the main driver of the organ autoimmunity in that sibship. In Relb-knockout mice, RelB likewise suppresses a set of inflammatory response genes independently of interferon signaling.
Organ autoimmunity from loss of RelB restraint on RelA
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Downstream
Organ-Infiltrating Autoimmunity Organ autoimmunity from loss of RelB restraint on RelA
Show evidence (2 references)
PMID:36402602 SUPPORT In Vitro
"Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function."
Transcriptional measurement in patient fibroblasts.
PMID:37460023 SUPPORT Model Organism
"Instead, we found that RelB suppresses a different set of inflammatory response genes in a manner that is independent of interferon signaling but associated with NF-κB binding motifs."
Mouse genetic evidence that RelB restrains NF-kappaB-motif inflammatory genes.
Organ-Infiltrating Autoimmunity
In the two older of three siblings homozygous for P364L, chronic hepatitis with portal fibrosis (with sclerosing cholangitis in one), autoimmune enteritis with villous atrophy, inflammatory lung disease and T cell and plasma cell skin infiltrates progressed through the second decade. The youngest sibling, aged 4, has had only one severe infection so far. The resected lung lobe also grew Mycobacterium tuberculosis, and the authors describe the lung lesion as an exaggerated inflammatory response rather than calling it autoimmune. Organ autoimmunity has not been reported in the complete-deficiency patients or in P2, whose autoimmunity is limited to anti-type I IFN autoantibodies.
Animal models
Relb knockout mouse Mouse partially recapitulates
Downstream
Chronic hepatitis
Hepatic fibrosis
Sclerosing cholangitis
Villous atrophy
Inflammatory abnormality of the skin
Chronic diarrhea
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life."
Clinical description of the organ autoimmunity in the P364L sibship.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 53 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

31
Blood 8
Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogammaglobulinemia, annotated with Decreased circulating immunoglobulin concentration (HP:0004313). HP:0004313 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39231201 SUPPORT Human Clinical
"At 6 y of age, she was diagnosed with hypogammaglobulinemia, and intravenous immunoglobulin (IVIg) replacement therapy was initiated."
Hypogammaglobulinemia in P1.
PMID:39231201 SUPPORT Human Clinical
"P1, P2, and the three siblings homozygous for the Y397* RELB variant presented with hypogammaglobulinemia and recurrent bacterial respiratory tract infections"
Reported in five patients from two kindreds.
Decreased class-switched memory B cell proportion HP:0030388 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased class-switched memory B cell proportion (HP:0030388). HP:0030388 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39231201 SUPPORT Human Clinical
"By contrast, <5% of the residual memory B cells detected in P1 before HCST had undergone class switching in vivo to express immunoglobulin G (IgG) or immunoglobulin A (IgA)."
Flow cytometry of P1's memory B cells.
PMID:26385063 SUPPORT Human Clinical
"Critically, CD27(+) memory cells were absent."
Absent memory B cells in the original complete-deficiency kindred.
Decreased naive T cell proportion HP:0031397 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased naive CD4+ and CD8+ T cell proportion, annotated with Decreased naive T cell proportion (HP:0031397). HP:0031397 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells."
Immunophenotyping of two patients.
Abnormally low T cell receptor excision circle level HP:0031545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low TREC level, annotated with Abnormally low T cell receptor excision circle level (HP:0031545). HP:0031545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"P1 had low T cell receptor excision circle (TREC) levels"
Measured in P1; not assessed in P2.
Decreased mitogen-induced T-cell proliferation HP:0031381 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased mitogen-induced T-cell proliferation (HP:0031381). HP:0031381 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26385063 SUPPORT Human Clinical
"In vitro responses to T cell mitogens were markedly depressed and so were PHA induced IL2 and IFNγ production."
Original complete-deficiency kindred.
Decreased total B cell count HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"Patients also suffered progressive loss of the entire B cell compartment."
Progressive B cell loss in the P364L sibship.
Decreased total CD4+ T cell count HP:5210418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total CD4+ T cell count (HP:5210418). HP:5210418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"Counts of CD3+, CD4+, and CD8+ T cells were normal in P1 (assessed at the age of 12 y), but markedly low in P2 (assessed at the age of 19 y), except for CD8+ T cells"
Low CD4+ count in P2; normal in P1.
Decreased Th17 T cell proportion HP:0025832 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased Th17 T cell proportion (HP:0025832). HP:0025832 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"Consistently, P1 and P2 had low proportions of Th17 cells ex vivo, and P1 displayed low levels of IL-17A and IL-17F production by memory CD4+ T cells (P2 was not tested)."
Ex vivo Th17 proportions in both patients.
Cardiovascular 1
Hypoplasia of the thymus HP:0000778 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the thymus (HP:0000778). HP:0000778 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:39231201 SUPPORT Human Clinical
"At the age of 14 y (before transplantation) the thymus from P1 was strongly hypoplastic"
Thymic imaging in P1.
PMID:26385063 SUPPORT Human Clinical
"We show that the thymus in this patient is dysplastic and consequently new thymus emigrants are rare"
Dysplastic thymus in the original complete-deficiency kindred.
PMID:33791233 SUPPORT Human Clinical
"Enhanced CT and MRI scanning demonstrated thymic dysplasia, diffuse pulmonary and liver nodules, and many balloon-like air sacs in both lungs."
Thymic dysplasia on imaging in the Q135dup patient.
Digestive 5
Chronic hepatitis HP:0200123 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic autoimmune liver disease, annotated with Chronic hepatitis (HP:0200123). HP:0200123 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"Together, these findings demonstrate advanced chronic autoimmune liver disease."
Liver biopsy findings in the oldest sibling.
Hepatic fibrosis HP:0001395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Portal fibrosis, annotated with Hepatic fibrosis (HP:0001395). HP:0001395 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"Remarkably, similar to her older sister, the biopsy demonstrated stage 3–4 portal fibrosis with massive infiltrates of lymphocytes and plasma cells (Fig 1E–H)."
Portal fibrosis in both older siblings.
Sclerosing cholangitis HP:0030991 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sclerosing cholangitis (HP:0030991). HP:0030991 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"Concentric peri-bile ductal fibrosis was noted, consistent with sclerosing cholangitis."
Liver biopsy finding in the P364L sibship.
Villous atrophy HP:0011473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Villous atrophy (HP:0011473). HP:0011473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"Villus atrophy and the presence of intra-epithelial lymphocytic infiltrates supported the notion of autoimmune enteritis."
Duodenal biopsy in the P364L sibship.
Chronic diarrhea HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028). HP:0002028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"The oldest patient (Pt 1, 18yrs) at her most recent evaluation was found to be very short, underweight, and suffering from chronic diarrhea as well as chronic severe lung, liver, and skin manifestations."
Oldest P364L sibling.
Ear 1
Recurrent otitis media HP:0000403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent otitis media (HP:0000403). HP:0000403 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"She had a history of recurrent oral candidiasis, facial skin lesions suspected to be of viral origin, sinusitis, multiple episodes of otitis media (leading to an episode of mastoiditis), and recurrent bacterial pneumonia."
Multiple episodes of otitis media in P1, one complicated by mastoiditis.
Endocrine 1
Delayed puberty HP:0000823 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed puberty (HP:0000823). HP:0000823 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"She too is delayed in her linear growth and puberty."
Second P364L sibling.
Head and Neck 1
Mastoiditis HP:0000265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mastoiditis (HP:0000265). HP:0000265 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"She had a history of recurrent oral candidiasis, facial skin lesions suspected to be of viral origin, sinusitis, multiple episodes of otitis media (leading to an episode of mastoiditis), and recurrent bacterial pneumonia."
One episode, complicating otitis media in P1.
Immune 12
Chronic mucocutaneous candidiasis HP:0002728 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic mucocutaneous candidiasis (HP:0002728). HP:0002728 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"Both RelB-deficient patients experienced infections related to a T cell defect: CMC (P1 and P2), C. neoformans meningitis (P1), epidermodysplasia verruciformis and recalcitrant skin warts (P2), and JC virus-induced PML (P2)."
CMC is reported in both patients.
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"P1, P2, and the three siblings homozygous for the Y397* RELB variant presented with hypogammaglobulinemia and recurrent bacterial respiratory tract infections"
Reported in five patients from two kindreds.
Recurrent pneumonia HP:0006532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial pneumonia, annotated with Recurrent pneumonia (HP:0006532). HP:0006532 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"She had a history of recurrent oral candidiasis, facial skin lesions suspected to be of viral origin, sinusitis, multiple episodes of otitis media (leading to an episode of mastoiditis), and recurrent bacterial pneumonia."
Clinical history of P1.
Cryptococcal meningitis HP:0032160 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptococcal meningitis (HP:0032160). HP:0032160 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"At the age of 12 y, she was hospitalized for Cryptococcus neoformans meningitis (28) and CID was diagnosed."
Single-patient observation.
Unusual Talaromyces marneffei infection HP:5210374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disseminated Talaromyces marneffei infection, annotated with Unusual Talaromyces marneffei infection (HP:5210374). HP:5210374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33791233 SUPPORT Human Clinical
"The patient was HIV-negative and bone marrow and blood culture showed T. marneffei infection."
Single-patient observation.
Unusual warts HP:5210303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recalcitrant cutaneous warts, annotated with Unusual warts (HP:5210303). HP:5210303 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"He also suffered from severe viral infections, including varicella pneumonia requiring intensive care and mechanical ventilation at the age of 3 y, recalcitrant skin warts and epidermodysplasia verruciformis, both histologically documented."
Single-patient observation.
Severe varicella zoster infection HP:0032170 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Varicella pneumonia, annotated with Severe varicella zoster infection (HP:0032170). HP:0032170 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39231201 SUPPORT Human Clinical
"He also suffered from severe viral infections, including varicella pneumonia requiring intensive care and mechanical ventilation at the age of 3 y, recalcitrant skin warts and epidermodysplasia verruciformis, both histologically documented."
Severe varicella in P2.
PMID:36402602 SUPPORT Human Clinical
"Her history is remarkable for an episode of severe and prolonged chicken pox complicated by pneumonitis and secondary skin infections occurring at 2 years of age."
Severe varicella in a P364L homozygous sibling.
Unusual JC virus infection HP:5210334 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is JC virus progressive multifocal leukoencephalopathy, annotated with Unusual JC virus infection (HP:5210334). HP:5210334 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"He subsequently died of JC polyomavirus-induced progressive multifocal leukoencephalitis (PML)."
Single-patient observation.
Severe adenovirus infection HP:0031694 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe adenovirus pneumonitis, annotated with Severe adenovirus infection (HP:0031694). HP:0031694 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"Of special note is an episode of severe pneumonitis occurring at 1 year of age due to adenovirus infections which required prolonged hospitalization."
Single-patient observation.
Decreased specific antibody response to vaccination HP:0032140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased specific antibody response to vaccination (HP:0032140). HP:0032140 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39231201 SUPPORT Human Clinical
"P2 had inadequate specific Ab responses following vaccination against tetanus, diphtheria, and measles/mumps/rubella (MMR), and VZV"
Vaccine responses in P2.
PMID:36402602 SUPPORT Human Clinical
"These age-correlated anomalies coincided with the gradual decline of the patients’ ability to produce specific antibodies in response to vaccination and necessitated immunoglobulin replacement therapy."
Progressive loss of vaccine responses in the P364L sibship.
Pulmonary tuberculosis HP:0032262 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary tuberculosis (HP:0032262). HP:0032262 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"While Mycobacterium tuberculosis was identified in the resected lobe, the florid inflammatory changes suggested an aberrantly exaggerated inflammatory response."
Tuberculosis in the resected lobe, with the authors' reading of the inflammation.
Inflammatory abnormality of the skin HP:0011123 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic inflammatory skin lesions, annotated with Inflammatory abnormality of the skin (HP:0011123). HP:0011123 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36402602 SUPPORT Human Clinical
"Skin biopsy of a lesion revealed diffuse inflammatory infiltrates consisting of T cells and plasma cells."
Skin histology in the oldest P364L sibling.
PMID:36402602 SUPPORT Human Clinical
"She suffered chronic cutaneous lesions starting at age 3 that appeared autoinflammatory in nature as response to antimicrobial treatment was inadequate."
Chronic inflammatory skin lesions in the second P364L sibling.
Growth 2
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT BACKGROUND Human Clinical
"Previously, we identified complete RelB deficiency in three children who presented very early in infancy (7 days-4 months) with severe infections and failure to thrive [17, 18]."
The authors' summary of their earlier complete-deficiency kindred.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36402602 SUPPORT Human Clinical
"The oldest patient (Pt 1, 18yrs) at her most recent evaluation was found to be very short, underweight, and suffering from chronic diarrhea as well as chronic severe lung, liver, and skin manifestations."
Oldest P364L sibling.
🧬

Genetic Associations

1
RELB
Gene: RELB hgnc:9956 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RELB (hgnc:9956). hgnc:9956 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
DOI:10.14785/lpsn-2015-0005 SUPPORT Human Clinical
"We identified a homozygous mutation in the gene for the NFκB transcription factor RelB in 3 patients who suffered repeated infection despite the presence of circulating T and B cells."
First report of RELB deficiency. The journal is not indexed in PubMed, so this DOI is the citation.
PMID:39231201 SUPPORT Human Clinical
"We report two unrelated adults with homozygous (P1) or compound heterozygous (P2) private loss-of-function variants of V-Rel Reticuloendotheliosis Viral Oncogene Homolog B (RELB)."
Two further unrelated patients with biochemically characterized loss-of-function alleles.
💊

Medical Actions

2
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
HSCT corrected the T and B cell-related infectious susceptibility in the four patients with complete deficiency who were transplanted. P1 had normal immunoglobulins and was off IVIg three years after HSCT. It does not correct the thymic stromal defect: P1 developed anti-type I IFN autoantibodies five years after transplantation. Whether HSCT corrects organ autoimmunity in partial deficiency is unknown.
Mechanism Target:
Impaired Thymopoiesis and T Cell Maturation
B Cell-Intrinsic Failure of Class Switching and Antibody Secretion
Show evidence (2 references)
PMID:39231201 SUPPORT Human Clinical
"HSCT corrected the infectious susceptibility associated with T and B cells in the four patients with AR complete RelB deficiency who underwent transplantation."
Outcome across the four transplanted patients.
PMID:39231201 SUPPORT Human Clinical
"3 y after transplantation, P1 had normal proportions of B cells, normal serum levels of IgG, IgA, and IgM, was off IVIg replacement therapy, and reported no B cell-related infections"
Durable B cell reconstitution in P1.
Immunoglobulin Replacement Therapy
Action: immunoglobulin replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunoglobulin replacement therapy, annotated with Immunoglobulin Therapy (NCIT:C62710). NCIT:C62710 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunoglobulin Therapy NCIT:C62710
Platform: Protein replacement
Used for hypogammaglobulinemia before HSCT and in the partial-deficiency sibship as antibody responses declined.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"At 6 y of age, she was diagnosed with hypogammaglobulinemia, and intravenous immunoglobulin (IVIg) replacement therapy was initiated."
Documents use; no response measure is reported.
🔬

Diagnosis

4
Lymphocyte immunophenotyping
Flow cytometry shows low naive CD4+ and CD8+ T cells, low Th17 cells and few class-switched memory B cells, with normal monocyte and granulocyte counts.
immunological flow cytometry NCIT:C113003 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells."
The core immunophenotype in both characterized patients.
Neutralizing anti-type I interferon autoantibody testing
A luciferase reporter assay measures whether plasma neutralizes IFN-alpha2, IFN-omega or IFN-beta. The antibodies can appear years after transplantation, so the authors recommend repeat testing.
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"These observations highlight the importance of evaluating changes in the levels of these auto-Abs over time."
Authors' recommendation to monitor the autoantibodies over time.
Fibroblast alternative NF-kappaB pathway assay
Induction of NFKB2 and VCAM1 after lymphotoxin or TWEAK stimulation of patient fibroblasts confirms that a RELB variant impairs the alternative pathway, and complementation with wild-type RELB confirms causality.
Show evidence (1 reference)
PMID:39231201 SUPPORT In Vitro
"The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients."
The functional readout used to characterize patient alleles.
Exome sequencing
Biallelic RELB variants have been found by exome or genome sequencing in each reported kindred, followed by Sanger confirmation and segregation.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39231201 SUPPORT Human Clinical
"By screening our in-house database of whole-exome sequencing (WES) data for over 25,000 patients with various infectious diseases, we identified a single patient (P1) carrying a biallelic private variant of RELB that was predicted to be deleterious."
Exome sequencing identified the variant in P1.
📊

Prevalence

1
Worldwide (published case reports)
Cases In Literature
Nine patients from five kindreds reported as of the 2026 review.
Show evidence (1 reference)
PMID:41608125 SUPPORT REVIEW SYNTHESIS Other
"Nine patients from five kindreds originating from Canada (Irish descent), Israel (Iranian Jewish descent), Turkey, and China with biallelic rare or private variants of RELB (26, 60, 61, 62, 63) have been reported (Table S1)."
Review count of all published RELB-deficient patients and their ancestries.
🐁

Animal Models

1
Relb knockout mouse
Relb-null mice lack thymic UEA-1+ medullary epithelial cells and have reduced thymic dendritic cells. Unlike human patients, they develop multiorgan inflammatory infiltration and myeloid hyperplasia. The 2-to-6-week lethality is cited from PMID:39231201, not from the primary mouse reports.
Species
Mouse
Genotype
Relb-/- (germline targeted disruption)
Publication
PMID:7845467
Pathograph links
Defective Medullary Thymic Epithelial Cell Maturation recapitulates fidelity: moderate observes: cellular
Limitations: The mouse shows complete absence of UEA-1+ mTECs, while the human thymus retains rare mTECs that fail to mature to AIRE+ cells. The mouse's lethal multiorgan inflammation is not seen in human complete deficiency.
Show evidence (1 reference)
PMID:7845467 SUPPORT Model Organism
"Thymic UEA-1+ medullary epithelial cells from normal mice show striking similarities to DC and, interestingly, these cells are also absent in relB mutant mice."
The mTEC defect is present in the knockout.
Organ-Infiltrating Autoimmunity partially recapitulates fidelity: low observes: organism
Limitations: Knockout mice die at 2 to 6 weeks from T cell-dependent inflammation of many organs. Human complete deficiency shows only anti-type I IFN autoantibodies, and organ autoimmunity is limited to partial deficiency.
Show evidence (1 reference)
PMID:7834753 SUPPORT Model Organism
"Mice homozygous for the disrupted relB locus had phenotypic abnormalities including multifocal, mixed inflammatory cell infiltration in several organs, myeloid hyperplasia, splenomegaly due to extramedullary hematopoiesis, and a reduced population of thymic dendritic cells."
Multiorgan inflammatory infiltration in the knockout.
{ }

Source YAML

click to show 
name: Immunodeficiency 53
creation_date: "2026-10-14T18:30:00Z"
category: Mendelian
synonyms:
- IMD53
- RelB deficiency
- RELB deficiency
- Autosomal recessive RelB deficiency
description: >-
  Immunodeficiency 53 is the autosomal recessive combined immunodeficiency caused by
  biallelic loss-of-function or severely hypomorphic variants in RELB, the
  transcription factor of the alternative (non-canonical) NF-kappaB pathway.
  RelB is required in hematopoietic cells for T cell maturation, Th17
  differentiation and B cell class switching, and in thymic stromal cells for
  the development of AIRE-expressing medullary thymic epithelial cells. Patients
  therefore combine opportunistic viral, bacterial and fungal infections
  (including chronic mucocutaneous candidiasis) with neutralizing autoantibodies
  against type I interferons, which can arise even after hematopoietic stem cell
  transplantation because the thymic stromal defect is not corrected. The three
  siblings homozygous for the amorphic Y397* allele presented in early infancy,
  but a patient with another amorphic allele was diagnosed with combined
  immunodeficiency only at 12 years. In one sibship with the hypomorphic P364L
  allele, progressive autoimmunity of the liver, gut, lung and skin dominated
  the second decade.
disease_term:
  preferred_term: immunodeficiency 53
  term:
    id: MONDO:0054696
    label: immunodeficiency 53
parents:
- Combined immunodeficiency
- Inborn error of immunity
notes: >-
  Ultra-rare. Nine patients from five kindreds have been reported. PMID:39231201
  classifies four as complete deficiency (P1 with Q72fs and the three Y397*
  siblings) and five as partial (the three P364L siblings, P2 with E145K/P364L,
  and the Q135dup infant). The 2026 review PMID:41608125 states three complete
  and five partial, which does not add up to its own count of nine. Every
  count in this entry is therefore n out of a handful of patients, and no
  `frequency` value is set. No GeneReviews chapter exists for this disease, and
  no Orphanet record maps to MONDO:0054696 in the committed Orphanet cache.
  Findings reported in a single patient and not attributed to RelB deficiency by
  the reporting authors (large B cell lymphoma, thyroid disease, osteomyelitis
  and peritonitis in one adult) are not recorded as phenotypes. The same adult
  (P2, partial deficiency) also had chronic malabsorption with cholestatic liver
  disease and portal hypertension. The reporting authors do not call it
  autoimmune, so it is not attached to the organ-autoimmunity node. Rituximab
  given to P2 and the lung lobe resected in the P364L sibship are
  single-patient interventions whose indications are not specific to RelB
  deficiency, so they are not recorded as treatments. ClinGen's RELB summary
  also cites PMID:33083013, a Pakistani diagnostic cohort. The RELB case there
  appears only in supplementary tables, which were not reviewed, so it is not
  known whether it adds a tenth patient or a further allele. A 2026 fungal
  infection review lists Pneumocystis pneumonia for RELB deficiency; no primary
  report read for this entry describes Pneumocystis infection, so it is not
  recorded. No mechanism module covers the alternative NF-kappaB pathway or
  thymic central tolerance, so no node declares conforms_to.
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  notes: Nine patients from five kindreds reported as of the 2026 review.
  evidence:
  - reference: PMID:41608125
    reference_title: Human inborn errors of the alternative NF-κB pathway.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Nine patients from five kindreds originating from Canada (Irish descent), Israel (Iranian Jewish descent), Turkey, and China with biallelic rare or private variants of RELB (26, 60, 61, 62, 63) have been reported (Table S1)."
    explanation: >-
      Review count of all published RELB-deficient patients and their
      ancestries.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Patients are homozygous or compound heterozygous for RELB variants.
    Heterozygous parents and siblings are unaffected, and their plasma lacks
    autoantibodies against type I interferons.
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial segregation was, therefore, consistent with AR inheritance and complete clinical penetrance"
    explanation: >-
      Segregation of the homozygous frameshift in P1's family, with
      heterozygous parents and siblings healthy.
  - reference: PMID:37938781
    reference_title: Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, no AAN-I-IFNs were detected in patients with autosomal-recessive BAFFR or X-linked CD40L deficiency, or in the plasma from heterozygous relatives of patients with autosomal-recessive RELB deficiency (n = 8)"
    explanation: >-
      Heterozygous carriers lack the autoantibody phenotype, consistent with
      recessive inheritance.
pathophysiology:
- name: Biallelic RELB Loss of Function
  description: >-
    Biallelic RELB variants either abolish RelB protein (the Q72fs frameshift
    and Y397* nonsense alleles are amorphic) or encode a protein with strongly
    reduced transcriptional activity (Q135dup, E145K, P364L are hypomorphic).
    The P364L protein is also unstable and expressed at very low levels.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: RelB DNA-binding transcription factor activity
    modifier: DECREASED
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  genes:
  - preferred_term: RELB
    term:
      id: hgnc:9956
      label: RELB
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data suggest that Q72fs and Y397* are amorphic, whereas Q135dup, P364L, and E145K, are strongly hypomorphic."
    explanation: >-
      Overexpression and reporter assays classify the patient alleles as null
      or strongly hypomorphic.
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation."
    explanation: >-
      Shows that the P364L hypomorph acts through low protein abundance with
      residual function.
  - reference: PMID:33791233
    reference_title: Disseminated Talaromyces marneffei Infection in a Non-HIV Infant With a Homozygous Private Variant of RELB.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reverse transcription-polymerase chain reaction and Western blot analysis showed that the expression of RelB in the patient was lower than that in the healthy controls at mRNA and protein levels."
    explanation: >-
      Reduced RelB expression in the patient homozygous for the Q135dup
      in-frame insertion.
  downstream:
  - target: Impaired Alternative NF-kappaB Pathway Activation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These defects are rescued by transduction with wild-type RELB complementary DNA (cDNA)."
      explanation: >-
        Wild-type RELB restores the alternative-pathway response in patient
        fibroblasts, tying the signaling defect to the RELB lesion.
- name: Impaired Alternative NF-kappaB Pathway Activation
  description: >-
    Without functional RelB, p52/RelB heterodimers cannot drive target-gene
    induction after lymphotoxin or TWEAK stimulation. NFKB2 and VCAM1 induction
    is impaired, while p100 processing to p52 and canonical NF-kappaB responses
    to TNF and IL-1beta are intact.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: non-canonical NF-kappaB signal transduction
    modifier: DECREASED
    term:
      id: GO:0038061
      label: non-canonical NF-kappaB signal transduction
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients."
    explanation: >-
      Direct measurement of the alternative-pathway defect in patient
      fibroblasts.
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1β via the canonical NF-κB pathway remains intact."
    explanation: >-
      Shows the defect is confined to the alternative pathway.
  downstream:
  - target: Defective Medullary Thymic Epithelial Cell Maturation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37938781
      reference_title: Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We detected no AIRE expression in human thymuses lacking RELB or heterozygous for a p52LOF/IκBδGOF variant."
      explanation: >-
        Thymic biopsy from a patient with complete (Y397*) RELB deficiency
        shows no AIRE expression. No thymus from a partial-deficiency patient
        was examined.
  - target: Impaired Thymopoiesis and T Cell Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Th17 Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: B Cell-Intrinsic Failure of Class Switching and Antibody Secretion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Derepressed RelA-Driven Inflammatory Gene Expression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rela_derepression_autoimmunity
- name: Defective Medullary Thymic Epithelial Cell Maturation
  description: >-
    The human thymus in RelB deficiency is hypoplastic and has a poorly formed
    medulla. mTEC specification is not fully blocked, but differentiation into
    AIRE-expressing and post-AIRE mTECs fails. This is a stromal defect, so
    hematopoietic stem cell transplantation does not correct it.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: medullary thymic epithelial cell
    term:
      id: CL:0002365
      label: medullary thymic epithelial cell
  biological_processes:
  - preferred_term: thymus development
    modifier: DECREASED
    term:
      id: GO:0048538
      label: thymus development
  evidence:
  - reference: PMID:37938781
    reference_title: Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that RELB deficiency does not completely block mTEC specification but, rather, prevents differentiation into AIRE-expressing and post-AIRE mTECs."
    explanation: >-
      Thymic biopsy from a patient with complete RELB deficiency.
  - reference: PMID:41608125
    reference_title: Human inborn errors of the alternative NF-κB pathway.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "AR RelB deficiency results in an abnormal thymic architecture, characterized by a poorly formed medulla"
    explanation: >-
      Review synthesis of the thymic pathology across reported patients.
  downstream:
  - target: Hypoplasia of the thymus
    causal_link_type: DIRECT
  - target: Failure of Central Tolerance to Type I Interferons
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37938781
      reference_title: Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases."
      explanation: >-
        States the causal step from missing AIRE+ mTECs to loss of tolerance
        to type I IFNs.
  - target: Organ-Infiltrating Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mtec_central_tolerance_autoimmunity
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "By contrast, the liver, lung, and skin-related autoimmunity reported in two patients with AR partial RelB deficiency (25) closely mimics the T cell infiltration of organs in mice with a conditional Relb-KO in mTECs (67), providing additional evidence for the mTEC-intrinsic essential role of human RelB in central tolerance."
      explanation: >-
        The argument rests on resemblance to a conditional mouse knockout,
        not on a human measurement, so it is graded INDIRECT.
- name: Failure of Central Tolerance to Type I Interferons
  description: >-
    Without AIRE-expressing mTECs, T cells reactive to type I interferons are
    not deleted in the thymus. In proteome-wide autoantibody screening, type I
    interferons were the most enriched autoantigens in RelB-deficient patients.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: central tolerance induction to self antigen
    modifier: DECREASED
    term:
      id: GO:0002509
      label: central tolerance induction to self antigen
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, these data suggest that RelB is essential for thymic T cell tolerance to type I IFNs."
    explanation: >-
      Conclusion from autoantigen profiling of two patients' plasma.
  downstream:
  - target: Neutralizing Autoantibodies Against Type I Interferons
    causal_link_type: DIRECT
- name: Neutralizing Autoantibodies Against Type I Interferons
  description: >-
    Seven of eight tested patients with partial or complete RELB deficiency
    carry autoantibodies that neutralize IFN-alpha and IFN-omega. They can
    arise after hematopoietic stem cell transplantation: P1 had none before
    transplantation and developed them five years after. They are absent from
    heterozygous relatives. No HPO term exists for this finding,
    so it is recorded as a mechanism node rather than a phenotype.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:37938781
    reference_title: Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AAN-I-IFNs were also detected in patients with autosomal-recessive RELB deficiency (n = 7 out of 8: four patients with partial and three with complete deficiency)."
    explanation: >-
      Frequency of anti-type I IFN autoantibodies in the RELB-deficient
      cohort.
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the critical mTEC-intrinsic role of p52/RelB heterodimers in establishing tolerance to type I IFNs, HSCT did not prevent the development of thymic stromal cell-dependent autoimmunity in P1, who developed auto-Abs against type I IFNs after transplantation."
    explanation: >-
      The autoantibodies arose after HSCT, consistent with a stromal rather
      than hematopoietic origin.
  downstream:
  - target: Severe varicella zoster infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37938781
      reference_title: Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two out of the eight patients with autosomal-recessive RELB deficiency developed a severe viral disease (varicella pneumonia, n = 2; and PML, n = 1), and both had autoantibodies neutralizing IFNα and IFNω (Supplementary Table 2)."
      explanation: >-
        Co-occurrence in two patients, not a demonstrated cause; the same
        patients also had a combined T cell defect.
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The severe varicella may have been due to the neutralizing auto-Abs against type I IFNs detected in the plasma of P2 as an adult"
      explanation: >-
        The authors propose the link and hedge it; the antibodies were
        measured in adulthood, decades after the varicella.
- name: Impaired Thymopoiesis and T Cell Maturation
  description: >-
    Patients have low TRECs and few recent thymic emigrants, low naive CD4+
    and CD8+ T cells with expanded effector memory cells, skewed TCR
    repertoires with clonal expansion, and depressed T cell proliferation to
    mitogens. In partial deficiency, naive T cells decline with age. HSCT
    corrects the T cell-related infections, so part of the defect is
    hematopoietic-intrinsic.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: naive CD4-positive T cell
    term:
      id: CL:0000895
      label: naive thymus-derived CD4-positive, alpha-beta T cell
  - preferred_term: naive CD8-positive T cell
    term:
      id: CL:0000900
      label: naive thymus-derived CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell differentiation in thymus
    modifier: DECREASED
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, these results suggest that partial or complete forms of AR RelB deficiency caused inadequate thymopoiesis, defects of T lymphocyte development, maturation, and differentiation."
    explanation: >-
      Summary of the immunophenotyping of two patients.
  - reference: PMID:26385063
    reference_title: The effects of RelB deficiency on lymphocyte development and function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that the thymus in this patient is dysplastic and consequently new thymus emigrants are rare and there is an accumulation of CD45 RO(+) T cells with an increase in CD62L(+) central memory cells."
    explanation: >-
      Same finding in the original complete-deficiency kindred.
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+ cells."
    explanation: >-
      Progressive loss of naive T cells in the partial-deficiency sibship.
  downstream:
  - target: Decreased naive T cell proportion
    causal_link_type: DIRECT
  - target: Decreased total CD4+ T cell count
    causal_link_type: DIRECT
  - target: Abnormally low T cell receptor excision circle level
    causal_link_type: DIRECT
  - target: Decreased mitogen-induced T-cell proliferation
    causal_link_type: DIRECT
  - target: Cryptococcal meningitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both RelB-deficient patients experienced infections related to a T cell defect: CMC (P1 and P2), C. neoformans meningitis (P1), epidermodysplasia verruciformis and recalcitrant skin warts (P2), and JC virus-induced PML (P2)."
      explanation: >-
        The authors attribute these opportunistic infections to the T cell
        defect.
  - target: Unusual warts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "HPV lesions and PML may be related to the low CD4+ T cell counts found in P2"
      explanation: >-
        A hedged attribution in one patient.
  - target: Unusual JC virus infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "HPV lesions and PML may be related to the low CD4+ T cell counts found in P2"
      explanation: >-
        A hedged attribution in one patient.
  - target: Unusual Talaromyces marneffei infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Th17 Differentiation
  description: >-
    Naive CD4+ T cells fail to differentiate into IL-17A/F- and IL-22-producing
    memory cells. Th17 proportions are low ex vivo, and IL-17A/F production
    stayed low six months after HSCT although no fungal infection recurred.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    modifier: DECREASED
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like patients with STAT1 GOF (39, 40), P1 had low proportions of IL-17A-, IL-17F-, and IL-22- producing, but not of IFN-γ-producing, memory CD4+ T cells ex vivo"
    explanation: >-
      Ex vivo measurement of the selective Th17 cytokine defect.
  downstream:
  - target: Decreased Th17 T cell proportion
    causal_link_type: DIRECT
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "They also suggest that the observed Th17 defect (in terms of cell proportions and cytokine production) probably accounted for CMC in both RelB-deficient patients."
      explanation: >-
        The authors attribute CMC to the Th17 defect, the same IL-17
        mechanism as in other CMC-predisposing inborn errors.
- name: B Cell-Intrinsic Failure of Class Switching and Antibody Secretion
  description: >-
    RelB-deficient naive B cells proliferate and upregulate activation markers
    normally but barely secrete IgM and cannot switch to IgG or IgA after
    CD40L plus IL-21 stimulation. Class-switched memory B cells are almost
    absent. These defects were corrected by HSCT.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: class switched memory B cell
    term:
      id: CL:0000972
      label: class switched memory B cell
  biological_processes:
  - preferred_term: isotype switching
    modifier: DECREASED
    term:
      id: GO:0045190
      label: isotype switching
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, their naïve B cells cannot differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells is strongly impaired in vitro."
    explanation: >-
      In vitro differentiation assay on patient naive B cells.
  - reference: PMID:26385063
    reference_title: The effects of RelB deficiency on lymphocyte development and function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies."
    explanation: >-
      Same B cell arrest in the original complete-deficiency kindred.
  downstream:
  - target: Decreased class-switched memory B cell proportion
    causal_link_type: DIRECT
  - target: Decreased total B cell count
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, these results suggest that there is a B cell-intrinsic requirement of RelB for the generation of class-switched memory B cells and Ab-secreting cells, accounting for the severe hypogammaglobulinemia and recurrent infections observed in P1 (pretransplantation) and P2"
      explanation: >-
        Authors' causal reading from the B cell defect to the
        hypogammaglobulinemia and bacterial infections.
  - target: Decreased specific antibody response to vaccination
    causal_link_type: DIRECT
  - target: Recurrent respiratory infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients suffered from recurrent respiratory tract infections, otitis media (complicated by an episode of mastoiditis in P1), and repeated bacterial pneumonia, suggestive of a severe B cell defect."
      explanation: >-
        The infection pattern is read as the consequence of the B cell
        defect, through low antibody levels.
  - target: Recurrent pneumonia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients suffered from recurrent respiratory tract infections, otitis media (complicated by an episode of mastoiditis in P1), and repeated bacterial pneumonia, suggestive of a severe B cell defect."
      explanation: >-
        Repeated bacterial pneumonia is attributed to the B cell defect.
  - target: Recurrent otitis media
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients suffered from recurrent respiratory tract infections, otitis media (complicated by an episode of mastoiditis in P1), and repeated bacterial pneumonia, suggestive of a severe B cell defect."
      explanation: >-
        Otitis media is attributed to the B cell defect.
- name: Derepressed RelA-Driven Inflammatory Gene Expression
  description: >-
    In fibroblasts from patients homozygous for the hypomorphic P364L allele,
    stimulation induces a cluster of hyper-expressed pro-inflammatory
    transcripts. The authors read this as loss of RelB's inhibitory effect on
    RelA and propose it as the main driver of the organ autoimmunity in that
    sibship. In Relb-knockout mice, RelB likewise suppresses a set of
    inflammatory response genes independently of interferon signaling.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function."
    explanation: >-
      Transcriptional measurement in patient fibroblasts.
  - reference: PMID:37460023
    reference_title: "RelB-deficient autoinflammatory pathology presents as interferonopathy, but in mice is interferon-independent."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Instead, we found that RelB suppresses a different set of inflammatory response genes in a manner that is independent of interferon signaling but associated with NF-κB binding motifs."
    explanation: >-
      Mouse genetic evidence that RelB restrains NF-kappaB-motif inflammatory
      genes.
  downstream:
  - target: Organ-Infiltrating Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rela_derepression_autoimmunity
    evidence:
    - reference: PMID:36402602
      reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "This is likely the main driver of autoimmune manifestations in these patients."
      explanation: >-
        The authors' inference from fibroblast transcriptomics to organ
        autoimmunity; not tested in lymphocytes or tissue.
- name: Organ-Infiltrating Autoimmunity
  description: >-
    In the two older of three siblings homozygous for P364L, chronic hepatitis
    with portal fibrosis (with sclerosing cholangitis in one), autoimmune
    enteritis with villous atrophy, inflammatory lung disease and T cell and
    plasma cell skin infiltrates progressed through the second decade. The
    youngest sibling, aged 4, has had only one severe infection so far. The
    resected lung lobe also grew Mycobacterium tuberculosis, and the authors
    describe the lung lesion as an exaggerated inflammatory response rather
    than calling it autoimmune. Organ autoimmunity has not been reported in
    the complete-deficiency patients or in P2, whose autoimmunity is limited
    to anti-type I IFN autoantibodies.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life."
    explanation: >-
      Clinical description of the organ autoimmunity in the P364L sibship.
  downstream:
  - target: Chronic hepatitis
    causal_link_type: DIRECT
  - target: Hepatic fibrosis
    causal_link_type: DIRECT
  - target: Sclerosing cholangitis
    causal_link_type: DIRECT
  - target: Villous atrophy
    causal_link_type: DIRECT
  - target: Inflammatory abnormality of the skin
    causal_link_type: DIRECT
  - target: Chronic diarrhea
    causal_link_type: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: mtec_central_tolerance_autoimmunity
  hypothesis_label: Organ autoimmunity from defective mTEC-dependent central tolerance
  status: ALTERNATIVE
  description: >-
    The liver, lung and skin autoimmunity of partial RelB deficiency arises
    from the same thymic stromal defect that causes anti-type I IFN
    autoantibodies: too few AIRE-expressing mTECs to delete organ-reactive T
    cells. The supporting argument is resemblance to mice lacking Relb only in
    mTECs.
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, the liver, lung, and skin-related autoimmunity reported in two patients with AR partial RelB deficiency (25) closely mimics the T cell infiltration of organs in mice with a conditional Relb-KO in mTECs (67), providing additional evidence for the mTEC-intrinsic essential role of human RelB in central tolerance."
    explanation: >-
      States this hypothesis. The patients' clinical picture is human data,
      but the causal argument rests on resemblance to an mTEC-conditional
      Relb knockout mouse, which is model-organism evidence.
- hypothesis_group_id: rela_derepression_autoimmunity
  hypothesis_label: Organ autoimmunity from loss of RelB restraint on RelA
  status: ALTERNATIVE
  description: >-
    Residual but unstable RelB in P364L patients fails to restrain RelA-driven
    pro-inflammatory transcription, and this hyper-inflammatory state drives
    the organ autoimmunity. This would explain why organ autoimmunity is seen
    in the P364L sibship but not in complete deficiency.
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function."
    explanation: >-
      The fibroblast transcriptional finding the hypothesis rests on.
phenotypes:
- name: Chronic mucocutaneous candidiasis
  category: Infectious
  description: >-
    Recurrent oral candidiasis or CMC in both adult patients, attributed to
    the Th17 defect. P1 remained free of fungal disease three years after HSCT.
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both RelB-deficient patients experienced infections related to a T cell defect: CMC (P1 and P2), C. neoformans meningitis (P1), epidermodysplasia verruciformis and recalcitrant skin warts (P2), and JC virus-induced PML (P2)."
    explanation: CMC is reported in both patients.
- name: Recurrent respiratory infections
  category: Infectious
  description: >-
    Recurrent respiratory tract infections, otitis media and repeated
    bacterial pneumonia, reported in both adult patients and in the
    complete-deficiency siblings.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1, P2, and the three siblings homozygous for the Y397* RELB variant presented with hypogammaglobulinemia and recurrent bacterial respiratory tract infections"
    explanation: Reported in five patients from two kindreds.
- name: Recurrent pneumonia
  category: Infectious
  phenotype_term:
    preferred_term: Recurrent bacterial pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had a history of recurrent oral candidiasis, facial skin lesions suspected to be of viral origin, sinusitis, multiple episodes of otitis media (leading to an episode of mastoiditis), and recurrent bacterial pneumonia."
    explanation: Clinical history of P1.
- name: Recurrent otitis media
  category: Infectious
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had a history of recurrent oral candidiasis, facial skin lesions suspected to be of viral origin, sinusitis, multiple episodes of otitis media (leading to an episode of mastoiditis), and recurrent bacterial pneumonia."
    explanation: Multiple episodes of otitis media in P1, one complicated by mastoiditis.
- name: Cryptococcal meningitis
  category: Infectious
  description: Cryptococcus neoformans meningitis at age 12 in P1.
  phenotype_term:
    preferred_term: Cryptococcal meningitis
    term:
      id: HP:0032160
      label: Cryptococcal meningitis
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 12 y, she was hospitalized for Cryptococcus neoformans meningitis (28) and CID was diagnosed."
    explanation: Single-patient observation.
- name: Unusual Talaromyces marneffei infection
  category: Infectious
  description: >-
    Disseminated Talaromyces marneffei infection in an HIV-negative
    8-month-old girl homozygous for the Q135dup in-frame insertion.
  phenotype_term:
    preferred_term: Disseminated Talaromyces marneffei infection
    term:
      id: HP:5210374
      label: Unusual Talaromyces marneffei infection
  evidence:
  - reference: PMID:33791233
    reference_title: Disseminated Talaromyces marneffei Infection in a Non-HIV Infant With a Homozygous Private Variant of RELB.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was HIV-negative and bone marrow and blood culture showed T. marneffei infection."
    explanation: Single-patient observation.
- name: Unusual warts
  category: Infectious
  description: >-
    Recalcitrant skin warts and epidermodysplasia verruciformis, both
    histologically documented, in P2.
  phenotype_term:
    preferred_term: Recalcitrant cutaneous warts
    term:
      id: HP:5210303
      label: Unusual warts
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also suffered from severe viral infections, including varicella pneumonia requiring intensive care and mechanical ventilation at the age of 3 y, recalcitrant skin warts and epidermodysplasia verruciformis, both histologically documented."
    explanation: Single-patient observation.
- name: Severe varicella zoster infection
  category: Infectious
  description: >-
    Varicella pneumonia in two of eight tested patients, one requiring
    intensive care and mechanical ventilation at age 3.
  phenotype_term:
    preferred_term: Varicella pneumonia
    term:
      id: HP:0032170
      label: Severe varicella zoster infection
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also suffered from severe viral infections, including varicella pneumonia requiring intensive care and mechanical ventilation at the age of 3 y, recalcitrant skin warts and epidermodysplasia verruciformis, both histologically documented."
    explanation: Severe varicella in P2.
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her history is remarkable for an episode of severe and prolonged chicken pox complicated by pneumonitis and secondary skin infections occurring at 2 years of age."
    explanation: Severe varicella in a P364L homozygous sibling.
- name: Unusual JC virus infection
  category: Infectious
  description: >-
    Fatal JC polyomavirus-induced progressive multifocal leukoencephalopathy
    at age 34 in P2.
  phenotype_term:
    preferred_term: JC virus progressive multifocal leukoencephalopathy
    term:
      id: HP:5210334
      label: Unusual JC virus infection
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He subsequently died of JC polyomavirus-induced progressive multifocal leukoencephalitis (PML)."
    explanation: Single-patient observation.
- name: Severe adenovirus infection
  category: Infectious
  description: Adenovirus pneumonitis at 1 year requiring prolonged hospitalization, in one P364L sibling.
  phenotype_term:
    preferred_term: Severe adenovirus pneumonitis
    term:
      id: HP:0031694
      label: Severe adenovirus infection
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of special note is an episode of severe pneumonitis occurring at 1 year of age due to adenovirus infections which required prolonged hospitalization."
    explanation: Single-patient observation.
- name: Mastoiditis
  category: Infectious
  phenotype_term:
    preferred_term: Mastoiditis
    term:
      id: HP:0000265
      label: Mastoiditis
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had a history of recurrent oral candidiasis, facial skin lesions suspected to be of viral origin, sinusitis, multiple episodes of otitis media (leading to an episode of mastoiditis), and recurrent bacterial pneumonia."
    explanation: One episode, complicating otitis media in P1.
- name: Failure to thrive
  category: Growth
  description: >-
    The three children with complete deficiency presented between 7 days and
    4 months of age with severe infections and failure to thrive.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, we identified complete RelB deficiency in three children who presented very early in infancy (7 days-4 months) with severe infections and failure to thrive [17, 18]."
    explanation: The authors' summary of their earlier complete-deficiency kindred.
- name: Hypogammaglobulinemia
  category: Immunological
  description: >-
    Low IgG and IgA, requiring immunoglobulin replacement, in the
    complete-deficiency patients and in the P364L sibship as antibody
    production declined.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 6 y of age, she was diagnosed with hypogammaglobulinemia, and intravenous immunoglobulin (IVIg) replacement therapy was initiated."
    explanation: Hypogammaglobulinemia in P1.
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1, P2, and the three siblings homozygous for the Y397* RELB variant presented with hypogammaglobulinemia and recurrent bacterial respiratory tract infections"
    explanation: Reported in five patients from two kindreds.
- name: Decreased specific antibody response to vaccination
  category: Immunological
  phenotype_term:
    preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P2 had inadequate specific Ab responses following vaccination against tetanus, diphtheria, and measles/mumps/rubella (MMR), and VZV"
    explanation: Vaccine responses in P2.
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These age-correlated anomalies coincided with the gradual decline of the patients’ ability to produce specific antibodies in response to vaccination and necessitated immunoglobulin replacement therapy."
    explanation: Progressive loss of vaccine responses in the P364L sibship.
- name: Decreased class-switched memory B cell proportion
  category: Immunological
  phenotype_term:
    preferred_term: Decreased class-switched memory B cell proportion
    term:
      id: HP:0030388
      label: Decreased class-switched memory B cell proportion
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, <5% of the residual memory B cells detected in P1 before HCST had undergone class switching in vivo to express immunoglobulin G (IgG) or immunoglobulin A (IgA)."
    explanation: Flow cytometry of P1's memory B cells.
  - reference: PMID:26385063
    reference_title: The effects of RelB deficiency on lymphocyte development and function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Critically, CD27(+) memory cells were absent."
    explanation: Absent memory B cells in the original complete-deficiency kindred.
- name: Decreased naive T cell proportion
  category: Immunological
  description: Low naive CD4+ and CD8+ T cells in every patient tested.
  phenotype_term:
    preferred_term: Decreased naive CD4+ and CD8+ T cell proportion
    term:
      id: HP:0031397
      label: Decreased naive T cell proportion
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells."
    explanation: Immunophenotyping of two patients.
- name: Abnormally low T cell receptor excision circle level
  category: Immunological
  phenotype_term:
    preferred_term: Low TREC level
    term:
      id: HP:0031545
      label: Abnormally low T cell receptor excision circle level
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 had low T cell receptor excision circle (TREC) levels"
    explanation: Measured in P1; not assessed in P2.
- name: Decreased mitogen-induced T-cell proliferation
  category: Immunological
  phenotype_term:
    preferred_term: Decreased mitogen-induced T-cell proliferation
    term:
      id: HP:0031381
      label: Decreased mitogen-induced T-cell proliferation
  evidence:
  - reference: PMID:26385063
    reference_title: The effects of RelB deficiency on lymphocyte development and function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In vitro responses to T cell mitogens were markedly depressed and so were PHA induced IL2 and IFNγ production."
    explanation: Original complete-deficiency kindred.
- name: Decreased total B cell count
  category: Immunological
  description: >-
    Progressive loss of circulating B cells in the P364L sibship, and a low
    B cell count in P2 at 19 years.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients also suffered progressive loss of the entire B cell compartment."
    explanation: Progressive B cell loss in the P364L sibship.
- name: Decreased total CD4+ T cell count
  category: Immunological
  phenotype_term:
    preferred_term: Decreased total CD4+ T cell count
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Counts of CD3+, CD4+, and CD8+ T cells were normal in P1 (assessed at the age of 12 y), but markedly low in P2 (assessed at the age of 19 y), except for CD8+ T cells"
    explanation: Low CD4+ count in P2; normal in P1.
- name: Decreased Th17 T cell proportion
  category: Immunological
  phenotype_term:
    preferred_term: Decreased Th17 T cell proportion
    term:
      id: HP:0025832
      label: Decreased Th17 T cell proportion
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistently, P1 and P2 had low proportions of Th17 cells ex vivo, and P1 displayed low levels of IL-17A and IL-17F production by memory CD4+ T cells (P2 was not tested)."
    explanation: Ex vivo Th17 proportions in both patients.
- name: Hypoplasia of the thymus
  category: Immunological
  description: >-
    Strongly hypoplastic or dysplastic thymus, reported in P1, in the original
    complete-deficiency kindred and in the infant with the Q135dup variant.
  phenotype_term:
    preferred_term: Hypoplasia of the thymus
    term:
      id: HP:0000778
      label: Hypoplasia of the thymus
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 14 y (before transplantation) the thymus from P1 was strongly hypoplastic"
    explanation: Thymic imaging in P1.
  - reference: PMID:26385063
    reference_title: The effects of RelB deficiency on lymphocyte development and function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that the thymus in this patient is dysplastic and consequently new thymus emigrants are rare"
    explanation: Dysplastic thymus in the original complete-deficiency kindred.
  - reference: PMID:33791233
    reference_title: Disseminated Talaromyces marneffei Infection in a Non-HIV Infant With a Homozygous Private Variant of RELB.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enhanced CT and MRI scanning demonstrated thymic dysplasia, diffuse pulmonary and liver nodules, and many balloon-like air sacs in both lungs."
    explanation: Thymic dysplasia on imaging in the Q135dup patient.
- name: Chronic hepatitis
  category: Hepatic
  description: >-
    Progressive liver enzyme elevation with biopsy-proven advanced chronic
    liver disease, which the authors call autoimmune, in the two older P364L
    siblings. They do not diagnose autoimmune hepatitis as such, so the
    broader chronic hepatitis term is bound.
  phenotype_term:
    preferred_term: Chronic autoimmune liver disease
    term:
      id: HP:0200123
      label: Chronic hepatitis
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these findings demonstrate advanced chronic autoimmune liver disease."
    explanation: Liver biopsy findings in the oldest sibling.
- name: Hepatic fibrosis
  category: Hepatic
  description: Stage 2-4 portal fibrosis on liver biopsy in the two older P364L siblings.
  phenotype_term:
    preferred_term: Portal fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, similar to her older sister, the biopsy demonstrated stage 3–4 portal fibrosis with massive infiltrates of lymphocytes and plasma cells (Fig 1E–H)."
    explanation: Portal fibrosis in both older siblings.
- name: Sclerosing cholangitis
  category: Hepatic
  phenotype_term:
    preferred_term: Sclerosing cholangitis
    term:
      id: HP:0030991
      label: Sclerosing cholangitis
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Concentric peri-bile ductal fibrosis was noted, consistent with sclerosing cholangitis."
    explanation: Liver biopsy finding in the P364L sibship.
- name: Villous atrophy
  category: Digestive
  description: Autoimmune enteritis with villous atrophy and intra-epithelial lymphocytes.
  phenotype_term:
    preferred_term: Villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Villus atrophy and the presence of intra-epithelial lymphocytic infiltrates supported the notion of autoimmune enteritis."
    explanation: Duodenal biopsy in the P364L sibship.
- name: Chronic diarrhea
  category: Digestive
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The oldest patient (Pt 1, 18yrs) at her most recent evaluation was found to be very short, underweight, and suffering from chronic diarrhea as well as chronic severe lung, liver, and skin manifestations."
    explanation: Oldest P364L sibling.
- name: Pulmonary tuberculosis
  category: Infectious
  description: >-
    A lobe resected for chronic bronchiolitis with organizing peribronchial
    fibrosis in the P364L sibship grew Mycobacterium tuberculosis. The authors
    read the florid inflammation as an exaggerated response rather than the
    infection alone. No HPO term for non-infectious bronchiolitis exists
    (HP:0011950 is now Unusual bronchiolitis, an infection-susceptibility
    term), so the histology is recorded here and on the organ-autoimmunity
    node rather than as its own phenotype. It has no incoming edge on
    purpose: it is a single isolate, and the authors do not attribute it to a
    specific immune defect.
  phenotype_term:
    preferred_term: Pulmonary tuberculosis
    term:
      id: HP:0032262
      label: Pulmonary tuberculosis
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While Mycobacterium tuberculosis was identified in the resected lobe, the florid inflammatory changes suggested an aberrantly exaggerated inflammatory response."
    explanation: Tuberculosis in the resected lobe, with the authors' reading of the inflammation.
- name: Inflammatory abnormality of the skin
  category: Dermatological
  description: >-
    Chronic cutaneous lesions from early childhood in the two older P364L
    siblings. A biopsy showed diffuse T cell and plasma cell infiltrates, and
    the lesions responded poorly to antimicrobial treatment. HPO has no
    autoimmune-dermatosis term matching this description, so the general
    inflammatory skin term is bound.
  phenotype_term:
    preferred_term: Chronic inflammatory skin lesions
    term:
      id: HP:0011123
      label: Inflammatory abnormality of the skin
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin biopsy of a lesion revealed diffuse inflammatory infiltrates consisting of T cells and plasma cells."
    explanation: Skin histology in the oldest P364L sibling.
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She suffered chronic cutaneous lesions starting at age 3 that appeared autoinflammatory in nature as response to antimicrobial treatment was inadequate."
    explanation: Chronic inflammatory skin lesions in the second P364L sibling.
- name: Short stature
  category: Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The oldest patient (Pt 1, 18yrs) at her most recent evaluation was found to be very short, underweight, and suffering from chronic diarrhea as well as chronic severe lung, liver, and skin manifestations."
    explanation: Oldest P364L sibling.
- name: Delayed puberty
  category: Growth
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: PMID:36402602
    reference_title: NFκB pathway dysregulation due to reduced RelB expression leads to severe autoimmune disorders and declining immunity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She too is delayed in her linear growth and puberty."
    explanation: Second P364L sibling.
genetic:
- name: RELB
  gene_term:
    preferred_term: RELB
    term:
      id: hgnc:9956
      label: RELB
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Reported alleles are Y397* and Q72fs (amorphic) and Q135dup, E145K and
    P364L (strongly hypomorphic). P364L was found homozygous in an Iranian
    Jewish sibship and, as a de novo allele in trans with a maternal E145K, in
    an unrelated patient of European descent. Two rare missense variants seen
    homozygous in gnomAD (D417N, D487Y) behaved like wild type.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_eb3415ab-4fa5-4f53-8ae4-7b4c620a3391-2026-05-21T160000.000Z
    evidence:
    - reference: CGGV:assertion_eb3415ab-4fa5-4f53-8ae4-7b4c620a3391-2026-05-21T160000.000Z
      reference_title: "RELB / immunodeficiency 53 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "RELB | HGNC:9956 | immunodeficiency 53 | MONDO:0054696 | AR | Definitive"
      explanation: >-
        ClinGen SCID-CID expert panel classification, 2026-05-21. It
        supersedes the 2023 Limited classification still present in the
        older committed ClinGen export.
  evidence:
  - reference: DOI:10.14785/lpsn-2015-0005
    reference_title: RelB deficiency causes combined immunodeficiency
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous mutation in the gene for the NFκB transcription factor RelB in 3 patients who suffered repeated infection despite the presence of circulating T and B cells."
    explanation: >-
      First report of RELB deficiency. The journal is not indexed in PubMed,
      so this DOI is the citation.
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two unrelated adults with homozygous (P1) or compound heterozygous (P2) private loss-of-function variants of V-Rel Reticuloendotheliosis Viral Oncogene Homolog B (RELB)."
    explanation: >-
      Two further unrelated patients with biochemically characterized
      loss-of-function alleles.
diagnosis:
- name: Lymphocyte immunophenotyping
  description: >-
    Flow cytometry shows low naive CD4+ and CD8+ T cells, low Th17 cells and
    few class-switched memory B cells, with normal monocyte and granulocyte
    counts.
  diagnosis_term:
    preferred_term: immunological flow cytometry
    term:
      id: NCIT:C113003
      label: Immunological Flow Cytometry
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells."
    explanation: The core immunophenotype in both characterized patients.
- name: Neutralizing anti-type I interferon autoantibody testing
  description: >-
    A luciferase reporter assay measures whether plasma neutralizes IFN-alpha2,
    IFN-omega or IFN-beta. The antibodies can appear years after
    transplantation, so the authors recommend repeat testing.
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations highlight the importance of evaluating changes in the levels of these auto-Abs over time."
    explanation: Authors' recommendation to monitor the autoantibodies over time.
- name: Fibroblast alternative NF-kappaB pathway assay
  description: >-
    Induction of NFKB2 and VCAM1 after lymphotoxin or TWEAK stimulation of
    patient fibroblasts confirms that a RELB variant impairs the alternative
    pathway, and complementation with wild-type RELB confirms causality.
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients."
    explanation: The functional readout used to characterize patient alleles.
- name: Exome sequencing
  description: >-
    Biallelic RELB variants have been found by exome or genome sequencing in
    each reported kindred, followed by Sanger confirmation and segregation.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By screening our in-house database of whole-exome sequencing (WES) data for over 25,000 patients with various infectious diseases, we identified a single patient (P1) carrying a biallelic private variant of RELB that was predicted to be deleterious."
    explanation: Exome sequencing identified the variant in P1.
treatments:
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    HSCT corrected the T and B cell-related infectious susceptibility in the
    four patients with complete deficiency who were transplanted. P1 had
    normal immunoglobulins and was off IVIg three years after HSCT. It does
    not correct the thymic stromal defect: P1 developed anti-type I IFN
    autoantibodies five years after transplantation. Whether HSCT corrects
    organ autoimmunity in partial deficiency is unknown.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired Thymopoiesis and T Cell Maturation
  - target: B Cell-Intrinsic Failure of Class Switching and Antibody Secretion
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HSCT corrected the infectious susceptibility associated with T and B cells in the four patients with AR complete RelB deficiency who underwent transplantation."
    explanation: Outcome across the four transplanted patients.
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3 y after transplantation, P1 had normal proportions of B cells, normal serum levels of IgG, IgA, and IgM, was off IVIg replacement therapy, and reported no B cell-related infections"
    explanation: Durable B cell reconstitution in P1.
- name: Immunoglobulin Replacement Therapy
  description: >-
    Used for hypogammaglobulinemia before HSCT and in the partial-deficiency
    sibship as antibody responses declined.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 6 y of age, she was diagnosed with hypogammaglobulinemia, and intravenous immunoglobulin (IVIg) replacement therapy was initiated."
    explanation: Documents use; no response measure is reported.
animal_models:
- name: Relb knockout mouse
  species: Mouse
  genotype: Relb-/- (germline targeted disruption)
  publication: PMID:7845467
  description: >-
    Relb-null mice lack thymic UEA-1+ medullary epithelial cells and have
    reduced thymic dendritic cells. Unlike human patients, they develop
    multiorgan inflammatory infiltration and myeloid hyperplasia. The
    2-to-6-week lethality is cited from PMID:39231201, not from the primary
    mouse reports.
  modeled_mechanisms:
  - target: Defective Medullary Thymic Epithelial Cell Maturation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      The mouse shows complete absence of UEA-1+ mTECs, while the human thymus
      retains rare mTECs that fail to mature to AIRE+ cells. The mouse's lethal
      multiorgan inflammation is not seen in human complete deficiency.
    evidence:
    - reference: PMID:7845467
      reference_title: Expression of relB is required for the development of thymic medulla and dendritic cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thymic UEA-1+ medullary epithelial cells from normal mice show striking similarities to DC and, interestingly, these cells are also absent in relB mutant mice."
      explanation: The mTEC defect is present in the knockout.
  - target: Organ-Infiltrating Autoimmunity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    limitations: >-
      Knockout mice die at 2 to 6 weeks from T cell-dependent inflammation of
      many organs. Human complete deficiency shows only anti-type I IFN
      autoantibodies, and organ autoimmunity is limited to partial deficiency.
    evidence:
    - reference: PMID:7834753
      reference_title: "Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice homozygous for the disrupted relB locus had phenotypic abnormalities including multifocal, mixed inflammatory cell infiltration in several organs, myeloid hyperplasia, splenomegaly due to extramedullary hematopoiesis, and a reduced population of thymic dendritic cells."
      explanation: Multiorgan inflammatory infiltration in the knockout.
discussions:
- discussion_id: relb_organ_autoimmunity_mechanism
  prompt: >-
    Is the organ autoimmunity of partial RelB deficiency caused by the thymic
    stromal tolerance defect, by loss of RelB restraint on RelA, or both?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Organ-Infiltrating Autoimmunity
  - mechanistic_hypotheses#mtec_central_tolerance_autoimmunity
  - mechanistic_hypotheses#rela_derepression_autoimmunity
  rationale: >-
    Sharfe et al. (2022) attribute the autoimmunity to RelA derepression
    measured in fibroblasts. Le Voyer et al. (2024) attribute it to the mTEC
    defect, by analogy with mTEC-specific Relb knockout mice. Neither was
    tested in the patients' T cells or tissues. The two hypotheses also
    leave open why complete deficiency spares the organs. A thymic account
    predicts that organ autoimmunity persists after HSCT; a hematopoietic RelA
    account predicts it resolves. No partial-deficiency patient with organ
    autoimmunity has been transplanted.
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It would therefore be interesting to determine whether this procedure can also correct organ-related autoimmunity in patients with AR partial RelB deficiency."
    explanation: The authors name the untested HSCT outcome.
- discussion_id: relb_mouse_human_autoimmunity_mismatch
  prompt: >-
    Why does germline Relb loss cause lethal multiorgan inflammation in mice
    but only anti-type I IFN autoantibodies in human complete deficiency?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Organ-Infiltrating Autoimmunity
  rationale: >-
    The mouse knockout is the main experimental basis for RelB's role in
    tolerance and inflammation, but its autoimmune phenotype is far more
    severe than the human one. Mouse findings about inflammation should not
    be transferred to patients without human data.
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autoimmune phenotype observed in P1 and P2, restricted to the development of auto-Abs against type I IFNs, sharply contrasts with that of Relb-KO mice, which die from overwhelming T lymphocyte-dependent multiple-organ inflammation at the age of 2 to 6 wk"
    explanation: States the mismatch directly.
- discussion_id: relb_thymic_stromal_defect_after_hsct
  prompt: >-
    Can the thymic stromal defect be corrected, so that transplanted patients
    stop producing anti-type I IFN autoantibodies?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Defective Medullary Thymic Epithelial Cell Maturation
  - treatments#Hematopoietic Stem Cell Transplantation
  rationale: >-
    HSCT restores lymphocyte function but leaves patients at risk of severe
    viral disease from persistent anti-type I IFN autoantibodies. Thymus
    implantation and TEC regeneration have been suggested but not tried.
  evidence:
  - reference: PMID:39231201
    reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They also suggest that therapeutic options for correcting the thymic stromal defect in these patients, such as thymic implantation or stem-cell-based TEC regeneration, are worth considering"
    explanation: The authors propose untested stromal-directed therapies.
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      All nine reported patients have a combined T and B cell
      immunodeficiency.
    evidence:
    - reference: PMID:39231201
      reference_title: Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All nine patients with AR RelB deficiency display CID, like patients with AR NIK or IKK-α deficiency, whereas patients with AD inborn errors of NF-κB2 display PAD"
      explanation: Places RELB deficiency among the combined immunodeficiencies.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Immunodeficiency 53 (RELB deficiency) · 2026-10-14T20:32:57Z · View source

Entry type decided as DISEASE: one gene (RELB), one MONDO leaf term (MONDO:0054696), and one conserved pathograph. The stub stubs/Immunodeficiency_53.yaml is deleted in the same change. This session continued a skeleton entry from an earlier session on the same branch. Deep research. The claude_code report (from the earlier session) was used. Its references all resolved (6/6). preflight-dr returned WARN, which is benign: "CD4" there is the CD4+ T cell marker, and OMIM 604758 is the RELB gene record. Falcon was attempted twice and failed with "Failed to authenticate", so no Falcon report exists. OpenScientist completed, but its report is about CARMIL2 deficiency, not RELB deficiency. It mentions RELB zero times, although all 22 references resolved, and preflight-dr told us to discard it. It was deleted uncommitted, and nothing in the entry comes from it. Sources. The entry rests mainly on full texts of PMID:39231201 (Le Voyer 2024; two patients plus a nine-patient synthesis), PMID:36402602 (Sharfe 2022; P364L sibship), PMID:37938781 (anti-type I IFN autoantibodies and patient thymus) and PMID:33791233 (Q135dup infant). The abstracts of PMID:26385063 and the 2015 LymphoSign DOI cover the original kindred. PMID:7834753, PMID:7845467 and PMID:37460023 supply the mouse data. ClinGen now classifies RELB / IMD53 as Definitive (2026-05-21, AR); the committed cache/clingen export still shows the 2023 Limited record. The Definitive record was fetched as a CGGV: cache file and copied into gene_disease_validity. Citations considered and not used: - PMID:28552761 (HSCT for RelB deficiency) has no cached text. - PMID:33083013, which ClinGen cites, mentions RELB only in a supplement. - The fungal review PMID:42461459 claims Pneumocystis pneumonia in RELB deficiency; no primary report supports this. Modelling. The organ autoimmunity of the P364L sibship has two published explanations, mTEC tolerance failure (Le Voyer 2024) and loss of RelB restraint on RelA (Sharfe 2022). Both are recorded as ALTERNATIVE mechanistic hypotheses with a CONTROVERSY discussion. Anti-type I IFN autoantibodies have no HPO term, so they are a pathophysiology node. No mechanism module fits, so there is no conforms_to. Review. An independent red-team subagent review led to these fixes: - Patient counts corrected to four complete and five partial, per PMID:39231201; the 2026 review's "three complete" is noted as inconsistent. - Organ autoimmunity limited to two of the three P364L siblings. - HP:0011950 replaced. Its current label is "Unusual bronchiolitis", an infection term; the committed cache still says "Bronchiolitis", so validation did not catch it. Pulmonary tuberculosis was added from the same resected lobe. - Hepatitis narrowed to Chronic hepatitis plus Hepatic fibrosis. - Verrucae replaced by Unusual warts. - Phenotypes added: B cell count, CD4 count, adenovirus infection and mastoiditis. - evidence_source, quote_role and the post-HSCT autoantibody wording corrected. Validation. just validate passes (schema, terms, references). All 87 snippets verify, including the DOI item via --unskip-prefix DOI. The entity-ref, causal-target, duplicate-key, coarse-phenotype, snippet-length, title-snippet, snippet-grading, retired-prose, enum and folded-hyphen gates pass. PR review round 1 (PR #14207). The reviewer's one blocking item was a missing skin phenotype. HP:0011123 Inflammatory abnormality of the skin was added, with two PMID:36402602 snippets and an edge from the organ-autoimmunity node. All four suggestions were taken: - a diagnosis section (flow cytometry, anti-type I IFN autoantibody testing, fibroblast pathway assay, exome sequencing); - a notes sentence on rituximab and the lung resection; - a notes sentence on PMID:33083013, whose RELB case is supplement-only; - a stated reason the tuberculosis phenotype has no incoming edge. CI's gene-activity-grounding gate failed because RELB landed on a node with no molecular function. GO:0003700 DNA-binding transcription factor activity (DECREASED) is now bound on the RELB node, and the gate passes against origin/main. Snippets: 93/93 verified.

Claude Code ▸
Immunodeficiency 53 (IMD53; RELB deficiency): research report
claude-haiku-5-5, claude-sonnet-5-5 8 citations 2026-10-14T18:29:01.230899

I've pulled the two main RELB papers (Le Voyer 2024, Sharfe 2022). I'm now checking the PMID of the original 2015 RELB report before I write the report.

Immunodeficiency 53 (IMD53; RELB deficiency): research report

Sourcing. I could not open OMIM, Orphanet, ClinGen or GenCC directly, so those statements come from search snippets or aggregators. Two papers I read in full text through PMC (Le Voyer 2024 and Sharfe 2022), except the last ~39k characters of the Le Voyer page. Anything not in a paper I read is marked unverified.

  • Do not use any PMID marked unverified as evidence until it has been fetched. The repository's just fetch-reference check applies.
  • Every CURIE below is a suggestion from memory. None was looked up in OAK or the term caches. Per CLAUDE.md, each one must be checked before it is bound.

1. Disease information

Overview. IMD53 is a rare autosomal recessive combined T- and B-cell immunodeficiency caused by biallelic loss-of-function or hypomorphic variants in RELB. RelB is a subunit of the alternative (non-canonical) NF-κB pathway. The syndrome combines recurrent viral, bacterial and fungal infections with immune decline over time. Autoimmunity and neutralizing anti-type I interferon autoantibodies are also seen.

Identifiers.

Item Value Source
MONDO MONDO:0054696 DrugMap, GenCC submission
OMIM phenotype #617585, listed with a "?" prefix in the phenotype map search snippets only; OMIM page not opened
Gene RELB (OMIM 604758, 19q13.32, HGNC:9956) GenCC URL and aggregators
UMLS C4539811 MedGen mirror
DOID DOID:0111992 Disease Ontology

In this repository the gene would be written hgnc:9956 (lowercase prefix).

Synonyms. RELB deficiency, RelB deficiency, and combined immunodeficiency due to RELB deficiency.

Data origin. The evidence comes from individual-patient case reports and small series (3 + 3 + 2 patients), not from registries or EHR data.

2. Etiology

  • Cause. Biallelic RELB variants, either homozygous or compound heterozygous, inherited from carrier parents. No environmental cause is described.
  • Genetic risk and modifiers. None are described. gnomAD homozygous missense variants D417N and D487Y behaved like wild type in the assay (Le Voyer 2024, PMID 39231201).
  • Protective factors. None are known.
  • Gene–environment interaction. Not described. The patients' infections are of ordinary community pathogens, plus JC polyomavirus and Cryptococcus, as a consequence of the immunodeficiency.
  • Strength of gene–disease evidence. This is graded unevenly.
  • ClinGen's SCID-CID group rates RELB "limited", per a search snippet.
  • PanelApp lists it as high evidence, per a search snippet.
  • OMIM marks the phenotype with "?".
  • Curators should record the validity classification only as classified_by an external source, never assign it themselves.

3. Phenotypes

The frequencies below are qualitative or n/N from at most 8 patients. HPO suggestions are unverified.

Phenotype Details Suggested HPO
Recurrent bacterial respiratory infections (pneumonia, sinusitis, otitis media, mastoiditis) Seen in the adult cohort HP:0002783 (recurrent lower respiratory tract infections), HP:0004429 (recurrent viral infections)
Chronic mucocutaneous / oral candidiasis P1 and P2 HP:0100550
Cryptococcal meningitis P1, at age 12 HP:0005407? Use a meningitis or fungal-infection term; verify
Viral skin disease (warts, epidermodysplasia verruciformis) P2 HP:0200043 (verrucae); verify
Varicella pneumonia P2, at age 3 search HPO
Progressive multifocal leukoencephalopathy P2, fatal at age 34 HP:0012774? verify
Hypogammaglobulinemia P1 HP:0001880 (decreased IgG) or HP:0004313 (hypogammaglobulinemia)
Poor vaccine response Sharfe 2022 siblings HP:0003290
Decreased naïve CD4⁺ and CD8⁺ T cells Both cohorts HP:0005415 (decreased CD4 count), HP:0010987
Decreased memory and class-switched B cells P1; siblings (progressive loss of CD19⁺ and CD27⁺ B cells) search HPO
Autoimmune enteritis, chronic diarrhea Siblings HP:0002014
Autoimmune hepatitis-like disease, sclerosing cholangitis-like changes Siblings HP:0001392 area; verify
Chronic bronchiolitis requiring lobectomy Siblings search HPO
Chronic inflammatory skin lesions Siblings search HPO
Short stature, underweight Oldest sibling (Sharfe 2022) HP:0004322
Large B-cell lymphoma P2 HP:0012191 area; verify
Thymic hypoplasia P1 HP:0000778
Anti-type I IFN autoantibodies Both adults no HPO term; use a lab-abnormality description

Onset and course. - Presentation is in infancy to early childhood, per MalaCards (secondary source). - The 2015 index family presented between 7 days and 4 months of age, per search-result summaries (unverified). - Immune function declines over time. The siblings showed age-related loss of naïve T cells and B cells. - Some adults escape early diagnosis. P1 and P2 were diagnosed as adults.

Quality of life. No formal measures are reported. P2 died of progressive multifocal leukoencephalopathy at age 34.

4. Genetic and molecular information

Variants.

Variant Genotype Consequence Source
c.212dup, p.Gln72ThrfsTer152 Homozygous (P1, consanguineous Turkish parents) Abolished RelB expression Le Voyer 2024
c.433G>A, p.E145K and c.1091C>T, p.P364L Compound heterozygous (P2) Stable protein, hypomorphic function Le Voyer 2024
c.1091C>T, p.P364L Homozygous in three Iranian Jewish siblings Highly unstable protein at very low levels, residual function, transiently inducible by TLR stimulation Sharfe 2022, PMID 36402602
Homozygous nonsense Three children, found by linkage analysis, WGS and Sanger Complete RelB deficiency Merico/Sharfe 2015 (see below)
  • The Le Voyer variants are absent from gnomAD and other databases.
  • The same P364L allele appears in two independent reports, once homozygous and once in trans with E145K.
  • All variants are germline.
  • There is no known modifier gene and no epigenetic or chromosomal data.

Mechanism type. Loss of function (complete) or hypomorphism (partial). Use functional_impact_category: LOSS_OF_FUNCTION or PARTIAL_LOSS_OF_FUNCTION per variant, and cite the functional assay.

Primary literature for the original report. - Merico et al. 2015, LymphoSign Journal, DOI 10.14785/lpsn-2015-0005. It is not in PubMed, so it cannot go through fetch-reference as a PMID. A DOI fetch may work. - Sharfe N et al. 2015, "The effects of RelB deficiency on lymphocyte development and function", PMID 26385063. This PMID comes from a GenCC-derived search summary and is unverified. Fetch it before use.

5. Environmental information

None are known. - Infectious agents as consequences, not causes: Candida, Cryptococcus neoformans, varicella-zoster virus, JC polyomavirus and human papillomaviruses (epidermodysplasia verruciformis-type warts). These are opportunistic outcomes, so they belong under phenotypes or complications, not infectious_agent. - If a curator wants NCBITaxon terms, look each one up individually.

6. Mechanism and pathophysiology

Causal chain.

  1. Biallelic RELB variants lead to absent or hypomorphic RelB protein. This is demonstrated by loss of expression for Q72fs and by reduced stability for P364L.
  2. Loss of RelB impairs lymphotoxin- and TWEAK-induced alternative NF-κB signaling, shown as reduced NFKB2 and VCAM1 induction in patient fibroblasts. Canonical NF-κB responses to TNF and IL-1β stay intact (Le Voyer 2024).
  3. In the thymus, loss of RelB in stromal cells is thought to give hypoplastic thymus and few AIRE-expressing medullary thymic epithelial cells. The thymic hypoplasia in P1 is observed. The AIRE-deficiency link is an inference from the 2022 Le Voyer study in the search results, which I did not read (unverified).
  4. Defective stromal-driven central tolerance leads to anti-type I IFN autoantibodies. This is observed in both adults, and the antibodies persist after HSCT, which supports a stromal (not hematopoietic) origin. That reading is the authors' inference.
  5. Naïve T-cell depletion, low Th17 cells and reduced IL-17A/F/IL-22 production, together with poor memory and class-switched B-cell output, lead to combined immunodeficiency. For B cells, P1's naïve cells could not make IgG or IgA in response to CD40L plus IL-21 in vitro.
  6. Combined immunodeficiency leads to chronic mucocutaneous candidiasis, bacterial respiratory infections, cryptococcal meningitis, viral skin disease and PML.
  7. Branch for partial deficiency (P364L). In Sharfe 2022, fibroblasts showed elevated pro-inflammatory NF-κB target genes after poly(I:C) or LIGHT stimulation. The authors interpret this as loss of RelB's inhibitory effect on RelA, and they describe their evidence as indirect. This is inferred, not demonstrated. Reduced RelB then leads to autoimmune enteritis, hepatitis-like liver disease, bronchiolitis and skin inflammation, with a decline in immune cells in the second decade.

Suggested GO and CL terms (unverified). - GO: non-canonical NF-κB signal transduction (GO:0038061), positive regulation of non-canonical NF-κB signal transduction (GO:1901224), T cell differentiation in thymus (GO:0033077), B cell differentiation (GO:0030183), central tolerance induction (GO:0002507), type 17 immune response (GO:0072538). - CL: naïve thymus-derived CD4-positive alpha-beta T cell (CL:0000895), memory B cell (CL:0000787), medullary thymic epithelial cell (CL:0002293), fibroblast (CL:0000057).

Not reported. No transcriptomic, proteomic, metabolomic, single-cell or screen data were found.

7. Anatomical structures affected

  • Primary: thymus (hypoplastic in P1; UBERON:0002370), lymphoid tissue and blood.
  • Secondary: upper and lower airways, gut, liver and biliary tree, skin, CNS (cryptococcal meningitis, PML) and thyroid.
  • Cells: naïve and effector memory T cells, Th17 cells, B cells, medullary thymic epithelial cells and fibroblasts.
  • Subcellular: cytoplasm to nucleus translocation of the RelB/p52 dimer.
  • Lateralization: not applicable; the disease is systemic.

8. Temporal development

  • Onset: infancy to childhood in the complete-deficiency families. Partial deficiency can present later, and the two adults in Le Voyer 2024 were diagnosed in adulthood.
  • Progression: progressive immune decline and escalating organ autoimmunity in the second decade (P364L).
  • Duration: lifelong without definitive therapy.
  • Remission: no spontaneous remission is described.
  • Critical period: early HSCT in infancy is associated with survival in the complete-deficiency children (search summary; unverified).

9. Inheritance and population

  • Inheritance: autosomal recessive (HP:0000007). Consanguinity is documented in all three kindreds with homozygous variants.
  • Prevalence and incidence: not documented (prevalence_class: NOT_YET_DOCUMENTED). At most 8 patients have been published.
  • Populations: Turkish, Iranian Jewish, and (per the 2015 report) other consanguineous families.
  • Penetrance, anticipation, mosaicism, carrier frequency: no data. Heterozygous parents were healthy in the families reported.
  • Founder effect: P364L has been seen in two unrelated reports. This is a lead, not evidence of a founder effect.
  • Sex ratio: both sexes are affected.

10. Diagnostics

  • Immunophenotyping:
  • Low naïve CD4⁺ and CD8⁺ T cells.
  • Raised CD4/CD8 ratio, per MalaCards and the aggregator snippets.
  • Reduced TREC levels, per MalaCards (secondary).
  • Low memory B cells, hypogammaglobulinemia and poor vaccine responses.
  • Reduced PHA and anti-CD3 proliferation (Sharfe 2022).
  • Functional assays:
  • Fibroblast stimulation with lymphotoxin or TWEAK, reading out NFKB2 and VCAM1.
  • Western blot for RelB protein.
  • Autoantibodies: neutralizing anti-type I IFN antibody testing. These antibodies appeared about 5 years after HSCT in P1.
  • Genetic testing:
  • WES or WGS, or an inborn-errors-of-immunity panel that includes RELB.
  • Sanger confirmation.
  • Segregation analysis in consanguineous families.
  • Differential diagnosis: other combined immunodeficiencies (NIK/MAP3K14 deficiency, which shares the alternative NF-κB pathway; NFKB2 haploinsufficiency; APS-1/AIRE deficiency; CD40 ligand deficiency).
  • Screening: reduced TRECs might be detectable on newborn screening. No program is established.

11. Outcome and prognosis

  • Survival data are limited to individual cases.
  • P2 died of progressive multifocal leukoencephalopathy at age 34.
  • P1 was alive 3 years post-HSCT with normal immunoglobulins.
  • Complications are CNS infection, lymphoma (P2), liver disease and lung damage requiring lobectomy.
  • Prognostic factors are unknown. Complete deficiency presents earlier and more severely.
  • No quality-of-life instruments have been applied.

12. Treatment

  • Definitive: allogeneic HSCT.
  • P1 had HSCT at age 14 from a fully matched sibling, with successful engraftment (Le Voyer 2024).
  • At 6 months, most T-cell cytokine defects and naïve B-cell defects had corrected. IL-17A/F production stayed low.
  • At 3 years, B-cell proportions and immunoglobulin levels were normal, IVIg had been stopped, and no fungal infection occurred.
  • Anti-IFN autoantibodies persisted.
  • NCIT suggestion: hematopoietic cell transplantation (NCIT:C15431), therapeutic_modality: CELL_THERAPY.
  • Supportive: immunoglobulin replacement (used in Sharfe 2022 siblings and in P1 before HSCT), antimicrobial prophylaxis or treatment, and rituximab (given to P2).
  • NCIT suggestion: Pharmacotherapy (NCIT:C15986). Bind specific agents as therapeutic_agent only after a CHEBI or NCIT lookup.
  • Surgical: lobectomy for chronic bronchiolitis (Sharfe 2022).
  • Not found: gene therapy, targeted therapy and clinical trials. I did not search ClinicalTrials.gov, so absence is unconfirmed.
  • Whether HSCT stops autoimmunity of stromal origin is unknown, because the autoantibodies persisted.

13. Prevention

  • Genetic counseling for families, with carrier testing of relatives and prenatal or preimplantation diagnosis in known families.
  • Early diagnosis permits prophylaxis and early HSCT.
  • No vaccination guidance specific to RELB deficiency was found. Live vaccines are usually avoided in combined immunodeficiency, but I did not find a source stating this for IMD53.

14. Other species and natural disease

No naturally occurring animal disease is documented (OMIA not checked). Relb is conserved across mammals. The mouse ortholog is Relb (MGI).

15. Model organisms

  • Relb knockout mice die at 2–6 weeks from severe, T-cell-dependent, multi-organ inflammation (Le Voyer 2024 discussion).
  • Human patients show a narrower picture: mainly infection, IFN autoantibodies and, in partial deficiency, organ autoimmunity.
  • Fidelity is therefore partial (PARTIALLY_RECAPITULATES, fidelity: MODERATE).
  • Limitation: species difference in the severity and timing of autoimmunity.
  • Conditional mouse models: a Relb knockout restricted to medullary thymic epithelial cells gives T-cell infiltration of liver, lung and skin. This resembles the organ pattern of the partial-deficiency patients and supports an epithelial-intrinsic role in central tolerance (Le Voyer 2024 discussion). Use evidence_source: MODEL_ORGANISM.
  • In vitro: patient fibroblasts, T cells and B cells (IN_VITRO).
  • No zebrafish, Drosophila or iPSC models were found. I searched only briefly.

Curation cautions

  • PMIDs read in full text: 39231201 (Le Voyer 2024, PNAS) and 36402602 (Sharfe 2022, J Autoimmun). Page 1 of the Le Voyer text covers only the first 100,000 of 139,108 characters.
  • Snippets are not verified. WebFetch returned summaries because of its 125-character quote limit. Do not paste any wording from this report as a snippet. Run just fetch-reference PMID:39231201 and PMID:36402602, then copy the exact sentences from the cache files.
  • Fetch before use: PMID 26385063 and the LymphoSign DOI.
  • Not read: the 2022 Le Voyer study (autoantibodies in NIK and RELB deficiency, AIRE-expressing thymic cells) was cited only from search-result snippets.
  • Retrieval issue: the PubMed fetch for 36402602 failed with a proxy error. I used the PMC copy instead.
  • Run just preflight-dr on this report before using its content, per CLAUDE.md.
  • Record RELB gene validity only by copying an external classification (ClinGen via CGGV: or GenCC), never by assigning one.

Sources - Le Voyer et al., PNAS 2024 (PMC11406260) - Sharfe et al., J Autoimmun 2022 (PMC10861023) - MalaCards: Immunodeficiency 53 - GenCC submission for RELB / MONDO:0054696 - Disease Ontology DOID:0111992 - DrugMap disease record - MedGen C4539811 mirror - GenCC SGC-106323.2

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 33
Resolved 30
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 1
Terms whose name was checked 11
Terms named correctly 2
Terms named as a different term 5
Terms whose name is worth a second look 4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0054696 (2 mentions) - the report calls it "MONDO"; MONDO calls it immunodeficiency 53
  • DOID:0111992 (5 mentions) - the report calls it "DOID"; DOID calls it immunodeficiency 53
  • HP:0100550 (1 mention) - the report calls it "P1 and P2"; HP calls it Tendon rupture
  • HP:0002014 (1 mention) - the report calls it "Siblings"; HP calls it Diarrhea
  • HP:0004322 (1 mention) - the report calls it "Oldest sibling (Sharfe 2022)"; HP calls it Short stature

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0003290 (1 mention), reported as "Sharfe 2022 siblings" - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0005407 (obsolete Decreased proportion of CD4-positive helper T cells) (1 mention) - replaced by HP:0032218

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0038061 (1 mention) - the report calls it "GO: non-canonical NF-κB signal transduction"; GO calls it non-canonical NF-kappaB signal transduction
  • CL:0000895 (1 mention) - the report calls it "CL: naïve thymus-derived CD4-positive alpha-beta T cell"; CL calls it naive thymus-derived CD4-positive, alpha-beta T cell
  • NCIT:C15431 (1 mention) - the report calls it "NCIT suggestion: hematopoietic cell transplantation"; NCIT calls it Hematopoietic Cell Transplantation
  • NCIT:C15986 (1 mention) - the report calls it "NCIT suggestion: Pharmacotherapy"; NCIT calls it Pharmacotherapy