Immunodeficiency 32B (IMD32B) is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in IRF8, the gene encoding interferon regulatory factor 8, a transcription factor that specifies the mononuclear phagocyte system. Biallelic IRF8 loss abolishes the development of circulating monocytes and dendritic cells, producing a myeloid compartment with no blood monocytes and no conventional or plasmacytoid dendritic cells, and a compensatory granulocytic hyperplasia. Clinically it presents in infancy as a severe immunodeficiency: disseminated disease after Bacille Calmette-Guerin (BCG) vaccination, mucocutaneous candidiasis, severe viral infections and, in some patients, intracerebral calcification and pulmonary alveolar proteinosis. The complete deficiency is typically fatal in early childhood without hematopoietic stem-cell transplantation (reported patients have died in infancy or been transplanted between nine months and four years of age) and only a handful of patients have been reported. IMD32B is the severe, recessive pole of a two-tiered IRF8 disorder. The original report of Hambleton and colleagues (2011) described two distinct IRF8 alleles: a homozygous K108E variant causing autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells (this entry, IMD32B), and a T80A variant causing a milder, autosomal dominant immunodeficiency with selective depletion of CD11c+CD1c+ dendritic cells (immunodeficiency 32A, MONDO:0009193, curated separately). Both alleles map to the DNA-binding domain and impair IRF8 transcriptional activity by disrupting the IRF8-DNA interaction; the two forms differ in dose (biallelic versus monoallelic) and hence in the severity of the mononuclear-phagocyte lesion. The disease is mechanistically informative about human myelopoiesis: it shows that IRF8 is non-redundantly required for the differentiation of the entire mononuclear phagocyte lineage in humans, and that losing the antigen-presenting and macrophage-effector compartment is sufficient to abolish antimycobacterial and antifungal immunity even when lymphoid development is otherwise preserved.
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name: Immunodeficiency 32B
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
synonyms:
- IMD32B
- Autosomal recessive IRF8 deficiency
- IRF8 deficiency, autosomal recessive
- Monocyte and dendritic cell deficiency, autosomal recessive
- Recessive IRF8 dendritic cell immunodeficiency
description: >
Immunodeficiency 32B (IMD32B) is an autosomal recessive inborn error of immunity
caused by biallelic loss-of-function variants in IRF8, the gene encoding interferon
regulatory factor 8, a transcription factor that specifies the mononuclear phagocyte
system. Biallelic IRF8 loss abolishes the development of circulating monocytes and
dendritic cells, producing a myeloid compartment with no blood monocytes and no
conventional or plasmacytoid dendritic cells, and a compensatory granulocytic
hyperplasia. Clinically it presents in infancy as a severe immunodeficiency:
disseminated disease after Bacille Calmette-Guerin (BCG) vaccination, mucocutaneous
candidiasis, severe viral infections and, in some patients, intracerebral
calcification and pulmonary alveolar proteinosis. The complete deficiency is
typically fatal in early childhood without hematopoietic stem-cell transplantation
(reported patients have died in infancy or been transplanted between nine months and
four years of age) and only a handful of patients have been reported.
IMD32B is the severe, recessive pole of a two-tiered IRF8 disorder. The original
report of Hambleton and colleagues (2011) described two distinct IRF8 alleles: a
homozygous K108E variant causing autosomal recessive severe immunodeficiency with a
complete lack of circulating monocytes and dendritic cells (this entry, IMD32B), and
a T80A variant causing a milder, autosomal dominant immunodeficiency with selective
depletion of CD11c+CD1c+ dendritic cells (immunodeficiency 32A, MONDO:0009193, curated
separately). Both alleles map to the DNA-binding domain and impair IRF8 transcriptional
activity by disrupting the IRF8-DNA interaction; the two forms differ in dose (biallelic
versus monoallelic) and hence in the severity of the mononuclear-phagocyte lesion.
The disease is mechanistically informative about human myelopoiesis: it shows that IRF8
is non-redundantly required for the differentiation of the entire mononuclear phagocyte
lineage in humans, and that losing the antigen-presenting and macrophage-effector
compartment is sufficient to abolish antimycobacterial and antifungal immunity even when
lymphoid development is otherwise preserved.
disease_term:
preferred_term: immunodeficiency 32B
term:
id: MONDO:0009194
label: immunodeficiency 32B
parents:
- Primary immunodeficiency
- Inborn error of immunity
references:
- reference: PMID:21524210
title: "IRF8 mutations and human dendritic-cell immunodeficiency."
- reference: PMID:29128673
title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
- reference: PMID:35338423
title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
- reference: PMID:25122610
title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
- reference: PMID:32735845
title: "Differential IRF8 Transcription Factor Requirement Defines Two Pathways of Dendritic Cell Development in Humans."
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: UNKNOWN
notes: >-
Autosomal recessive complete IRF8 deficiency is exceedingly rare. At the time of the
Rosain et al. report only three unrelated patients had been described (from Ireland,
England and China), with the Argentinian patient in that paper the fourth. No
population rate can be derived from a handful of reported individuals, so the class
is UNKNOWN rather than an ultra-rare band.
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of
immunity underlying an absence of blood myeloid mononuclear cells, intracerebral
calcifications, and multiple infections. Only three unrelated patients have been
reported.
explanation: >-
Establishes the rarity of AR complete IRF8 deficiency as a handful of reported
cases, which is why prevalence is recorded as cases-in-literature with an unknown
class.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
IMD32B is inherited in an autosomal recessive manner: complete IRF8 deficiency
requires biallelic loss-of-function variants. The index case was homozygous for the
K108E variant, present in both healthy parents in a heterozygous state; subsequent
patients have been compound heterozygous (for example R83C/R291Q, or c.55del/R111*).
This distinguishes IMD32B from the milder autosomal dominant IRF8 disorder
(immunodeficiency 32A, T80A), in which a single allele produces a selective dendritic
cell depletion rather than the complete monocyte and dendritic cell aplasia seen here.
evidence:
- reference: PMID:21524210
reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The K108E variant was associated with an autosomal recessive severe immunodeficiency
with a complete lack of circulating monocytes and dendritic cells.
explanation: >-
States that the K108E allele underlying IMD32B is inherited in an autosomal
recessive manner and produces the complete monocyte/dendritic cell deficiency.
genetic:
- name: IRF8
gene_term:
preferred_term: IRF8
term:
id: hgnc:5358
label: IRF8
association: CAUSATIVE
variant_origin: GERMLINE
features: >
IRF8 encodes interferon regulatory factor 8, a transcription factor that controls the
development and function of mononuclear myeloid cells. IMD32B is caused by biallelic
loss-of-function variants: the paradigmatic allele is the homozygous missense K108E,
which maps to the DNA-binding domain and abolishes transcriptional activity, and
additional recessive alleles include compound-heterozygous missense (R83C, R291Q) and
truncating (R111*, c.55del) variants, all experimentally shown to be loss-of-function
in overexpression/luciferase assays. Loss of IRF8 removes the transcriptional
instruction for monocyte and dendritic cell differentiation while sparing granulopoiesis,
which expands.
evidence:
- reference: PMID:21524210
reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They also show that human IRF8 is critical for the development of monocytes and
dendritic cells and for antimycobacterial immunity.
explanation: >-
Establishes IRF8 as the causative gene and its role in mononuclear phagocyte
development and antimycobacterial immunity.
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
However, both variants were loss-of-function in a luciferase assay, suggesting that
the patient had AR complete IRF8 deficiency.
explanation: >-
Confirms that the recessive IRF8 variants are loss-of-function, the molecular basis
for classifying this as complete IRF8 deficiency.
pathophysiology:
- name: IRF8 Biallelic Loss of Function
biological_scale: MOLECULAR
genetic_context:
allele_type: SNV
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >
The initiating lesion is biallelic loss of function of IRF8. IRF8 is a sequence-specific
DNA-binding transcription factor; the disease-causing variants map to its DNA-binding
domain and disrupt the IRF8-DNA interaction, abolishing transcriptional activity. For
the K108E allele this proceeds through protein destabilization: loss of the positively
charged side chain causes loss of nuclear localization and of transcriptional activity,
with enhanced proteasomal degradation of the misfolded protein.
molecular_functions:
- preferred_term: IRF8 sequence-specific DNA-binding transcription factor activity
term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
modifier: LOSS_OF_FUNCTION
downstream:
- target: Failed Mononuclear Phagocyte and Dendritic Cell Development
causal_link_type: DIRECT
description: >-
Loss of IRF8 transcriptional activity removes the lineage-specification signal for
monocyte and dendritic cell differentiation.
evidence:
- reference: PMID:21524210
reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They also show that human IRF8 is critical for the development of monocytes and
dendritic cells and for antimycobacterial immunity.
explanation: >-
States the causal step: IRF8 is required for the development of monocytes and
dendritic cells, the lineages that fail in this node's downstream target.
- target: Widespread Immune Dysregulation
causal_link_type: DIRECT
description: >-
Beyond the mononuclear phagocyte block, biallelic IRF8 loss has pleiotropic effects
across other hematopoietic lineages, producing the widespread immune dysregulation
that distinguishes the complete (biallelic) syndrome.
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This analysis defines the clinical features of human biallelic IRF8 deficiency,
revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency
combined with widespread immune dysregulation.
explanation: >-
Establishes that biallelic IRF8 deficiency produces immune dysregulation beyond
the dendritic-cell and monocyte compartment, the content of this downstream node.
evidence:
- reference: PMID:21524210
reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the
interaction between IRF8 and DNA.
explanation: >-
Functional characterization establishing that the causal variants abolish IRF8
transcription factor activity through loss of DNA binding.
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Biochemical characterization of the IRF8(K108E) mutant in vitro shows that loss of
the positively charged side chain at K108 causes loss of nuclear localization and
loss of transcriptional activity
explanation: >-
Details the molecular mechanism of the K108E allele: loss of nuclear localization
and transcriptional activity, the functional consequence of the loss-of-function.
- name: Failed Mononuclear Phagocyte and Dendritic Cell Development
biological_scale: CELLULAR
description: >
Without IRF8, the mononuclear phagocyte lineage fails to develop. Circulating monocytes
are absent and both conventional and plasmacytoid dendritic cells are absent from blood,
while other lymphoid subsets are largely preserved. This is a developmental block in
myelopoiesis rather than a signalling defect, and it defines the cellular lesion of
IMD32B.
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
- preferred_term: conventional dendritic cell
term:
id: CL:0000990
label: conventional dendritic cell
- preferred_term: plasmacytoid dendritic cell
term:
id: CL:0000784
label: plasmacytoid dendritic cell
biological_processes:
- preferred_term: monocyte differentiation
term:
id: GO:0030224
label: monocyte differentiation
modifier: DECREASED
- preferred_term: dendritic cell differentiation
term:
id: GO:0097028
label: dendritic cell differentiation
modifier: DECREASED
downstream:
- target: Decreased total monocyte count
- target: Absent circulating dendritic cells
- target: Compensatory Granulocytic Hyperplasia
- target: Impaired Antimicrobial Effector Immunity
causal_link_type: DIRECT
description: >-
The mononuclear phagocytes that fail to develop are the antigen-presenting and
macrophage-effector cells required to control intracellular and fungal pathogens, so
their absence directly impairs antimicrobial immunity.
evidence:
- reference: PMID:21524210
reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They also show that human IRF8 is critical for the development of monocytes and
dendritic cells and for antimycobacterial immunity.
explanation: >-
Links the failed development of monocytes and dendritic cells to the loss of
antimycobacterial immunity, which is this edge.
- target: Pulmonary alveolar proteinosis
causal_link_type: DIRECT
description: >-
Alveolar macrophages, which clear surfactant, derive from the same IRF8-dependent
mononuclear phagocyte lineage; their defective development or function causes the
pulmonary alveolar proteinosis reported in complete IRF8 deficiency.
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This diagnosis should be considered in children with PAP, which is probably due to
the defective development or function of alveolar macrophages.
explanation: >-
Attributes PAP to defective alveolar macrophages, a developmental (not
antimicrobial) consequence of the failed mononuclear phagocyte lineage.
- target: Microglial Dysfunction
causal_link_type: DIRECT
description: >-
Microglia are the IRF8-dependent mononuclear phagocytes of the central nervous
system, so the same developmental lesion that empties the blood mononuclear
phagocyte compartment also affects microglia.
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
which has led to the suggestion that its complete deficiency is a microgliopathy
explanation: >-
Records the microgliopathy hypothesis for complete IRF8 deficiency, linking the
mononuclear phagocyte developmental defect to a microglial (CNS) node.
evidence:
- reference: PMID:21524210
reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The K108E variant was associated with an autosomal recessive severe immunodeficiency
with a complete lack of circulating monocytes and dendritic cells.
explanation: >-
Reports the complete absence of circulating monocytes and dendritic cells, the
cellular content of this node.
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient had no blood monocytes or dendritic cells, associated with neutrophilia,
and normal counts of NK and other lymphoid cell subsets.
explanation: >-
Independently confirms absent monocytes and dendritic cells with preserved lymphoid
subsets, establishing the lineage-selective developmental block.
- reference: PMID:32735845
reference_title: "Differential IRF8 Transcription Factor Requirement Defines Two Pathways of Dendritic Cell Development in Humans."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs
(pDCs) and the classical DC lineages cDC1 and cDC2.
explanation: >-
Establishes, via an allelic series of human IRF8 deficiency and in vitro
differentiation, that IRF8 controls the development of the dendritic cell subsets
absent in this node.
- name: Compensatory Granulocytic Hyperplasia
biological_scale: CELLULAR
description: >
The block in mononuclear phagocyte development is accompanied by an expansion of the
granulocytic compartment. IRF8 normally restrains granulopoiesis, and its loss diverts
myeloid output toward neutrophils, producing a striking granulocytic hyperplasia and
peripheral neutrophilia alongside the monocyte and dendritic cell aplasia. The
expanded granulocytes are not merely increased in number: in the biallelic syndrome
they are also consistently dysplastic and hypofunctional.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
downstream:
- target: Increased total neutrophil count
- target: Dysplastic hypofunctional granulocytes
evidence:
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
absence of CD11c1 conventional dendritic cells (DCs) and CD11c1/CD1231 plasmacytoid
DCs, and striking granulocytic hyperplasia
explanation: >-
Reports the granulocytic hyperplasia accompanying the dendritic cell aplasia in the
IRF8 K108E patient.
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Granulocytes were consistently increased, dysplastic, and hypofunctional.
explanation: >-
Establishes that the expanded granulocytes are qualitatively abnormal (dysplastic and
hypofunctional), not only increased in number.
- name: Impaired Antimicrobial Effector Immunity
biological_scale: ORGANISM
description: >
The net consequence is a failure of antimicrobial effector immunity. Loss of the
monocyte/macrophage and dendritic-cell compartments removes the cells that control
intracellular pathogens (mycobacteria), present antigen, and clear fungi, and also
impairs IL-12 and IFN-gamma production. The result is a selective susceptibility to
weakly virulent mycobacteria including the BCG vaccine strain, to mucocutaneous fungal
infection, and to severe viral infection.
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: defense response to bacterium
term:
id: GO:0042742
label: defense response to bacterium
modifier: DECREASED
downstream:
- target: Disseminated BCG disease
- target: Mucocutaneous candidiasis
- target: Susceptibility to severe viral infection
evidence:
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient initially presented with severe disseminated mycobacterial and
mucocutaneous fungal infections and was ultimately cured by cord blood transplant.
explanation: >-
Documents the organism-level infectious phenotype: disseminated mycobacterial and
mucocutaneous fungal infection resulting from the loss of antimicrobial effector
immunity.
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Production of interleukin (IL) 12 and IFN-γ by blood cells in response to bacterial
products or nonspecific stimuli was impaired.
explanation: >-
Grounds the node's claim that IL-12 and IFN-gamma production is impaired, the
cytokine axis underlying the antimycobacterial defect.
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
whole blood from the patient was completely unable to produce IL-1β, IL-10, IL-12p70,
and IL-23, and TNF levels were low
explanation: >-
Independently documents abolished IL-12p70 (and other myeloid cytokine) production,
corroborating the impaired IL-12/IFN-gamma effector axis.
- name: Widespread Immune Dysregulation
biological_scale: CELLULAR
description: >
Biallelic (complete) IRF8 deficiency is not confined to the mononuclear phagocyte
compartment: it produces widespread immune dysregulation across other hematopoietic
lineages. Natural killer cell development and maturation are arrested; TH1, TH17 and
CD8+ memory T-cell differentiation is reduced with loss of CXCR3; and B-cell
development is impaired with fewer memory cells, reduced class-switching and reduced
somatic hypermutation. The T-cell component is at least partly secondary to the absent
antigen-presenting compartment, whereas the NK and B-cell defects reflect the broader
roles of IRF8. This axis distinguishes the complete recessive syndrome from the milder
dominant IRF8 disorder.
cell_types:
- preferred_term: natural killer cell
term:
id: CL:0000623
label: natural killer cell
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
downstream:
- target: Impaired natural killer cell development
causal_link_type: DIRECT
description: >-
IRF8 loss arrests natural killer cell development and maturation, a component of the
broader immune dysregulation.
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Natural killer cell development and maturation were arrested.
explanation: >-
Reports arrested NK cell development and maturation in a biallelic IRF8 deficiency
patient, the content of this downstream node.
- target: Impaired memory B-cell generation
causal_link_type: DIRECT
description: >-
IRF8 loss impairs B-cell development, reducing memory B cells, class-switching and
somatic hypermutation.
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
B-cell development was impaired, with fewer memory cells, reduced class-switching,
and lower frequency and complexity of somatic hypermutation.
explanation: >-
Documents the impaired B-cell development and memory/class-switch defect that this
downstream node captures.
- target: Reduced memory T-cell differentiation
causal_link_type: DIRECT
description: >-
TH1, TH17 and CD8+ memory T-cell differentiation is reduced, with loss of CXCR3
expression on T cells.
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T
cells did not express CXCR3.
explanation: >-
Reports the reduced TH1/TH17/CD8+ memory T-cell differentiation captured by this
downstream node.
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated
transcripts.
explanation: >-
Establishes the widespread, multilineage transcriptional dysregulation that defines
this node.
- name: Microglial Dysfunction
biological_scale: CELLULAR
description: >
IRF8 is expressed by microglia, the resident mononuclear phagocytes of the central
nervous system. Complete IRF8 deficiency has been proposed to be a microgliopathy,
resembling other disorders of microglial genes that produce intracerebral
calcification. This node links the IRF8-dependent mononuclear phagocyte defect to the
neurological (calcification) phenotype.
cell_types:
- preferred_term: microglial cell
term:
id: CL:0000129
label: microglial cell
downstream:
- target: Intracerebral calcification
causal_link_type: DIRECT
description: >-
Loss of microglial IRF8 function is the proposed mechanism of the intracerebral
calcification, by analogy with other microglial-gene disorders that cause it.
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
resembling other conditions caused by mutations of genes expressed by microglia,
variants of which have been shown to lead to intracerebral calcification
explanation: >-
Links a microgliopathy mechanism to intracerebral calcification, the downstream
neurological phenotype.
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
which has led to the suggestion that its complete deficiency is a microgliopathy
explanation: >-
Records the microgliopathy hypothesis for complete IRF8 deficiency behind this node.
phenotypes:
- category: Immunologic
name: Decreased total monocyte count
description: >
Circulating monocytes are absent, reflecting the IRF8-dependent block in monocyte
development. Monocytopenia together with absent dendritic cells is the diagnostic
hematological signature of the disease.
phenotype_term:
preferred_term: Monocytopenia
term:
id: HP:0012312
label: Decreased total monocyte count
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient had no blood monocytes or dendritic cells, associated with neutrophilia,
and normal counts of NK and other lymphoid cell subsets.
explanation: >-
Reports the absence of blood monocytes directly in an AR complete IRF8 deficiency
patient.
- category: Immunologic
name: Absent circulating dendritic cells
description: >
Both conventional and plasmacytoid dendritic cells are absent from blood, removing the
principal antigen-presenting compartment. In the milder autosomal dominant IRF8 disorder
the depletion is selective (CD11c+CD1c+ dendritic cells); in IMD32B it is complete.
phenotype_term:
preferred_term: Absent circulating dendritic cells
term:
id: HP:0020178
label: Abnormal dendritic cell count
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid.
explanation: >-
Documents dendritic cell deficiency alongside monocytopenia in biallelic IRF8
deficiency.
- category: Infectious
name: Disseminated BCG disease
description: >
Disseminated disease caused by the M. bovis BCG vaccine strain after routine
vaccination. Because BCG is often the first mycobacterial challenge an infant meets,
disseminated BCG disease is a common presenting event of complete IRF8 deficiency.
phenotype_term:
preferred_term: BCGosis
term:
id: HP:0020087
label: BCGosis
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He had a history of viral pulmonary diseases, disseminated disease due to bacillus
Calmette-Guérin (BCG), PAP, and cerebral calcifications.
explanation: >-
Reports disseminated BCG disease directly in an AR complete IRF8 deficiency patient.
- category: Infectious
name: Mucocutaneous candidiasis
description: >
Mucocutaneous fungal infection, reflecting the loss of the mononuclear-phagocyte and
dendritic-cell compartments needed to control fungi. Oral candidiasis has been a
recurrent feature of reported complete IRF8 deficiency patients.
phenotype_term:
preferred_term: Mucocutaneous candidiasis
term:
id: HP:0002728
label: Chronic mucocutaneous candidiasis
temporality: RECURRENT
evidence:
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient initially presented with severe disseminated mycobacterial and
mucocutaneous fungal infections and was ultimately cured by cord blood transplant.
explanation: >-
Reports mucocutaneous fungal infection in the index IRF8 K108E patient, the basis for
this candidiasis phenotype.
- category: Infectious
name: Susceptibility to severe viral infection
description: >
Reported patients have severe viral infections, including respiratory viral disease.
Loss of the dendritic-cell compartment impairs antiviral priming and, with the wider
immune dysregulation of biallelic IRF8 deficiency, contributes to recurrent viral
infection.
phenotype_term:
preferred_term: Recurrent viral infections
term:
id: HP:0004429
label: Recurrent viral infections
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient
with recurrent viral infection, granuloproliferation, and intracerebral calcification
explanation: >-
Reports recurrent viral infection in a biallelic IRF8 deficiency patient.
- category: Immunologic
name: Impaired natural killer cell development
description: >
In one reported biallelic IRF8 patient, natural killer cell development and maturation
were arrested. This is a maturation/differentiation defect, not a numerical deficiency:
reported AR complete IRF8 patients have had normal or increased NK cell counts, so the
abnormality is qualitative and variant-dependent rather than a reduced NK count. The
term is therefore bound to abnormal NK physiology rather than to a count-reduction term.
phenotype_term:
preferred_term: Impaired natural killer cell development and maturation
term:
id: HP:0012177
label: Abnormal natural killer cell physiology
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Natural killer cell development and maturation were arrested.
explanation: >-
Documents arrested NK cell development and maturation in a biallelic IRF8 deficiency
patient, an abnormality of NK cell physiology.
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
while the patient reported here had a normal count of NK cells, and a normal
distribution of CD56dim and CD56br NK cells
explanation: >-
Counterbalancing observation: the reported AR complete IRF8 patient had a normal NK
count and distribution (others had normal or increased counts), refuting any
reduced-NK-count reading of this phenotype.
- category: Neurologic
name: Intracerebral calcification
description: >
Intracerebral (cerebral) calcification has been reported in several complete IRF8
deficiency patients, part of the immune-dysregulation and multisystem spectrum of the
biallelic disease.
phenotype_term:
preferred_term: Cerebral calcification
term:
id: HP:0002514
label: Cerebral calcification
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of
immunity underlying an absence of blood myeloid mononuclear cells, intracerebral
calcifications, and multiple infections.
explanation: >-
Names intracerebral calcification as a feature of AR complete IRF8 deficiency.
- category: Respiratory
name: Pulmonary alveolar proteinosis
description: >
Pulmonary alveolar proteinosis, reported in a complete IRF8 deficiency patient, is
attributed to defective development or function of alveolar macrophages, which clear
surfactant and which derive from the IRF8-dependent mononuclear phagocyte lineage.
phenotype_term:
preferred_term: Pulmonary alveolar proteinosis
term:
id: HP:0006517
label: Intraalveolar phospholipid accumulation
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This diagnosis should be considered in children with PAP, which is probably due to
the defective development or function of alveolar macrophages.
explanation: >-
Links pulmonary alveolar proteinosis to defective alveolar macrophages, the
IRF8-dependent mechanism behind this phenotype.
- category: Hematologic
name: Increased total neutrophil count
description: >
Peripheral neutrophilia accompanies the granulocytic hyperplasia that fills in for the
failed monocyte and dendritic cell lineages.
phenotype_term:
preferred_term: Neutrophilia
term:
id: HP:0011897
label: Increased total neutrophil count
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient had no blood monocytes or dendritic cells, associated with neutrophilia,
and normal counts of NK and other lymphoid cell subsets.
explanation: >-
Reports neutrophilia in an AR complete IRF8 deficiency patient.
- category: Immunologic
name: Impaired memory B-cell generation
description: >
B-cell development is impaired in biallelic IRF8 deficiency, with fewer memory B cells,
reduced class-switching, and reduced frequency and complexity of somatic hypermutation.
phenotype_term:
preferred_term: Impaired memory B-cell generation
term:
id: HP:0002847
label: Impaired memory B cell generation
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
B-cell development was impaired, with fewer memory cells, reduced class-switching,
and lower frequency and complexity of somatic hypermutation.
explanation: >-
Reports impaired B-cell development with a memory and class-switch defect.
- category: Immunologic
name: Reduced memory T-cell differentiation
description: >
TH1, TH17 and CD8+ memory T-cell differentiation is significantly reduced in biallelic
IRF8 deficiency, and T cells fail to express CXCR3. This T-cell defect is at least
partly secondary to the absent antigen-presenting compartment.
phenotype_term:
preferred_term: Decreased memory T-cell differentiation (TH1/TH17/CD8+)
term:
id: HP:0032183
label: Decreased memory T cell proportion
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T
cells did not express CXCR3.
explanation: >-
Reports the reduced TH1/TH17/CD8+ memory T-cell differentiation of this phenotype.
- category: Hematologic
name: Dysplastic hypofunctional granulocytes
description: >
The expanded granulocytes in biallelic IRF8 deficiency are not only increased in number
but are also consistently dysplastic and functionally impaired.
phenotype_term:
preferred_term: Dysplastic hypofunctional granulocytes
term:
id: HP:0011992
label: Abnormal neutrophil morphology
evidence:
- reference: PMID:29128673
reference_title: "Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Granulocytes were consistently increased, dysplastic, and hypofunctional.
explanation: >-
Reports that the granulocytes are dysplastic and hypofunctional, not only increased.
treatments:
- name: Hematopoietic stem-cell transplantation
description: >
Allogeneic hematopoietic stem-cell transplantation is the only definitive treatment for
complete IRF8 deficiency: it restores the missing mononuclear phagocyte lineage from
donor cells. The index patient required transplantation, and reported patients have been
cured by cord blood or stem-cell transplant; untransplanted complete deficiency is fatal
in infancy.
treatment_term:
preferred_term: hematopoietic stem-cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
therapeutic_modality: CELL_THERAPY
evidence:
- reference: PMID:21524210
reference_title: "IRF8 mutations and human dendritic-cell immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
including early-onset disseminated BCG disease, who required hematopoietic stem-cell
transplantation.
explanation: >-
Records that the severe (recessive) IRF8 deficiency patient required hematopoietic
stem-cell transplantation.
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient initially presented with severe disseminated mycobacterial and
mucocutaneous fungal infections and was ultimately cured by cord blood transplant.
explanation: >-
Records that the index IRF8 K108E patient was cured by cord blood (hematopoietic
stem-cell) transplant.
- name: Antimicrobial therapy
description: >
Supportive antimicrobial therapy, including multidrug antimycobacterial and antifungal
treatment, is used to control the disseminated mycobacterial and mucocutaneous fungal
infections that dominate the clinical course before and around definitive
transplantation. The reported Argentinian patient received a rifampicin-based
antituberculous regimen for BCG disease and liposomal amphotericin for fungal cover.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: rifampicin
term:
id: CHEBI:28077
label: rifampicin
- preferred_term: ethambutol
term:
id: CHEBI:4877
label: ethambutol
- preferred_term: pyrazinamide
term:
id: CHEBI:45285
label: pyrazinecarboxamide
- preferred_term: levofloxacin
term:
id: CHEBI:63598
label: levofloxacin
- preferred_term: amphotericin B
term:
id: CHEBI:2682
label: amphotericin B
therapeutic_modality: SMALL_MOLECULE
evidence:
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient initially presented with severe disseminated mycobacterial and
mucocutaneous fungal infections and was ultimately cured by cord blood transplant.
explanation: >-
Establishes the disseminated mycobacterial and fungal infections that antimicrobial
therapy is directed against in this disease.
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient was treated with pyrazinamide, ethambutol, rifampicin, and levofloxacin
explanation: >-
Documents the specific antituberculous regimen used for BCG disease, grounding the
rifampicin/ethambutol/pyrazinamide/levofloxacin agents.
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient was treated with meropenem, vancomycin, colistin,
trimethoprim/sulfamethoxazole, and liposomal amphotericin.
explanation: >-
Documents antifungal cover with liposomal amphotericin, grounding the amphotericin B
agent.
- name: Whole-lung lavage and corticosteroids for pulmonary alveolar proteinosis
description: >
Pulmonary alveolar proteinosis in complete IRF8 deficiency is managed with supportive
lung lavage and corticosteroids, as definitive treatment of the underlying alveolar
macrophage defect requires hematopoietic stem-cell transplantation. In the reported
patient, steroid boluses and weekly partial lung washes gave a good initial response.
treatment_term:
preferred_term: whole-lung lavage and corticosteroid therapy
term:
id: NCIT:C49236
label: Therapeutic Procedure
evidence:
- reference: PMID:35338423
reference_title: "Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patient was treated with a bolus of steroids and partial lung washes that were
performed weekly at the ICU, with a good response at the start of treatment.
explanation: >-
Documents the whole-lung lavage and corticosteroid management of PAP in a complete
IRF8 deficiency patient.
- name: Avoidance of live attenuated vaccines
description: >
Live attenuated vaccines, in particular BCG, cause disseminated disease in complete
IRF8 deficiency and are contraindicated; avoiding them is a key preventive measure once
the diagnosis is suspected.
treatment_term:
preferred_term: avoidance of live attenuated vaccines
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:25122610
reference_title: "Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
Primary immunodeficiencies sometimes present with disseminated mycobacterial
infection following neonatal vaccination with liveBacillusCalmette-Guérin (BCG).
explanation: >-
Documents that live BCG vaccination triggers disseminated mycobacterial disease in
these immunodeficiencies, the rationale for avoiding live attenuated vaccines.