Immunodeficiency 81 is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in LCP2, the gene encoding SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa). SLP-76 is a cytosolic scaffold adaptor that sits immediately downstream of the T-cell receptor (TCR): once the receptor engages antigen and ZAP-70 phosphorylates the transmembrane adaptor LAT, SLP-76 is recruited into the LAT-SLP-76 signalosome, where it nucleates the assembly that activates phospholipase C-gamma-1 (PLCgamma1), calcium flux, and the ERK/MAP-kinase cascade. Because SLP-76 is the point at which these proximal signals converge, its loss collapses TCR signal transduction and, in parallel, the analogous immunoreceptor and integrin pathways in neutrophils and platelets on which SLP-76 is also required. The disease was first defined in 2021 in an infant with biallelic LCP2 mutations presenting with early-onset life-threatening infections, combined T- and B-cell immunodeficiency, severe neutrophil defects, and impaired platelet aggregation. Subsequently reported patients broaden the spectrum: a homozygous frameshift patient developed EBV-driven diffuse large B-cell lymphoma, and a compound heterozygous patient had a milder combined immunodeficiency with autoimmunity and inflammatory bowel disease but normal platelet function, showing that the platelet arm is not obligate. The mechanism is developmental as well as activational: in the mouse Slp76 knockout, thymocyte maturation is blocked at the double-negative 3 stage, with resulting absence of CD4+CD8+ double-positive thymocytes and peripheral T cells, because SLP-76 integrates the pre-TCR signals that drive double-positive thymocyte expansion. IMD81 is very rare, with only a handful of reported kindreds. The clinical severity ranges from a T-B+ severe combined immunodeficiency phenotype to a later-onset combined immunodeficiency with immune dysregulation.
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name: Immunodeficiency 81
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
synonyms:
- IMD81
- LCP2 deficiency
- SLP76 deficiency
- T-B+ severe combined immunodeficiency due to SLP76 deficiency
description: >
Immunodeficiency 81 is an autosomal recessive inborn error of immunity caused by
biallelic loss-of-function variants in LCP2, the gene encoding SLP-76 (SH2
domain-containing leukocyte protein of 76 kDa). SLP-76 is a cytosolic scaffold
adaptor that sits immediately downstream of the T-cell receptor (TCR): once the
receptor engages antigen and ZAP-70 phosphorylates the transmembrane adaptor LAT,
SLP-76 is recruited into the LAT-SLP-76 signalosome, where it nucleates the
assembly that activates phospholipase C-gamma-1 (PLCgamma1), calcium flux, and the
ERK/MAP-kinase cascade. Because SLP-76 is the point at which these proximal
signals converge, its loss collapses TCR signal transduction and, in parallel, the
analogous immunoreceptor and integrin pathways in neutrophils and platelets on
which SLP-76 is also required.
The disease was first defined in 2021 in an infant with biallelic LCP2 mutations
presenting with early-onset life-threatening infections, combined T- and B-cell
immunodeficiency, severe neutrophil defects, and impaired platelet aggregation.
Subsequently reported patients broaden the spectrum: a homozygous frameshift
patient developed EBV-driven diffuse large B-cell lymphoma, and a compound
heterozygous patient had a milder combined immunodeficiency with autoimmunity and
inflammatory bowel disease but normal platelet function, showing that the platelet
arm is not obligate. The mechanism is developmental as well as activational: in
the mouse Slp76 knockout, thymocyte maturation is blocked at the double-negative 3
stage, with resulting absence of CD4+CD8+ double-positive thymocytes and peripheral
T cells, because SLP-76 integrates the pre-TCR signals that drive double-positive
thymocyte expansion.
IMD81 is very rare, with only a handful of reported kindreds. The clinical
severity ranges from a T-B+ severe combined immunodeficiency phenotype to a
later-onset combined immunodeficiency with immune dysregulation.
disease_term:
preferred_term: immunodeficiency 81
term:
id: MONDO:0030302
label: immunodeficiency 81
external_assertions:
- name: OMIM immunodeficiency 81 record
source: OMIM
assertion_type: disease_record
external_id: OMIM:619374
description: >-
OMIM phenotype identifier for immunodeficiency 81 (IMD81), the LCP2/SLP-76
deficiency phenotype.
parents:
- Primary immunodeficiency
- Combined immunodeficiency
references:
- reference: PMID:33231617
title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
- reference: PMID:37211057
title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
- reference: PMID:36474126
title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
- reference: PMID:9695951
title: "Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76."
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
IMD81 is inherited in an autosomal recessive manner; reported patients carry
homozygous or compound heterozygous loss-of-function variants in LCP2.
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe an infant with severe immunodeficiency who was found to have
novel biallelic mutations in SLP76.
explanation: >-
Biallelic (recessive) mutations in the index patient support autosomal
recessive inheritance.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
An ultra-rare entity. LCP2/SLP-76 deficiency was first linked to a human disease
in 2021, and only a small number of unrelated patients have since been reported
(an index infant with SCID, a patient with EBV-related lymphoma, and a
compound-heterozygous patient with milder combined immunodeficiency). No
population rate can be derived from these case reports.
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our current study links this gene, for the first time, to a human
immunodeficiency characterized by early-onset life-threatening infections,
combined T and B cell immunodeficiency, severe neutrophil defects, and
impaired platelet aggregation.
explanation: >-
Establishes IMD81 as a newly defined, first-reported human disease, consistent
with an ultra-rare case-report-level entity.
genetic:
- name: LCP2
gene_term:
preferred_term: LCP2
term:
id: hgnc:6529
label: LCP2
association: CAUSATIVE
variant_origin: GERMLINE
features: >-
Biallelic loss-of-function variants in LCP2 (encoding SLP-76) cause IMD81.
Reported genotypes include novel biallelic mutations in the index infant, a
homozygous frameshift (c.991delC; p.Q331Sfs*6), and compound heterozygous
missense variants in the proline-rich repeat domain (p.P190R and p.R204W). The
net functional consequence is loss of SLP-76 adaptor function. Inheritance is
autosomal recessive.
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe an infant with severe immunodeficiency who was found to have
novel biallelic mutations in SLP76.
explanation: >-
Documents biallelic (recessive) LCP2/SLP76 mutations in the index patient.
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome sequencing revealed a novel homozygous mutation, c.991del.C; p.
Q331Sfs*6 in the SLP76 gene.
explanation: >-
A homozygous frameshift allele, one of the loss-of-function genotypes reported
for IMD81.
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Compound heterozygous missense variants were identified in LCP2, affecting the
proline-rich repeat domain of SLP76 (p.P190R and p.R204W).
explanation: >-
A compound-heterozygous genotype affecting the SLP-76 proline-rich repeat
domain, confirming biallelic LCP2 as causal and extending the allelic spectrum.
pathophysiology:
- name: LCP2 Biallelic Loss of Function
biological_scale: MOLECULAR
description: >-
Biallelic loss-of-function variants in LCP2 reduce or abolish functional SLP-76
protein. Frameshift alleles eliminate the protein; missense alleles in the
proline-rich repeat domain reduce its expression and signalosome function.
genetic_context:
gene:
preferred_term: LCP2
term:
id: hgnc:6529
label: LCP2
allele_type: frameshift, splice-site, and proline-rich-domain missense
functional_impact_category: LOSS_OF_FUNCTION
downstream:
- target: Loss of SLP-76 Adaptor Function
causal_link_type: DIRECT
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Complete loss of SLP76 protein expression was detected by both Western blot
explanation: >-
Directly demonstrates that the biallelic LCP2 lesion abolishes SLP-76 protein
in the index patient's cells, the molecular event this node describes.
- name: Loss of SLP-76 Adaptor Function
biological_scale: MOLECULAR
description: >-
SLP-76 is a scaffold adaptor that, once recruited to phosphorylated LAT, nucleates
the proximal TCR signalosome. Loss of the protein removes this assembly point for
downstream TCR (and other hematopoietic immunoreceptor) signaling.
molecular_functions:
- preferred_term: SLP-76 signaling adaptor activity
term:
id: GO:0035591
label: signaling adaptor activity
modifier: LOSS_OF_FUNCTION
downstream:
- target: Impaired Proximal TCR Signaling
causal_link_type: DIRECT
- target: Reduced natural killer cell degranulation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SLP76 is a key protein involved in TCR signaling and in other hematopoietic
pathways.
explanation: >-
Identifies SLP-76 as a central adaptor for TCR and other hematopoietic
signaling, whose loss removes the signalosome assembly point.
- name: Impaired Proximal TCR Signaling
biological_scale: CELLULAR
description: >-
Without SLP-76, the LAT-SLP-76 signalosome fails to activate PLCgamma1, so
downstream calcium mobilization and ERK/MAP-kinase signaling are blunted. Patient
T and B cells show reduced ligand-induced phospho-PLCgamma1 and phospho-S6, and a
SLP76-deficient T-cell line shows reduced ERK1/2 phosphorylation, CD69 induction,
and calcium mobilization.
biological_processes:
- preferred_term: T cell receptor signaling pathway
term:
id: GO:0050852
label: T cell receptor signaling pathway
modifier: DECREASED
- preferred_term: positive regulation of cytosolic calcium ion concentration
term:
id: GO:0007204
label: positive regulation of cytosolic calcium ion concentration
modifier: DECREASED
downstream:
- target: Impaired Thymic T-Cell Development
causal_link_type: DIRECT
- target: Defective T-Cell Activation
causal_link_type: DIRECT
- target: Autoimmunity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Tonic and ligand-induced levels of phosphorylated ribosomal protein S6 and
ligand-induced phosphorylated PLCĪ³1 were decreased in the patient's B cells and
CD4+ and CD8+ T cells.
explanation: >-
Directly shows impaired proximal antigen-receptor signaling (PLCgamma1, S6) in
patient lymphocytes.
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69
expression, and Ca2 + mobilization, were reduced in cells harboring the reported
mutation
explanation: >-
A SLP76-deficient Jurkat-derived T-cell line reconstituted with the patient
mutation shows the reduced proximal TCR signaling this node describes.
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
downstream events, including the phosphorylation of ERK, PLC-Ī³1, and phospho-S6,
all of which are dependent on the assembly of the LAT and SLP76 complex, were
significantly reduced or absent
explanation: >-
Confirms in the index patient's primary T cells that ERK, PLC-gamma1 and S6
phosphorylation downstream of the LAT-SLP76 signalosome are lost.
- name: Impaired Thymic T-Cell Development
biological_scale: CELLULAR
description: >-
SLP-76 integrates the pre-TCR signals that drive expansion of CD4+CD8+
double-positive thymocytes. In the mouse Slp76 knockout, thymocyte development is
blocked at the double-negative 3 stage, with resulting absence of CD4+CD8+
double-positive thymocytes and peripheral T cells, providing the developmental
basis for the T-cell lymphopenia seen in severe human cases.
cell_types:
- preferred_term: CD4+CD8+ double-positive thymocyte
term:
id: CL:0000809
label: double-positive, alpha-beta thymocyte
biological_processes:
- preferred_term: T cell differentiation in thymus
term:
id: GO:0033077
label: T cell differentiation in thymus
modifier: DECREASED
downstream:
- target: Combined T- and B-Cell Immunodeficiency
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Inverted CD4:CD8 ratio
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Abnormally low TREC level
causal_link_type: DIRECT
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
In the SLP76-deficient mouse model, thymocyte development was blocked at the
double-negative 3 stage, resulting in the absence of peripheral T cells.
explanation: >-
States the stage of the mouse thymic block (double-negative 3) that this node's
description reflects; a non-human model, hence indirect for the human disease.
- reference: PMID:9695951
reference_title: "Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
Analysis of lymphoid cells revealed a profound block in thymic development with
absence of double-positive CD4+8+ thymocytes and of peripheral T cells.
explanation: >-
The Slp76-null mouse establishes that loss of SLP-76 blocks thymic T-cell
development, with resulting absence of double-positive thymocytes; a non-human
model, hence indirect for the human disease.
- reference: PMID:9695951
reference_title: "Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
These results indicate that SLP-76 collects all pre-TCR signals that drive the
development and expansion of double-positive thymocytes.
explanation: >-
Identifies the developmental mechanism (pre-TCR signal integration) by which
SLP-76 loss impairs thymic T-cell development.
- name: Defective T-Cell Activation
biological_scale: CELLULAR
description: >-
Mature T cells that do develop cannot be properly activated through the TCR
because the SLP-76 signalosome is required to couple receptor engagement to
calcium/ERK signaling and activation-marker induction.
biological_processes:
- preferred_term: T cell activation
term:
id: GO:0042110
label: T cell activation
modifier: DECREASED
downstream:
- target: Combined T- and B-Cell Immunodeficiency
causal_link_type: DIRECT
- target: Decreased mitogen-induced T-cell proliferation
causal_link_type: DIRECT
evidence:
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In order to examine the effect of this new SLP76 mutation on T cell signaling, a
SLP76-deficient Jurkat-derived T cell line was transduced either with wild-type
(WT), or with the specific SLP76 mutant, or with a mock vector.
explanation: >-
Establishes the SLP76-deficient T-cell activation model whose reduced
activation readouts (ERK, CD69, calcium) indicate defective T-cell activation.
- name: Combined T- and B-Cell Immunodeficiency
biological_scale: ORGANISM
description: >-
The convergence of impaired T-cell development and activation, together with
defective T-cell help for B cells, produces a combined immunodeficiency with
failure of protective immunity. B-cell antigen-receptor signaling is itself
impaired by SLP-76 loss, and specific antibody deficiency with reduced IgA and
memory B cells is seen even when circulating cell numbers are near-normal.
downstream:
- target: Combined immunodeficiency
causal_link_type: DIRECT
- target: Recurrent infections
causal_link_type: DIRECT
- target: Decreased circulating IgA concentration
causal_link_type: DIRECT
- target: Decreased class-switched memory B cell proportion
causal_link_type: DIRECT
- target: Colitis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Susceptibility to EBV-Driven Lymphoproliferation
causal_link_type: DIRECT
evidence:
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic variants in LCP2 impair neutrophil function and T-cell and B-cell
antigen-receptor signaling and can cause combined immunodeficiency with
early-onset immune dysregulation, even in the absence of platelet defects.
explanation: >-
States that biallelic LCP2 loss impairs both T- and B-cell receptor signaling
and causes combined immunodeficiency, the central disease phenotype.
- name: Neutrophil Functional Defect
biological_scale: CELLULAR
description: >-
SLP-76 is also required in myeloid immunoreceptor and integrin signaling, so its
loss impairs neutrophil reactive-oxygen-species production, integrin-dependent
spreading and chemotaxis independently of the lymphocyte defect, contributing to
bacterial and fungal susceptibility.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
downstream:
- target: Recurrent infections
causal_link_type: DIRECT
- target: Abnormal neutrophil physiology
causal_link_type: DIRECT
- target: Fungal brain abscess
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, neutrophil function, numbers of unswitched and class-switched memory B
cells, and serum IgA were decreased.
explanation: >-
Documents reduced neutrophil function (and B-cell/IgA deficits) in a patient
with biallelic LCP2 variants.
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These results suggest a substantial defect in proximal neutrophil signaling,
which may be partially bypassed by PMA stimulation.
explanation: >-
The index patient's neutrophils show a proximal signaling defect, directly
supporting the neutrophil functional defect this node represents.
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
SLP76-deficient neutrophils have shown decreased FcĪ³ receptor-dependent and
adhesion-dependent production of reactive oxygen intermediates and decreased
integrin-dependent spreading
explanation: >-
Provides the ROS/integrin mechanism by which SLP-76 loss impairs neutrophil
function; based on SLP76-deficient (murine) neutrophils, hence indirect.
- name: Defective Platelet GPVI/Integrin Signaling
biological_scale: CELLULAR
description: >-
SLP-76 transmits signals from the platelet collagen receptor GPVI and integrin
pathways, so its loss impairs platelet activation and aggregation. This arm is
present in the severe index case but was spared in a milder compound-heterozygous
patient, so it is not obligate.
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
downstream:
- target: Impaired platelet aggregation
causal_link_type: DIRECT
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Nevertheless, platelet aggregation was reduced, specifically in response to
collagen (Table S1).
explanation: >-
Reports the collagen-specific platelet aggregation defect in the index patient,
the functional consequence this node represents.
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: >-
It is known that SLP76 is required for signaling downstream of glycoprotein VI,
which is an ITAM-bearing collagen receptor expressed by platelets
explanation: >-
Identifies GPVI, the collagen receptor whose SLP-76-dependent signaling is lost,
as the molecular basis of the collagen-specific platelet defect.
- name: Susceptibility to EBV-Driven Lymphoproliferation
biological_scale: ORGANISM
description: >-
Loss of cytotoxic T-cell surveillance in combined immunodeficiency permits
uncontrolled Epstein-Barr virus infection and EBV-driven B-cell proliferation,
which in one reported patient progressed to diffuse large B-cell lymphoma.
downstream:
- target: B-cell lymphoma
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
SLP76 deficiency should be added to the growing list of monogenetic diseases
that predispose affected individuals to acquire severe and uncontrolled EBV
infections and to develop substantial complications.
explanation: >-
States that SLP76 deficiency predisposes to severe, uncontrolled EBV infection,
the basis for EBV-driven lymphoproliferation.
phenotypes:
- name: Combined immunodeficiency
category: Immunological
description: >-
Combined defect of T- and B-cell immunity, ranging from a T-B+ severe combined
immunodeficiency presentation to a milder later-onset combined immunodeficiency.
phenotype_term:
preferred_term: Combined immunodeficiency
term:
id: HP:0005387
label: Combined immunodeficiency
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our current study links this gene, for the first time, to a human
immunodeficiency characterized by early-onset life-threatening infections,
combined T and B cell immunodeficiency, severe neutrophil defects, and
impaired platelet aggregation.
explanation: >-
Reports combined T- and B-cell immunodeficiency as the defining phenotype.
- name: Recurrent infections
category: Immunological
description: >-
Early-onset, recurrent, and life-threatening bacterial, viral, and other
infections reflecting the combined immune defect.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
sequelae:
- target: Failure to thrive
description: >-
Recurrent, severe early-onset infection drives the failure to thrive seen in
infancy.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
presented with recurrent infections, failure to thrive, and severe EBV-related
infection and proliferation.
explanation: >-
Reports recurrent infections in an LCP2/SLP76-deficient patient.
- name: Failure to thrive
category: Constitutional
description: >-
Failure to thrive in infancy/early childhood, a common consequence of severe
early-onset immunodeficiency.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
presented with recurrent infections, failure to thrive, and severe EBV-related
infection and proliferation.
explanation: >-
Reports failure to thrive in an LCP2/SLP76-deficient patient.
- name: Abnormal neutrophil physiology
category: Immunological
description: >-
Severe neutrophil functional defects contribute to infection susceptibility
independent of the lymphocyte defect.
phenotype_term:
preferred_term: Neutrophil functional defect
term:
id: HP:0011990
label: Abnormal neutrophil physiology
evidence:
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, neutrophil function, numbers of unswitched and class-switched memory B
cells, and serum IgA were decreased.
explanation: >-
Reports decreased neutrophil function in a patient with biallelic LCP2 variants.
- name: Fungal brain abscess
category: Immunological
description: >-
Invasive fungal (Aspergillus) brain abscesses developed in the index infant,
reflecting the severe neutrophil defect. Bound to the structural Brain abscess
HP term; the fungal etiology is carried in the preferred_term.
phenotype_term:
preferred_term: Fungal (Aspergillus) brain abscess
term:
id: HP:0030049
label: Brain abscess
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our patient developed fungal brain abscesses, likely due to a specific defect
in neutrophil function
explanation: >-
Reports fungal brain abscesses attributed to the neutrophil defect in the index
patient.
- name: Impaired platelet aggregation
category: Hematological
description: >-
Impaired platelet aggregation from defective SLP-76-dependent platelet signaling,
present in the severe index case but not in all reported patients.
phenotype_term:
preferred_term: Impaired platelet aggregation
term:
id: HP:0003540
label: Impaired platelet aggregation
sequelae:
- target: Bleeding tendency
description: >-
Reduced collagen-induced platelet aggregation and granule release produce the
bleeding tendency observed clinically.
causal_link_type: DIRECT
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our current study links this gene, for the first time, to a human
immunodeficiency characterized by early-onset life-threatening infections,
combined T and B cell immunodeficiency, severe neutrophil defects, and
impaired platelet aggregation.
explanation: >-
Reports impaired platelet aggregation in the index SLP76-deficient patient.
- name: Bleeding tendency
category: Hematological
description: >-
A bleeding tendency (petechial rash) in the index infant, attributed to defective
collagen-induced platelet aggregation and granule release.
phenotype_term:
preferred_term: Bleeding tendency
term:
id: HP:0001892
label: Abnormal bleeding
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The bleeding tendency that was observed in our patient is probably due to
decreased collagen-induced platelet aggregation and granule release
explanation: >-
Reports a bleeding tendency in the index patient linked to the platelet defect.
- name: Inverted CD4:CD8 ratio
category: Immunological
description: >-
A skewed peripheral T-cell compartment with a high proportion of CD8 T cells and
a very low proportion of CD4 T cells in the index infant.
phenotype_term:
preferred_term: Inverted CD4:CD8 ratio
term:
id: HP:0033222
label: Inverted CD4:CD8 ratio
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lymphocyte immune phenotyping showed a high proportion of CD8 T cells and a very
low proportion of CD4 T cells
explanation: >-
Reports the inverted CD4:CD8 proportion in the index patient.
- name: Decreased mitogen-induced T-cell proliferation
category: Immunological
description: >-
Absent peripheral lymphocyte proliferation to PHA or anti-CD3 (with or without
anti-CD28) in the index infant, partially restored by exogenous IL-2.
phenotype_term:
preferred_term: Absent mitogen-induced T-cell proliferation
term:
id: HP:0031381
label: Decreased mitogen-induced T-cell proliferation
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Peripheral lymphocyte proliferation, as determined by either thymidine
incorporation or CFSE, was absent in response to PHA or anti-CD3, with or without
anti-CD28
explanation: >-
Reports absent mitogen/anti-CD3-induced lymphocyte proliferation in the index
patient.
- name: Reduced natural killer cell degranulation
category: Immunological
description: >-
Normal NK cell numbers but diminished K562-induced degranulation (surface CD107a)
in the index infant, partially rescued by IL-2.
phenotype_term:
preferred_term: Reduced natural killer cell degranulation
term:
id: HP:0012177
label: Abnormal natural killer cell physiology
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
K562-induced degranulation was diminished, as reflected in
degranulation-associated surface expression of CD107a
explanation: >-
Reports reduced NK cell degranulation (CD107a) in the index patient.
- name: Abnormally low TREC level
category: Immunological
description: >-
Low thymic output measured by TCR excision circle (TREC) quantification in the
index infant, consistent with impaired thymic T-cell development.
phenotype_term:
preferred_term: Low T-cell receptor excision circles
term:
id: HP:0031545
label: Abnormally low T cell receptor excision circle level
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thymic activity, as determined by TCR excision circles quantification, was low
explanation: >-
Reports low TRECs (reduced thymic output) in the index patient.
- name: Decreased circulating IgA concentration
category: Immunological
description: >-
Reduced serum IgA as part of the specific antibody deficiency seen in milder
combined immunodeficiency.
phenotype_term:
preferred_term: Decreased circulating IgA concentration
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, neutrophil function, numbers of unswitched and class-switched memory B
cells, and serum IgA were decreased.
explanation: >-
Reports decreased serum IgA in a patient with biallelic LCP2 variants.
- name: Decreased class-switched memory B cell proportion
category: Immunological
description: >-
Reduced numbers of unswitched and class-switched memory B cells, reflecting
impaired T-cell help and B-cell antigen-receptor signaling.
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:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, neutrophil function, numbers of unswitched and class-switched memory B
cells, and serum IgA were decreased.
explanation: >-
Reports decreased class-switched memory B cells in a patient with biallelic LCP2
variants.
- name: Autoimmunity
category: Immunological
description: >-
Immune dysregulation with autoimmunity, reported both as early-onset
Coombs-positive hemolytic anemia in the index infant and as autoimmunity in the
milder combined immunodeficiency presentation.
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a 26-year-old man who presented with specific antibody deficiency,
autoimmunity, and inflammatory bowel disease since early childhood.
explanation: >-
Reports autoimmunity in an LCP2-deficient patient with immune dysregulation.
- name: Colitis
category: Gastrointestinal
description: >-
Inflammatory bowel disease, part of the early-onset immune-dysregulation
presentation.
phenotype_term:
preferred_term: Colitis
term:
id: HP:0002583
label: Colitis
evidence:
- reference: PMID:37211057
reference_title: "Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a 26-year-old man who presented with specific antibody deficiency,
autoimmunity, and inflammatory bowel disease since early childhood.
explanation: >-
Reports inflammatory bowel disease in an LCP2-deficient patient.
- name: B-cell lymphoma
category: Neoplastic
description: >-
EBV-driven diffuse large B-cell lymphoma developed in a homozygous
SLP76-deficient patient, reflecting failed control of EBV-infected B cells.
phenotype_term:
preferred_term: EBV-related diffuse large B-cell lymphoma
term:
id: HP:0012191
label: B-cell lymphoma
evidence:
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
presented with recurrent infections, failure to thrive, and severe EBV-related
infection and proliferation. A diagnosis of diffuse large B cell lymphoma was
made
explanation: >-
Reports EBV-related diffuse large B-cell lymphoma in an SLP76-deficient patient.
treatments:
- name: Hematopoietic Stem Cell Transplantation
description: >-
Allogeneic hematopoietic stem cell transplantation is the definitive treatment
for the severe combined immunodeficiency form, replacing the SLP-76-deficient
hematopoietic compartment. The index infant underwent haplo-identical HSCT but
died of transplant-related complications; HSCT is the standard curative approach
for T-B+ SCID generally.
treatment_term:
preferred_term: hematopoietic stem cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
therapeutic_modality: CELL_THERAPY
target_mechanisms:
- target: Loss of SLP-76 Adaptor Function
treatment_effect: RESTORES
description: >-
Allogeneic HSCT replaces the SLP-76-deficient hematopoietic compartment with
donor cells that express functional SLP-76, restoring the adaptor at the root of
the disease mechanism.
- name: Antimicrobial Prophylaxis and Treatment
description: >-
Broad antibacterial, antiviral, and antifungal prophylaxis and treatment to
manage the recurrent and opportunistic infections of the combined immune and
neutrophil defect.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: anti-infective agent
term:
id: NCIT:C254
label: Anti-Infective Agent
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Recurrent infections
treatment_effect: INHIBITS
description: >-
Antibacterial, antiviral, and antifungal agents treat and prevent the recurrent
opportunistic infections that result from the combined immune and neutrophil
defect.
- name: Immunoglobulin Replacement Therapy
description: >-
Immunoglobulin replacement supports the humoral immunodeficiency (antibody
deficiency, reduced IgA and memory B cells) seen in these patients.
treatment_term:
preferred_term: immunoglobulin replacement therapy
term:
id: NCIT:C62710
label: Immunoglobulin Therapy
therapeutic_modality: PROTEIN_REPLACEMENT
target_mechanisms:
- target: Combined T- and B-Cell Immunodeficiency
treatment_effect: BYPASSES
description: >-
Passive immunoglobulin replaces the antibody the patient cannot make, bypassing
the humoral arm of the combined immunodeficiency rather than correcting the
underlying signaling defect.
- name: Supportive and Oncologic Care
description: >-
Supportive care and, when EBV-driven lymphoproliferation or lymphoma develops,
directed oncologic therapy. One reported patient developed and succumbed to
EBV-related diffuse large B-cell lymphoma.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: B-cell lymphoma
treatment_effect: INHIBITS
description: >-
Directed oncologic therapy targets the EBV-driven B-cell lymphoma that arises
as a downstream complication of the immunodeficiency.
animal_models:
- name: Slp76-null mouse (Lcp2 knockout)
species: Mouse
genotype: Slp76 (Lcp2) null (homozygous knockout)
publication: PMID:9695951
description: >-
The germline Slp76-null mouse, generated by homologous recombination, was the
original in vivo model of SLP-76 loss. It exhibits impaired viability, a profound
thymic developmental block, and hemorrhage. It informs the human disease but
diverges from it in two ways relevant to IMD81: the complete null causes an
absolute developmental block with no peripheral T cells (human hypomorphic alleles
leave dysregulated peripheral T cells), and B-cell development is entirely normal
(human patients have a B-cell antigen-receptor signaling defect).
evidence:
- reference: PMID:9695951
reference_title: "Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We generated a SLP-76 null mutation in mice by homologous recombination in
embryonic stem cells to evaluate the role of SLP-76 in T cell development and
activation.
explanation: >-
Establishes the Slp76-null mouse as the in vivo model of SLP-76 loss informing
this disease.
modeled_mechanisms:
- target: Impaired Thymic T-Cell Development
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
The null reproduces the SLP-76-dependent thymic developmental block, with
absence of double-positive thymocytes and peripheral T cells.
limitations: >-
The complete null causes an absolute block with no peripheral T cells, whereas
human hypomorphic/leaky alleles leave dysregulated peripheral T cells (skewed
toward CD8 TEMRA), so the null overstates the human developmental defect.
readouts:
- name: Double-positive thymocyte and peripheral T-cell content
target: Impaired Thymic T-Cell Development
direction: DECREASED
interpretation: >-
Absence of CD4+8+ double-positive thymocytes and of peripheral T cells is the
structural correlate of the thymic-development node in this model.
evidence:
- reference: PMID:9695951
reference_title: "Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Analysis of lymphoid cells revealed a profound block in thymic development
with absence of double-positive CD4+8+ thymocytes and of peripheral T cells.
explanation: >-
Reports the thymic developmental block and loss of peripheral T cells
measured in this model.
evidence:
- reference: PMID:9695951
reference_title: "Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results indicate that SLP-76 collects all pre-TCR signals that drive the
development and expansion of double-positive thymocytes.
explanation: >-
Supports treating this model as informative for the thymic T-cell development
node.
- target: Combined T- and B-Cell Immunodeficiency
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
The Slp76-null mouse does not reproduce the B-cell arm of the human combined
immunodeficiency: murine B-cell development is entirely normal.
limitations: >-
B-cell development is normal in the null mouse, whereas human IMD81 patients have
a B-cell antigen-receptor signaling defect with reduced class-switched memory B
cells and antibody deficiency; the null therefore misses the B-cell component of
the human phenotype.
evidence:
- reference: PMID:9695951
reference_title: "Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
B cell development was normal.
explanation: >-
Documents that B-cell development is normal in the null mouse, the divergence
from the human B-cell phenotype.
experimental_models:
- name: SLP76-deficient Jurkat-derived T-cell line (J14)
experimental_model_type: CELL_LINE
publication: PMID:33231617
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_source: >-
J14, a SLP76-deficient subline of the Jurkat human leukemic T-cell line,
reconstituted with wild-type or patient-mutant SLP-76 to model and rescue the
signaling defect.
description: >-
The J14 line is the classical in vitro system for dissecting SLP-76 function
downstream of the TCR. Reconstituting it with the patient's SLP-76 mutant
reproduces the reduced proximal TCR signaling, and ectopic wild-type SLP-76
rescues it, linking the specific mutation to the signaling phenotype.
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we characterized aspects of the patient's immune phenotype, modeled them with an
SLP76-deficient Jurkat-derived T cell line, and rescued some consequences using
ectopic expression of wild-type SLP76.
explanation: >-
Establishes the J14 line as the model used to reproduce and rescue the patient's
TCR-signaling phenotype.
modeled_mechanisms:
- target: Impaired Proximal TCR Signaling
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Reconstituting J14 with the patient's SLP-76 mutant reproduces the reduced
proximal TCR signaling (ERK phosphorylation, CD69 induction, calcium
mobilization).
limitations: >-
A transformed leukemic line with fixed-promoter cDNA expression, not primary
cells; the clonal, supraphysiological context limits quantitative transfer to
the patient's cells.
readouts:
- name: TCR-induced ERK phosphorylation, CD69 expression and calcium mobilization
target: Impaired Proximal TCR Signaling
direction: DECREASED
interpretation: >-
Reduced ERK, CD69 and calcium responses in the mutant-reconstituted line are
the readouts of the proximal TCR-signaling node.
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
were moderately reduced in the mutant SLP76-expressing Jurkat cells, and this
reduction was statistically significant.
explanation: >-
Reports the statistically significant reduction of ERK, CD69 and calcium
responses in the mutant-reconstituted J14 line.
evidence:
- reference: PMID:36474126
reference_title: "SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69
expression, and Ca2 + mobilization, were reduced in cells harboring the reported
mutation
explanation: >-
A second patient's SLP76 mutation, modeled in the same J14 line, likewise
reduces proximal TCR signaling, supporting this model for the node.
- target: Impaired Proximal TCR Signaling
relationship: RESCUES
fidelity: MODERATE
description: >-
Ectopic expression of wild-type SLP-76 in the deficient line rescues the
signaling consequences, confirming the defect is SLP-76-dependent and reversible.
limitations: >-
Rescue is partial and demonstrated in a leukemic cell line rather than in
patient primary cells or in vivo.
evidence:
- reference: PMID:33231617
reference_title: "Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
rescued some consequences using ectopic expression of wild-type SLP76.
explanation: >-
Demonstrates that restoring wild-type SLP-76 rescues the signaling phenotype,
establishing SLP-76 dependence of the node.
discussions:
- discussion_id: slp76_mouse_human_bcell_and_thymic_divergence
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
The germline Slp76-null mouse shows a complete thymic block with no peripheral T
cells and entirely normal B-cell development, whereas human IMD81 patients retain
(dysregulated) peripheral T cells and have a B-cell antigen-receptor signaling
defect with reduced memory B cells and antibody deficiency. Does the complete-null
mouse therefore fail to model the human B-cell arm and overstate the T-cell
developmental block, and is the human phenotype instead captured by hypomorphic
Lcp2 alleles?
attaches_to:
- pathophysiology#Impaired Thymic T-Cell Development
- pathophysiology#Combined T- and B-Cell Immunodeficiency
rationale: >-
This is a model-evidence-exists-and-diverges situation, not an absence of data.
The complete Slp76 null causes an absolute block at the double-negative 3 stage
with no peripheral T cells and normal B-cell development, while human patients
carry hypomorphic or leaky alleles (splice, frameshift, proline-rich-domain
missense) that leave residual SLP-76 and, consequently, dysregulated peripheral T
cells skewed toward CD8 TEMRA plus a B-cell receptor signaling defect the null
does not show. Homozygous Lcp2 splice-hypomorph mice that retain about 10% of
wild-type SLP-76 protein reproduce the human pattern far better (a partial thymic
block with dysregulated peripheral T cells), indicating that model fidelity to
IMD81 depends on residual protein rather than on complete ablation. The B-cell arm
of the human disease is therefore best modeled in patient cells and in the J14
line, not in the null mouse.
proposed_experiments:
- experiment_id: exp_slp76_hypomorph_knockin
name: Knock-in mouse carrying a human hypomorphic LCP2 allele
description: >-
Generate a mouse expressing an actual human IMD81 hypomorphic allele (e.g. the
proline-rich-domain missense or the leaky splice variant) rather than a complete
null, and test whether it reproduces the human combination of dysregulated
peripheral T cells and a B-cell antigen-receptor signaling defect.
- experiment_id: exp_slp76_bcr_signaling
name: B-cell antigen-receptor signaling in a residual-protein model
description: >-
Measure BCR-induced calcium flux and class-switch/memory B-cell generation in a
residual-SLP-76 model to determine whether the human B-cell phenotype requires
partial rather than complete loss of the adaptor.