Mendelian susceptibility to mycobacterial disease (MSMD) due to complete IL-12p40 deficiency is an autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in IL12B, the gene encoding the p40 subunit. It presents as MSMD: a selective predisposition to clinical disease caused by weakly virulent mycobacteria, in particular the Bacille Calmette-Guerin (BCG) vaccine strain and environmental non-tuberculous mycobacteria, together with non-typhoidal salmonellosis, in individuals with otherwise unremarkable routine immunological testing. Almost every genetic etiology of MSMD converges on interferon gamma (IFN-gamma): each either impairs the production of the cytokine or the cellular response to it. IL-12p40 deficiency sits firmly in the production arm, and its molecular logic is the shared-subunit one. The p40 chain encoded by IL12B is not specific to interleukin-12: it pairs with p35 (IL12A) to form the IL-12p70 heterodimer and with p19 (IL23A) to form IL-23. A complete p40 defect therefore abolishes both cytokines at once. Loss of IL-12p70 removes the dominant signal that drives NK and T lymphocytes to produce IFN-gamma, so IFN-gamma-dependent activation of macrophages fails and intramacrophagic mycobacteria and Salmonella replicate unchecked. Loss of IL-23 additionally impairs the IL-23-dependent IL-17 axis, which is why a minority of patients also develop chronic mucocutaneous candidiasis. It was the first human disease shown to result from a cytokine gene defect, reported by Altare and colleagues in 1998 in a child with disseminated BCG and Salmonella enteritidis infection. The largest cohort, 49 patients from 30 kindreds, established the clinical picture: childhood-onset BCG disease (disseminated or regional), recurrent non-typhoidal salmonellosis, high but incomplete clinical penetrance, and a poor prognosis with mortality approaching one third of patients. Almost all reported alleles are private founder mutations concentrated in consanguineous populations of the Middle East, North Africa, and South Asia. The condition is clinically nearly indistinguishable from IL-12 receptor beta-1 (IL-12Rbeta1) deficiency, its downstream counterpart on the same signalling axis. Because the lesion is in cytokine production rather than in the response to IFN-gamma, recombinant IFN-gamma is a mechanistically rational adjunct to antimycobacterial chemotherapy — the therapeutic dividing line within MSMD.
Ask a research question about Mendelian Susceptibility To Mycobacterial Diseases Due To Complete IL12B Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: Mendelian Susceptibility To Mycobacterial Diseases Due To Complete IL12B Deficiency
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
synonyms:
- IL-12p40 deficiency
- Complete IL-12p40 deficiency
- IL-12B deficiency
- MSMD due to complete IL12B deficiency
- Immunodeficiency 29, mycobacteriosis
- IMD29
description: >
Mendelian susceptibility to mycobacterial disease (MSMD) due to complete IL-12p40
deficiency is an autosomal recessive inborn error of immunity caused by biallelic
loss-of-function variants in IL12B, the gene encoding the p40 subunit. It presents as
MSMD: a selective predisposition to clinical disease caused by weakly virulent
mycobacteria, in particular the Bacille Calmette-Guerin (BCG) vaccine strain and
environmental non-tuberculous mycobacteria, together with non-typhoidal salmonellosis,
in individuals with otherwise unremarkable routine immunological testing.
Almost every genetic etiology of MSMD converges on interferon gamma (IFN-gamma):
each either impairs the production of the cytokine or the cellular response to it.
IL-12p40 deficiency sits firmly in the production arm, and its molecular logic is the
shared-subunit one. The p40 chain encoded by IL12B is not specific to interleukin-12:
it pairs with p35 (IL12A) to form the IL-12p70 heterodimer and with p19 (IL23A) to
form IL-23. A complete p40 defect therefore abolishes both cytokines at once. Loss of
IL-12p70 removes the dominant signal that drives NK and T lymphocytes to produce
IFN-gamma, so IFN-gamma-dependent activation of macrophages fails and intramacrophagic
mycobacteria and Salmonella replicate unchecked. Loss of IL-23 additionally impairs the
IL-23-dependent IL-17 axis, which is why a minority of patients also develop chronic
mucocutaneous candidiasis.
It was the first human disease shown to result from a cytokine gene defect, reported by
Altare and colleagues in 1998 in a child with disseminated BCG and Salmonella
enteritidis infection. The largest cohort, 49 patients from 30 kindreds, established the
clinical picture: childhood-onset BCG disease (disseminated or regional), recurrent
non-typhoidal salmonellosis, high but incomplete clinical penetrance, and a poor
prognosis with mortality approaching one third of patients. Almost all reported alleles
are private founder mutations concentrated in consanguineous populations of the Middle
East, North Africa, and South Asia. The condition is clinically nearly indistinguishable
from IL-12 receptor beta-1 (IL-12Rbeta1) deficiency, its downstream counterpart on the
same signalling axis. Because the lesion is in cytokine production rather than in the
response to IFN-gamma, recombinant IFN-gamma is a mechanistically rational adjunct to
antimycobacterial chemotherapy — the therapeutic dividing line within MSMD.
disease_term:
preferred_term: Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency
term:
id: MONDO:0013954
label: Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency
parents:
- Primary immunodeficiency
- Mendelian susceptibility to mycobacterial disease
references:
- reference: PMID:9854038
title: "Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection."
- reference: PMID:23429356
title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
- reference: PMID:29589181
title: "Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia."
- reference: PMID:34134458
title: "Disseminated Mycobacterium simiae Infection in a Patient with Complete IL-12p40 Deficiency."
- reference: PMID:38025345
title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
classifications:
iuis_category:
classification_value: innate immunity defect
notes: >-
IUIS phenotypic classification of inborn errors of immunity, Mendelian
susceptibility to mycobacterial disease (MSMD) table. This entry is the IL12B
(IL-12p40) etiology of MSMD, a defect of IL-12/IL-23-dependent IFN-gamma immunity.
evidence:
- reference: PMID:38025345
reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mendelian susceptibility to mycobacterial diseases (MSMD) is the most characterized
of these IEIs, with 36 different disorders found in 20 distinct genes (IFNGR1,
IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1,
TYK2, IRF8, IRF1, CYBB, JAK1, RORC, NEMO, and SPPL2A)
explanation: >-
Places IL12B in the established gene set of Mendelian susceptibility to
mycobacterial disease, the inborn-error-of-immunity syndrome under which this
entry is classified.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: UNKNOWN
notes: >-
No population rate has been established. The largest series reported 49 patients from
30 kindreds across five countries (India, Iran, Pakistan, Saudi Arabia, Tunisia), and
IL-12p40 deficiency was estimated to account for less than 9% of MSMD cases. Almost
all patients carry private founder alleles concentrated in consanguineous populations,
and no patient had been diagnosed in a low-consanguinity country at the time of that
review, so the count reflects ascertainment as much as true frequency. Recorded as a
literature case count rather than a rate for that reason.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report the genetic, immunologic, and clinical features of 49 patients from 30
kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and
Tunisia).
explanation: >-
Gives the size and geographic distribution of the largest reported cohort, the basis
for treating occurrence as a literature case count.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IL-12p40 deficiency is therefore thought to be a very rare genetic etiology of MSMD,
estimated to account for less than 9% of cases.
explanation: >-
States the rarity of this etiology as a fraction of MSMD, supporting an UNKNOWN
population-rate class.
clinical_burden:
burden_level: HIGH
rationale: >-
Untreated or late-recognised disease is frequently fatal in early childhood.
Disseminated BCG disease is the dominant presentation and the leading cause of death,
global mortality approaches one third of patients, and the mean age at death is about
7 years. Even survivors require prolonged multidrug antimycobacterial chemotherapy and,
for the production-defect etiology, adjunctive recombinant IFN-gamma. Burden is
tempered by the incomplete penetrance and the relatively favourable outcome compared
with IFN-gamma receptor defects, but the mortality figures place the disease-level
burden at HIGH.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
However, the prognosis is poor, with mortality rates of up to 28.6%.
explanation: >-
States the poor prognosis and the global (all-patient) mortality figure driving the
HIGH burden assessment.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mortality rate among symptomatic patients was 31.8% (14 of 44 symptomatic patients)
explanation: >-
Gives the mortality rate restricted to symptomatic patients, the more direct burden
figure for clinically affected individuals.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mean age at death was 7.1 years for the 14 IL-12p40-deficient patients who died
explanation: >-
Establishes childhood as the typical age at death, underscoring the early-life
lethality behind the burden level.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
penetrance: INCOMPLETE
penetrance_percentage: >-
~80% overall (lifetime); Kaplan-Meier estimate 0.45 by 7 months rising to 0.71 by 48
months; 33.3% of genetically affected relatives remain asymptomatic
description: >
Disease requires biallelic loss-of-function IL12B variants. Affected individuals are
homozygous (or compound heterozygous) for null alleles; consanguinity is the rule in
reported kindreds, and heterozygous relatives are healthy. Clinical penetrance is high
but incomplete: a third of genetically affected relatives of index cases are
asymptomatic, and the age-dependent penetrance of infection rises from 0.45 at 7 months
to 0.71 by 48 months of age.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients are homozygous and display complete IL-12p40 deficiency.
explanation: >-
Establishes the recessive, biallelic-null genetic architecture across the cohort.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of
genetically affected relatives of index cases showing no symptoms.
explanation: >-
Quantifies the incomplete penetrance: a third of genotype-positive relatives never
develop symptoms, the basis for the INCOMPLETE penetrance classification.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
increased rapidly from 0.45 (95% CI, 0.1–0.65) at the age of 7 months, to 0.71 (95%
CI, 0.29–0.88) by the age of 48 months
explanation: >-
Gives the age-dependent (Kaplan-Meier) penetrance of infection underlying the
penetrance_percentage estimate.
genetic:
- name: IL12B
gene_term:
preferred_term: IL12B
term:
id: hgnc:5970
label: IL12B
association: CAUSATIVE
variant_origin: GERMLINE
features: >
IL12B encodes the p40 subunit shared by interleukin-12 (p35/p40) and interleukin-23
(p19/p40). Disease alleles are biallelic loss-of-function variants — small insertions
and deletions, splice-site changes, nonsense variants, and one large deletion — each
producing a frameshift or premature stop and abolishing p40 protein. Reported patients
are homozygous and display complete IL-12p40 deficiency, with no detectable IL-12p40 or
IL-12p70. Most alleles are private founder mutations restricted to a single ethnic
group (e.g. c.315insA in Saudi Arabia, c.297del8 in Tunisia, c.526del2 in Iran).
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3
small deletions, 2 splice site mutations, and 1 large deletion, each causing a
frameshift and leading to a premature stop codon, and 1 nonsense mutation.
explanation: >-
Enumerates the loss-of-function allele classes in IL12B responsible for the disease.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Individuals with IL12B mutations therefore have defects in both IL-12 and IL-23
immunity.
explanation: >-
Establishes that the IL12B lesion is a combined IL-12 and IL-23 defect, because p40
is shared by both cytokines.
- reference: PMID:9854038
reference_title: "Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding
expression of functional IL-12 p70 cytokine by activated dendritic cells and
phagocytes.
explanation: >-
The founding report identifying a homozygous IL12B (p40) deletion as the causal
lesion abolishing functional IL-12.
pathophysiology:
- name: IL12B Loss of Function
biological_scale: MOLECULAR
genetic_context:
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
description: >
The initiating lesion is biallelic loss of function of IL12B, abolishing the p40
protein. Because p40 is an obligate subunit of both IL-12p70 (p35/p40) and IL-23
(p19/p40), a complete p40 defect prevents assembly and secretion of both cytokines by
activated macrophages and dendritic cells.
downstream:
- target: Absent IL-12 and IL-23 Cytokine Production
causal_link_type: DIRECT
description: >-
Loss of the shared p40 subunit prevents assembly of both IL-12p70 and IL-23, so
neither heterodimer is produced.
evidence:
- reference: PMID:9854038
reference_title: "Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding
expression of functional IL-12 p70 cytokine by activated dendritic cells and
phagocytes.
explanation: >-
States that the p40 lesion precludes production of functional IL-12 by antigen
presenting cells, which is this causal step.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients are homozygous and display complete IL-12p40 deficiency.
explanation: >-
Establishes complete loss of the p40 protein as the initiating molecular state.
- name: Absent IL-12 and IL-23 Cytokine Production
biological_scale: MOLECULAR
description: >
With no p40 subunit, activated macrophages and dendritic cells secrete neither
IL-12p70 nor IL-23. IL-12p70 is the principal inducer of IFN-gamma by NK and T
lymphocytes; IL-23 drives the IL-17-producing T-cell program. The single subunit
defect therefore removes two effector cytokines at once.
biological_processes:
- preferred_term: interleukin-12 production
term:
id: GO:0032615
label: interleukin-12 production
modifier: DECREASED
- preferred_term: interleukin-23 production
term:
id: GO:0032627
label: interleukin-23 production
modifier: DECREASED
cell_types:
- preferred_term: dendritic cell
term:
id: CL:0000451
label: dendritic cell
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
downstream:
- target: Impaired IL-12-Dependent IFN-gamma Production
causal_link_type: DIRECT
description: >-
Loss of IL-12p70 removes the dominant signal driving IFN-gamma production by NK and
T cells.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
plays a major role in inducing the production of IFN-γ by NK and T lymphocytes.
explanation: >-
States that IL-12p70 induces IFN-gamma production by NK and T cells, so its absence
drives this downstream step.
- target: Impaired IL-23-Dependent IL-17 Immunity
causal_link_type: DIRECT
description: >-
Loss of IL-23 impairs the induction of IL-17-producing T cells.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
it can also associate with the IL-23p19 subunit to form IL-23, which is involved in
the induction of IL-17-producing T cells.
explanation: >-
States that IL-23 induces IL-17-producing T cells, the axis lost through the same
p40 defect.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels
of interferon gamma (IFN-γ).
explanation: >-
Documents the absence of detectable IL-12p70 downstream of the p40 defect.
- name: Impaired IL-12-Dependent IFN-gamma Production
biological_scale: CELLULAR
description: >
Without IL-12p70 the NK and T lymphocytes that supply IFN-gamma in response to
mycobacterial challenge produce markedly reduced amounts of the cytokine. IFN-gamma
production is not abolished — residual IL-12-independent secretion persists, which is
why the clinical phenotype is milder than in complete IFN-gamma receptor deficiency —
but it is insufficient for protective anti-mycobacterial immunity.
biological_processes:
- preferred_term: type II interferon (IFN-gamma) production
term:
id: GO:0032609
label: type II interferon production
modifier: DECREASED
cell_types:
- preferred_term: natural killer cell
term:
id: CL:0000623
label: natural killer cell
- preferred_term: T-helper 1 cell
term:
id: CL:0000545
label: T-helper 1 cell
downstream:
- target: Failed IFN-gamma-Dependent Macrophage Activation
causal_link_type: DIRECT
description: >-
Reduced IFN-gamma output fails to deliver the macrophage-activating signal needed to
kill intracellular mycobacteria.
evidence:
- reference: PMID:9854038
reference_title: "Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
As a result, IFN-gamma production by lymphocytes was markedly impaired.
explanation: >-
Documents markedly impaired IFN-gamma production, the immediate consequence feeding
the macrophage-activation failure.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The leukocytes of the patients described here displayed complete IL-12p40 and
IL-12p70 deficiencies and impaired, but not abolished, IFN-γ production.
explanation: >-
Establishes that IFN-gamma production is impaired but not abolished, the defining
quantitative feature of this node.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Stimulation with a combination of IL-12 plus BCG increased IFN-γ levels in the whole
blood of IL-12p40-deficient patients
explanation: >-
Adding exogenous IL-12 partially rescues IFN-gamma output in patient whole blood,
directly demonstrating that the IFN-gamma defect is downstream of, and dependent on,
the missing IL-12 signal.
- name: Failed IFN-gamma-Dependent Macrophage Activation
biological_scale: CELLULAR
description: >
IFN-gamma is the signal that licenses macrophages to kill the intracellular
mycobacteria and Salmonella they harbour. With IFN-gamma output insufficient, infected
macrophages are not activated and cannot restrict microbial growth. This is the shared
final mechanism across MSMD etiologies: the disease is defined by insufficient
IFN-gamma-mediated immunity, whether the lesion is in cytokine production (as here) or
in the response to the cytokine.
biological_processes:
- preferred_term: macrophage activation
term:
id: GO:0042116
label: macrophage activation
modifier: DECREASED
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
downstream:
- target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
causal_link_type: DIRECT
description: >-
Without macrophage activation the intracellular organisms are not killed and
replicate.
evidence:
- reference: PMID:38025345
reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
almost all genetic etiologies of MSMD alter the interferon-gamma (IFN-γ)- mediated
immunity by impairing or abolishing IFN-γ production or the response to this cytokine.
explanation: >-
Establishes impaired IFN-gamma-mediated immunity as the convergent mechanism of MSMD,
which is what fails at this node.
- name: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
biological_scale: ORGANISM
description: >
The organism-level consequence is disseminated or recurrent infection by intracellular
pathogens that a competent IFN-gamma response would contain: the BCG vaccine strain,
environmental non-tuberculous mycobacteria, Mycobacterium tuberculosis, and
non-typhoidal Salmonella. This node initiates the infectious phenotypes.
downstream:
- target: Disseminated BCG disease
- target: Non-tuberculous mycobacterial infection
- target: Non-typhoidal salmonellosis
- target: Nocardiosis
evidence:
- reference: PMID:9854038
reference_title: "Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It suggests that IL-12 is essential to and appears specific for protective immunity
to intracellular bacteria such as mycobacteria and salmonella.
explanation: >-
Ties loss of IL-12-mediated immunity to failed control of intracellular mycobacteria
and Salmonella, the pathogens that replicate at this node.
- name: Impaired IL-23-Dependent IL-17 Immunity
biological_scale: CELLULAR
description: >
A second, distinct arm follows from the same shared-subunit defect. Loss of IL-23
impairs the development and maintenance of IL-17-producing T cells, reducing mucosal
IL-17-dependent antifungal defence. This underlies the chronic mucocutaneous
candidiasis seen in a minority of patients, and is mechanistically separate from the
IFN-gamma arm that causes the mycobacterial disease.
biological_processes:
- preferred_term: interleukin-17 production
term:
id: GO:0032620
label: interleukin-17 production
modifier: DECREASED
downstream:
- target: Chronic mucocutaneous candidiasis
- target: Klebsiella infection
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
some suffer from Candida albicans infections because of impaired IL-23-dependent
IL-17 immunity.
explanation: >-
States that impaired IL-23-dependent IL-17 immunity underlies the candidiasis arm of
the disease.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IL-12p40-deficient patients have a lower than normal percentage of CD3+IL-17A+ cells
ex vivo.
explanation: >-
Direct ex vivo cellular readout of the impaired IL-17 arm: patients carry a reduced
fraction of IL-17A-producing T cells, grounding this node rather than only its
clinical candidiasis consequence.
phenotypes:
- category: Infectious
name: Disseminated BCG disease
description: >
Disease caused by the M. bovis BCG vaccine strain following routine vaccination, most
often disseminated (BCG-osis) but also regional (BCG-itis). In endemic countries this
is typically the presenting event, since BCG given at birth is the first mycobacterial
challenge an affected infant meets. In the largest cohort, BCG vaccination caused
disease in 40 of 41 vaccinated patients.
phenotype_term:
preferred_term: BCGosis
term:
id: HP:0020087
label: BCGosis
onset:
onset_category: INFANTILE
mean_age_years: 0.75
notes: >-
BCG disease is the earliest and most frequent presentation, with a mean age at
onset of about 9 months (as young as 1 month); it is typically the first
mycobacterial challenge an affected infant meets. Overall first clinical symptoms
of the disease occur at a mean age of 1.1 years.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%).
explanation: >-
Quantifies BCG disease as the near-universal outcome of vaccination in this disease.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
with a mean age at onset of 9 months
explanation: >-
Gives the infantile mean age at onset of BCG disease that grounds the onset
descriptor.
- reference: PMID:9854038
reference_title: "Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A child with bacille Calmette-Guérin and Salmonella enteritidis infection was
investigated.
explanation: >-
The index patient presented with BCG (and Salmonella) infection, the defining
presentation of this disease.
- category: Infectious
name: Non-tuberculous mycobacterial infection
description: >
Susceptibility to weakly virulent environmental non-tuberculous mycobacteria. In
countries that do not vaccinate with BCG, these organisms rather than the vaccine
strain are the usual precipitant. Susceptibility also extends to severe forms of
Mycobacterium tuberculosis.
phenotype_term:
preferred_term: Non-tuberculous mycobacterial infection
term:
id: HP:5210115
label: Non-tuberculous mycobacterial infection
evidence:
- reference: PMID:38025345
reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MSMD confers a selective susceptibility to infections with weakly virulent
mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines and
various environmental mycobacteria in patients, primarily children, without classical
immune defects.
explanation: >-
Establishes susceptibility to environmental mycobacteria as a defining feature of
MSMD, the syndrome this IL12B etiology produces.
- reference: PMID:34134458
reference_title: "Disseminated Mycobacterium simiae Infection in a Patient with Complete IL-12p40 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A homozygous mutation in the IL12B gene, c.527_528delCT (p.S176Cfs*12) was
identified, responsible for the complete IL-12p40 deficiency.
explanation: >-
A worked case of disseminated environmental (M. simiae) mycobacterial infection
caused specifically by complete IL-12p40 deficiency.
- category: Infectious
name: Non-typhoidal salmonellosis
description: >
Non-typhoidal salmonellosis, often disseminated and recurrent, reflecting the same
dependence on IFN-gamma-activated macrophages for control of intracellular bacteria.
In the largest cohort salmonellosis occurred in about a quarter of patients, and
recurrences of salmonellosis were more frequent than recurrences of mycobacterial
disease. It may be the sole presenting infection in unvaccinated patients.
phenotype_term:
preferred_term: Non-typhoidal salmonellosis
term:
id: HP:5210093
label: Unusual Salmonella infection
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical features are characterized by childhood onset of bacille Calmette-Guérin
(attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with
recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial
disease (25%).
explanation: >-
Establishes non-typhoidal salmonellosis, with a high recurrence rate, as a core
clinical feature of the disease.
- category: Infectious
name: Chronic mucocutaneous candidiasis
description: >
A minority of patients develop mucocutaneous Candida albicans infection (oral thrush
or disseminated candidiasis), attributed to the impaired IL-23-dependent IL-17 immunity
that follows loss of the shared p40 subunit. It is less frequent here than in
IL-12Rbeta1 deficiency.
phenotype_term:
preferred_term: Chronic mucocutaneous candidiasis
term:
id: HP:0002728
label: Chronic mucocutaneous candidiasis
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three patients displayed Candida albicans infections
explanation: >-
Records mucocutaneous candidiasis in a subset of the cohort, the minor IL-23/IL-17
arm of the disease.
- category: Infectious
name: Nocardiosis
description: >
A minority of patients develop nocardiosis. Nocardia is an intramacrophagic pathogen
phylogenetically close to Mycobacterium, so its control shares the same
IFN-gamma-dependent macrophage-activation requirement that fails in this disease. Both
reported cases occurred alongside BCG disease.
phenotype_term:
preferred_term: Nocardiosis
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Nocardia, an intramacrophagic pathogen closely phylogenetically related to
Mycobacterium, caused disease in 2 patients
explanation: >-
Records nocardiosis in the cohort and ties it to the shared intramacrophagic,
IFN-gamma-dependent mechanism.
- category: Infectious
name: Klebsiella infection
description: >
Klebsiella pneumoniae infection was reported in one patient. Klebsiella is a
gram-negative enterobacterium related to Salmonella whose clearance depends on the
IL-17/IL-23 axis, the same axis impaired by loss of the shared p40 subunit.
phenotype_term:
preferred_term: Klebsiella infection
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Klebsiella pneumoniae, a gram-negative enterobacterium closely related to Salmonella,
caused disease in 1 patient
explanation: >-
Records klebsiellosis in the cohort as part of the pathogen spectrum of this disease.
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both IL-17 and IL-23 have been shown to be important for the immune responses to
Klebsiella and Salmonella.
explanation: >-
Establishes the IL-17/IL-23 dependence of Klebsiella immunity, the mechanistic basis
for susceptibility here.
- category: Laboratory
name: Decreased circulating interferon-gamma
description: >
Whole-blood or PBMC IFN-gamma output after mycobacterial (BCG) stimulation is low,
reflecting the loss of the IL-12 signal that normally drives it. IFN-gamma is reduced
rather than absent, distinguishing this production defect from a response defect.
phenotype_term:
preferred_term: Reduced IFN-gamma production on BCG stimulation
term:
id: HP:0033253
label: Reduced circulating interferon gamma concentration
notes: >-
Concept-fit caveat: HP:0033253 names a reduced *circulating* IFN-gamma concentration,
whereas the cited measurement is reduced IFN-gamma *production* by BCG-stimulated
whole-blood/PBMC cells ex vivo. The binding is retained as the closest available HP
term, and preferred_term states the specific production-assay reading; the term is
slightly broader than the assay, not a false match.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
following stimulation with BCG, the patients’ cells produced significantly less IFN-γ
than the cells of healthy travel controls (p < 0.001)
explanation: >-
Quantifies the reduced IFN-gamma output on BCG stimulation that defines this
laboratory phenotype.
reports_on:
- target: Impaired IL-12-Dependent IFN-gamma Production
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
interpretation: >-
The measurement of that node, and the assay this diagnosis is made on.
Recorded as an observational readout rather than a causal edge: deficient
IFN-gamma production is the node being measured, not something the node
causes. Note the cited assays measure stimulated production rather than a
resting circulating level, which is the distinction this entry's notes
are written to preserve.
biochemical:
- name: Undetectable IL-12p40 and IL-12p70
presence: Absent
context: >-
The defining laboratory signature of complete IL-12p40 deficiency. On whole-blood or
EBV-B-cell stimulation neither IL-12p40 nor the IL-12p70 heterodimer is detectable,
because the shared p40 subunit is absent. This is measured by ELISA on BCG-stimulated
supernatants and distinguishes a production defect from a receptor/response defect.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patients lack detectable IL-12p70 and IL-12p40
explanation: >-
Establishes undetectable IL-12p40 and IL-12p70 as the biochemical hallmark of the
complete deficiency.
diagnosis:
- name: Whole blood IL-12 / IFN-gamma activation test
description: >
The functional screening assay for MSMD. Whole blood is stimulated with BCG, and the
production of IL-12 and IFN-gamma and the response to those cytokines are measured,
localising the lesion to the production or the response arm before any gene is named.
In IL-12p40 deficiency the expected pattern is undetectable IL-12p40 and IL-12p70 with
reduced IFN-gamma that rises toward normal when exogenous IL-12 is supplied.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The whole-blood cells of patients stimulated with live BCG alone or BCG plus exogenous
recombinant IFN-γ produced no IL-12p40, whereas IL-12p40 was generated by the cells of
healthy controls
explanation: >-
Describes the functional assay result that localises the lesion to IL-12p40
production.
- name: IL12B sequencing
description: >
Molecular confirmation identifies the biallelic IL12B loss-of-function genotype and
assigns the etiology. This matters clinically because the therapeutic split within MSMD
turns on whether the defect is in IFN-gamma production or in the response to it.
evidence:
- reference: PMID:29589181
reference_title: "Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene,
resulting in complete IL12p40 deficiency.
explanation: >-
Illustrates genetic confirmation of a homozygous IL12B null allele establishing the
diagnosis.
treatments:
- name: Antimycobacterial Therapy
description: >
Prolonged multidrug antimycobacterial chemotherapy is the mainstay of managing the
mycobacterial disease itself and is required regardless of the underlying immune
defect. Regimen composition should follow species identification and susceptibility
testing — drug-resistant BCG strains are reported — rather than being applied as a
fixed block; this entry does not assert a specific regimen or duration. It treats the
infection, not the immune defect.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: multidrug antimycobacterial chemotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: antitubercular agent
term:
id: NCIT:C280
label: Antitubercular Agent
- preferred_term: rifampicin
term:
id: CHEBI:28077
label: rifampicin
- preferred_term: isoniazid
term:
id: CHEBI:6030
label: isoniazide
target_mechanisms:
- target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
treatment_effect: INHIBITS
description: >-
Antimycobacterial drugs act directly on the organism, substituting pharmacological
killing for the macrophage-mediated killing the host cannot perform.
evidence:
- reference: PMID:29589181
reference_title: "Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Treatment with rifampin, isoniazid, ethambutol and streptomycin was initiated
explanation: >-
Documents multidrug antimycobacterial chemotherapy as the treatment applied in
IL12B-deficient patients.
- name: Recombinant Interferon Gamma
description: >
Subcutaneous recombinant IFN-gamma is the mechanistically indicated adjunct for this
etiology. The IL12B lesion impairs IFN-gamma production while leaving the IFN-gamma
receptor and downstream JAK-STAT1 machinery intact, so exogenous cytokine engages a
competent receptor and restores macrophage activation. This is the therapeutic dividing
line within MSMD: production defects such as IL-12p40 deficiency are candidates for
recombinant IFN-gamma, whereas defects abolishing the response to the cytokine are
managed with transplantation or gene therapy. It is given together with antibiotics,
not in place of them, and outcomes remain guarded.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: interferon gamma-1b
term:
id: NCIT:C100089
label: Interferon Gamma-1b
target_mechanisms:
- target: Failed IFN-gamma-Dependent Macrophage Activation
treatment_effect: ACTIVATES
description: >-
Exogenous recombinant IFN-gamma supplies the cytokine the IL-12-deprived lymphocyte
compartment cannot make, to a structurally intact receptor, restoring the
macrophage-activating signal.
evidence:
- reference: PMID:38025345
reference_title: "Mendelian susceptibility to mycobacterial diseases: State of the puzzle."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MSMD patients with impaired production of IFN-γ may benefit from injections of human
recombinant IFN-γ, while for patients with abolished response to this cytokine,
hematopoietic stem cell transplantation (HSCT) and promising gene therapy are the
only current therapeutic options.
explanation: >-
States the production-versus-response therapeutic split that places IL-12p40
deficiency, a production defect, on the recombinant IFN-gamma side.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Only 12 of 44 symptomatic patients received human recombinant IFN-γ together with
specific antibiotic treatment during infection
explanation: >-
Documents recombinant IFN-gamma being administered as an adjunct to antibiotics in
IL-12p40-deficient patients.
- name: Avoidance of BCG Vaccination
description: >
Live BCG vaccine is the commonest trigger of disease in MSMD, so it is contraindicated
in an affected child and should be delayed in at-risk newborn siblings pending genetic
testing. Because in endemic countries BCG is given at birth, the vaccine is frequently
administered before any diagnosis is possible.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: avoidance of live BCG vaccination
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
treatment_effect: INHIBITS
description: >-
Withholding the live vaccine removes the mycobacterial challenge that the
IFN-gamma-deficient host cannot contain.
evidence:
- reference: PMID:29589181
reference_title: "Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BCG vaccination should be re-evaluated and formally contraindicated in newborns with
siblings and relatives with a history of MSMD, to prevent life-threatening
complications of BCG infection.
explanation: >-
States the contraindication of BCG in affected families, the actionable preventive
content of this entry.
environmental:
- name: Bacille Calmette-Guerin (BCG) vaccination
description: >
Routine BCG immunisation is the sentinel environmental exposure in this disorder. The
attenuated Mycobacterium bovis BCG strain is harmless to immunocompetent infants but
disseminates in a host that cannot mount IFN-gamma-dependent macrophage activation,
which is how patients typically come to attention. In endemic countries the vaccine is
given at birth, so the exposure almost always precedes any possibility of diagnosis.
exposure_term:
preferred_term: exposure to Bacille Calmette-Guerin vaccine
term:
id: ECTO:2000129
label: exposure to vaccination
influences_mechanisms:
- target: Uncontrolled Intramacrophage Replication of Weakly Virulent Mycobacteria and Salmonella
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: >-
The live BCG strain is the mycobacterial challenge that the IFN-gamma-deficient host
cannot contain, initiating disseminated disease.
evidence:
- reference: PMID:23429356
reference_title: "Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%).
explanation: >-
Establishes BCG vaccination as the trigger of disease in nearly all vaccinated
patients.
notes: >-
The binding is deliberately broader than the exposure. ECTO has no BCG-, Calmette- or
M. bovis-specific exposure class: `runoak -i sqlite:obo:ecto search "l~BCG"`,
`"l~Calmette"` and `"l~bacille"` each return nothing, and `"l~mycobacter"` returns
only pathogen exposure classes for M. tuberculosis and M. avium and exposures to
antimycobacterial drugs, none of which is a vaccine. ECTO:2000129 exposure to
vaccination is the most specific true class available, and preferred_term carries the
vaccine identity.
evidence:
- reference: PMID:29589181
reference_title: "Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the three patients identified in this study had the same infectious phenotype,
characterized by BCG disease, with an onset a few months after BCG vaccination.
explanation: >-
Ties the BCG vaccination exposure to onset of disease a few months later in
IL12B-deficient patients.