Interleukin-10 Receptor Deficiency

Mendelian MONDO:0013153 Pathograph 6 Show in embeddings browser

Interleukin-10 receptor deficiency is an autosomal recessive monogenic form of very-early-onset inflammatory bowel disease and the archetype of the immune-mediated congenital enteropathies - the class that the three epithelial CODE mechanism modules explicitly exclude, because here the intestinal epithelium is intrinsically normal and is damaged secondarily by unrestrained immune activity. Biallelic loss-of-function variants in IL10RA or IL10RB disable the two chains of the interleukin-10 receptor, a heterotetramer of two IL10R1 (IL10RA) and two IL10R2 (IL10RB) subunits. Interleukin-10 is the principal brake on inflammatory cytokine output, so losing its receptor abolishes the negative-feedback loop that normally restrains myeloid cells: IL-10 fails to trigger JAK1/Tyk2-dependent STAT3 phosphorylation, and patient mononuclear cells secrete excess tumour necrosis factor alpha and other proinflammatory cytokines. In the gut - which is under continuous microbial stimulation and therefore most dependent on this brake - the result is severe enterocolitis presenting in the first months of life, with perianal disease, abscesses and enterocutaneous fistulas that are characteristically refractory to the entire conventional armamentarium including corticosteroids, immunosuppressants and anti-TNF antibodies. That refractoriness is mechanistically expected rather than incidental: blocking one downstream cytokine cannot substitute for a missing master regulator. Allogeneic haematopoietic stem-cell transplantation, which replaces the patient's myeloid compartment with cells carrying a functional receptor, is the definitive treatment and induced remission in the index case. Note that IL10R2 is shared by the receptors for interleukin-22 and interleukin-26, so IL10RB deficiency is not strictly confined to interleukin-10 signalling.

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Mappings

MONDO

MONDO:0012941 inflammatory bowel disease 25 Not Yet Curated

MONDO splits interleukin-10 receptor deficiency by receptor chain, with MONDO:0013153 (IBD28) for IL10RA and MONDO:0012941 (IBD25) for IL10RB, and provides no umbrella term for the receptor. This entry curates the receptor as one disease because both chains form a single heterotetramer and their loss produces the same clinical and functional phenotype, so IBD25 is a narrower concept fully covered here rather than a separate disease.

👪

Inheritance

Autosomal recessive inheritance HP:0000007

Autosomal recessive. The two index families were consanguineous - the first Turkish with first-cousin parents, the second of Lebanese descent - and all identified variants were homozygous.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB"

Documents homozygous variants in affected children from consanguineous families, the expected pattern for recessive inheritance.

◆

Subtypes

IL10RA deficiency (inflammatory bowel disease 28) MONDO:0013153

IL10RA hgnc:5964

Loss of the IL10R1 alpha chain, which is specific to the interleukin-10 receptor, so the defect is confined to interleukin-10 signalling.

IL10RB deficiency (inflammatory bowel disease 25) MONDO:0012941

IL10RB hgnc:5965

Loss of the IL10R2 beta chain, which is shared with the interleukin-22 and interleukin-26 receptors, so signalling through those cytokines is lost as well. Clinically similar to the IL10RA form.

⚙

Pathophysiology

Loss of a Functional Interleukin-10 Receptor

The initiating lesion. The interleukin-10 receptor is a heterotetramer of two IL10R1 chains (IL10RA) and two IL10R2 chains (IL10RB); biallelic loss of either chain prevents assembly of a signalling-competent receptor. The two genotypes are not quite equivalent, and the entry preserves the difference: IL10R1 is specific to this receptor, whereas IL10R2 is shared with the interleukin-22 and interleukin-26 receptors, so IL10RB deficiency additionally removes those signals.

Interleukin-10 receptor activity GO:0004920 ⇓ LOSS OF FUNCTION

Downstream

Abolished IL-10-Induced STAT3 Signaling

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"The receptor for interleukin-10 consists of two alpha molecules (IL10R1) and two beta molecules (IL10R2)."

Describes the receptor architecture whose disruption defines this node.

Abolished IL-10-Induced STAT3 Signaling

The rate-limiting step, and the one directly measured in patients. Assembly of the intact receptor normally activates the receptor-associated Janus kinases JAK1 and Tyk2, which phosphorylate STAT3 and induce STAT3-dependent genes. In patient peripheral-blood mononuclear cells, stimulation with interleukin-10 fails to produce STAT3 phosphorylation - a functional assay that confirms the variants are not merely present but signalling-dead, and that localises the block to the receptor-proximal step rather than to interleukin-10 production.

Peripheral-blood mononuclear cell CL:0000842

JAK-STAT signaling downstream of the IL-10 receptor GO:0007259 ↓ DECREASED

Downstream

Loss of Negative Feedback on Proinflammatory Cytokine Output

Show evidence (1 reference)

PMID:19890111 SUPPORT In Vitro

"The mutations abrogate interleukin-10-induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10."

Functional demonstration that the variants abolish receptor signalling, measured as absent STAT3 phosphorylation on IL-10 stimulation. Evidence source is IN_VITRO because the assay was performed on patients' isolated mononuclear cells.

Loss of Negative Feedback on Proinflammatory Cytokine Output

The effector step. Interleukin-10 restricts excessive immune responses, limiting secretion of proinflammatory cytokines such as tumour necrosis factor alpha and interleukin-12 from myeloid and other cells. Without receptor signalling this brake is released, and patient mononuclear cells show increased secretion of TNF-alpha and other proinflammatory cytokines. The lesion is therefore a loss of regulation rather than a gain of a pathogenic signal - the immune system is not driven abnormally so much as left unrestrained, which is what makes the disease continuous and self-sustaining wherever immune stimulation is continuous.

Peripheral-blood mononuclear cell CL:0000842

Negative regulation of TNF production GO:0032720 ⇓ LOSS OF FUNCTION Tumor necrosis factor production GO:0032640 ↑ INCREASED

Downstream

Hyperinflammatory Enterocolitis

Show evidence (1 reference)

PMID:19890111 SUPPORT In Vitro

"Consistent with this observation was the increased secretion of tumor necrosis factor alpha and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10-dependent "negative feedback"..."

Directly demonstrates the disrupted negative feedback this node models, in patient cells. Evidence source is IN_VITRO because cytokine secretion was measured in isolated mononuclear cells.

Hyperinflammatory Enterocolitis

The clinical output, and the reason the gut bears the brunt of a systemic regulatory defect: the intestine is under continuous microbial stimulation and is therefore the tissue most dependent on the interleukin-10 brake. The result is severe enterocolitis in the first months of life with multifocal ulceration, polymorphic inflammatory infiltrates, intramural abscesses extending into submucosa and muscularis, perianal abscesses, and enterocutaneous and rectovaginal fistulas often requiring repeated bowel resection and stoma formation. The epithelium here is intrinsically normal; it is damaged by the unrestrained inflammatory response around it, which is what places this disease in the immune-mediated rather than the epithelial class of congenital enteropathies.

Colon UBERON:0001155

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine."

States the clinical output of the chain and attributes it explicitly to hyperinflammatory immune responses in the intestine.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 2

Early-Onset Colitis OBLIGATE HP:0002583

Temporal: CHRONIC

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis"

Establishes early-onset enterocolitis as the defining clinical feature of the disorder, supporting the OBLIGATE band.

Perianal Abscess HP:0009789

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"presented at the age of 3 months with proctitis and abscesses in the peri-anal region, which required multiple surgical interventions"

Documents perianal abscesses at presentation and their surgical burden in the index patient. No frequency band is asserted: the cited report describes individual patients narratively rather than reporting a frequency, so it supports the association but not a band.

Immune 1

Recurrent Infections OCCASIONAL HP:0002719

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"Recurrent infections such as otitis media, bronchitis, and two episodes of purulent gonarthritis were potentially linked to immunosuppressive therapy."

Documents the infections and, importantly, the authors' own attribution of them to immunosuppressive therapy - which is why this is curated as OCCASIONAL and flagged as not necessarily intrinsic.

Other 1

Anal Fistula HP:0010447

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"Multiple enterocutaneous fistulas originating from the small intestine required further partial bowel resections and ileostomy."

Documents the fistulating disease and the resections it necessitated. The HP term Anal fistula is the closest available match; the preferred_term records the broader fistulating phenotype actually described, which includes enterocutaneous and rectovaginal fistulas. No frequency band is asserted, for the same reason as the perianal abscess phenotype above.

🧬

Genetic Associations

IL10RA loss-of-function variants (Causative)

Gene: IL10RA hgnc:5964 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor"

The gene-discovery report identifying both receptor chains as disease genes and stating that they assemble into one heterotetrameric receptor - the basis for curating them as one disease here.

IL10RB loss-of-function variants (Causative)

Gene: IL10RB hgnc:5965 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"Although IL10R1 is specific to the interleukin-10 receptor, IL10R2 is a subunit of the receptors for several additional cytokines (e.g., interleukin-22 and interleukin-26)."

Establishes the asymmetry between the two chains that distinguishes the two genetic forms: IL10R2 is shared with the interleukin-22 and -26 receptors, so its loss is not confined to interleukin-10 signalling.

💊

Medical Actions

Allogeneic Hematopoietic Stem-Cell Transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

The definitive treatment, and the one that follows from the mechanism: replacing the haematopoietic compartment supplies myeloid cells carrying a functional interleukin-10 receptor, restoring the negative-feedback brake that the patient's own cells cannot exert. It was performed in the index patient and induced remission. This is a rare instance in the congenital enteropathies where a curative therapy targets the causal mechanism rather than replacing lost intestinal function.

Mechanism Target:

RESTORES Loss of Negative Feedback on Proinflammatory Cytokine Output — Donor-derived myeloid cells express a functional interleukin-10 receptor and can therefore respond to interleukin-10, restoring the negative feedback on proinflammatory cytokine output that the patient's own cells have lost.

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"Allogeneic stem-cell transplantation resulted in disease remission in one patient."

Documents the clinical outcome of transplantation. Note this is a single patient in the original report, so the evidence base for this treatment at the time of the cited study is one case, not a series.

Conventional Anti-Inflammatory and Anti-TNF Therapy

Action: Pharmacotherapy NCIT:C15986

Curated as a treatment that FAILS, because its failure is mechanistically informative rather than incidental. Corticosteroids, methotrexate, thalidomide, azathioprine and anti-TNF-alpha monoclonal antibodies were all used in the index patients and none induced remission or long-term improvement, even alongside total colectomy. Blocking one downstream cytokine cannot replace a missing master regulator of the whole inflammatory programme, so refractoriness to conventional therapy is a diagnostic clue to monogenic very-early-onset inflammatory bowel disease rather than a reason to escalate it.

Mechanism Target:

MODULATES Hyperinflammatory Enterocolitis — Conventional immunosuppression and anti-TNF therapy act downstream of the receptor defect and do not restore interleukin-10 signalling; in reported patients they failed to induce remission.

Show evidence (1 reference)

PMID:19890111 REFUTE Human Clinical

"The patient was treated with a wide spectrum of anti-inflammatory agents, including corticosteroids, methotrexate, thalidomide, and anti-TNF-α monoclonal antibodies. None of these therapies induced remission or long-term improvement."

Refuting evidence for conventional therapy in this disease: a documented failure of the full conventional armamentarium in an index patient, which is the basis for curating this treatment as ineffective rather than omitting it.

🔬

Diagnosis

IL-10-induced STAT3 phosphorylation assay

Functional testing of patient peripheral-blood mononuclear cells for STAT3 phosphorylation on interleukin-10 stimulation distinguishes IL10R deficiency from other causes of very-early-onset inflammatory bowel disease and confirms that a candidate variant is signalling-dead.

Show evidence (1 reference)

PMID:19890111 SUPPORT In Vitro

"as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10"

Describes the functional readout used to confirm loss of receptor signalling. Evidence source is IN_VITRO because it is a cell-based assay.

IL10RA and IL10RB sequencing

Sequencing of both receptor chain genes. Because IL10R deficiency is treatable by transplantation while conventional therapy fails, establishing the molecular diagnosis in an infant with severe colitis changes management rather than merely labelling the disease.

Show evidence (1 reference)

PMID:19890111 SUPPORT Human Clinical

"We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease."

Documents the sequencing-based approach by which the diagnosis is established.

{ }

Source YAML

click to show

name: Interleukin-10 Receptor Deficiency
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
synonyms:
- IL-10 receptor deficiency
- IL10R deficiency
- inflammatory bowel disease 28
- IBD28
- inflammatory bowel disease 25
- IBD25
- infantile-onset inflammatory bowel disease
description: >-
  Interleukin-10 receptor deficiency is an autosomal recessive monogenic form of
  very-early-onset inflammatory bowel disease and the archetype of the
  immune-mediated congenital enteropathies - the class that the three epithelial
  CODE mechanism modules explicitly exclude, because here the intestinal
  epithelium is intrinsically normal and is damaged secondarily by unrestrained
  immune activity. Biallelic loss-of-function variants in IL10RA or IL10RB
  disable the two chains of the interleukin-10 receptor, a heterotetramer of two
  IL10R1 (IL10RA) and two IL10R2 (IL10RB) subunits. Interleukin-10 is the
  principal brake on inflammatory cytokine output, so losing its receptor
  abolishes the negative-feedback loop that normally restrains myeloid cells:
  IL-10 fails to trigger JAK1/Tyk2-dependent STAT3 phosphorylation, and patient
  mononuclear cells secrete excess tumour necrosis factor alpha and other
  proinflammatory cytokines. In the gut - which is under continuous microbial
  stimulation and therefore most dependent on this brake - the result is severe
  enterocolitis presenting in the first months of life, with perianal disease,
  abscesses and enterocutaneous fistulas that are characteristically refractory
  to the entire conventional armamentarium including corticosteroids,
  immunosuppressants and anti-TNF antibodies. That refractoriness is
  mechanistically expected rather than incidental: blocking one downstream
  cytokine cannot substitute for a missing master regulator. Allogeneic
  haematopoietic stem-cell transplantation, which replaces the patient's myeloid
  compartment with cells carrying a functional receptor, is the definitive
  treatment and induced remission in the index case. Note that IL10R2 is shared
  by the receptors for interleukin-22 and interleukin-26, so IL10RB deficiency is
  not strictly confined to interleukin-10 signalling.
disease_term:
  preferred_term: interleukin-10 receptor deficiency
  term:
    id: MONDO:0013153
    label: inflammatory bowel disease 28
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012941
      label: inflammatory bowel disease 25
    mapping_predicate: skos:narrowMatch
    mapping_source: OMIM:612567
    mapping_justification: >
      MONDO splits interleukin-10 receptor deficiency by receptor chain, with
      MONDO:0013153 (IBD28) for IL10RA and MONDO:0012941 (IBD25) for IL10RB, and
      provides no umbrella term for the receptor. This entry curates the receptor
      as one disease because both chains form a single heterotetramer and their
      loss produces the same clinical and functional phenotype, so IBD25 is a
      narrower concept fully covered here rather than a separate disease.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Autosomal recessive. The two index families were consanguineous - the first
    Turkish with first-cousin parents, the second of Lebanese descent - and all
    identified variants were homozygous.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In four of nine patients with early-onset colitis, we identified three
      distinct homozygous mutations in genes IL10RA and IL10RB
    explanation: >-
      Documents homozygous variants in affected children from consanguineous
      families, the expected pattern for recessive inheritance.
genetic:
- name: IL10RA loss-of-function variants
  gene_term:
    preferred_term: IL10RA
    term:
      id: hgnc:5964
      label: IL10RA
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: IL10RA deficiency
  features: >-
    Biallelic IL10RA variants abolish the IL10R1 alpha chain, which is specific
    to the interleukin-10 receptor. Because IL10R1 is not shared with any other
    cytokine receptor, IL10RA deficiency is a clean loss of interleukin-10
    signalling alone, which makes it the more mechanistically interpretable of
    the two forms.
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified three distinct homozygous mutations in genes IL10RA and
      IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a
      heterotetramer to make up the interleukin-10 receptor
    explanation: >-
      The gene-discovery report identifying both receptor chains as disease genes
      and stating that they assemble into one heterotetrameric receptor - the
      basis for curating them as one disease here.
- name: IL10RB loss-of-function variants
  gene_term:
    preferred_term: IL10RB
    term:
      id: hgnc:5965
      label: IL10RB
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: IL10RB deficiency
  features: >-
    Biallelic IL10RB variants abolish the IL10R2 beta chain. Unlike IL10R1, this
    subunit is shared by the receptors for interleukin-22 and interleukin-26, so
    IL10RB deficiency removes signalling through those cytokines as well. This
    is a real mechanistic difference between the two forms even though they are
    clinically similar, and it should not be curated away.
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although IL10R1 is specific to the interleukin-10 receptor, IL10R2 is a
      subunit of the receptors for several additional cytokines (e.g.,
      interleukin-22 and interleukin-26).
    explanation: >-
      Establishes the asymmetry between the two chains that distinguishes the two
      genetic forms: IL10R2 is shared with the interleukin-22 and -26 receptors,
      so its loss is not confined to interleukin-10 signalling.
pathophysiology:
- name: Loss of a Functional Interleukin-10 Receptor
  description: >-
    The initiating lesion. The interleukin-10 receptor is a heterotetramer of two
    IL10R1 chains (IL10RA) and two IL10R2 chains (IL10RB); biallelic loss of
    either chain prevents assembly of a signalling-competent receptor. The two
    genotypes are not quite equivalent, and the entry preserves the difference:
    IL10R1 is specific to this receptor, whereas IL10R2 is shared with the
    interleukin-22 and interleukin-26 receptors, so IL10RB deficiency
    additionally removes those signals.
  role: trigger
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: Interleukin-10 receptor activity
    term:
      id: GO:0004920
      label: interleukin-10 receptor activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The receptor for interleukin-10 consists of two alpha molecules (IL10R1)
      and two beta molecules (IL10R2).
    explanation: >-
      Describes the receptor architecture whose disruption defines this node.
  downstream:
  - target: Abolished IL-10-Induced STAT3 Signaling
    causal_link_type: DIRECT
- name: Abolished IL-10-Induced STAT3 Signaling
  description: >-
    The rate-limiting step, and the one directly measured in patients. Assembly
    of the intact receptor normally activates the receptor-associated Janus
    kinases JAK1 and Tyk2, which phosphorylate STAT3 and induce STAT3-dependent
    genes. In patient peripheral-blood mononuclear cells, stimulation with
    interleukin-10 fails to produce STAT3 phosphorylation - a functional assay
    that confirms the variants are not merely present but signalling-dead, and
    that localises the block to the receptor-proximal step rather than to
    interleukin-10 production.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Peripheral-blood mononuclear cell
    term:
      id: CL:0000842
      label: mononuclear leukocyte
  biological_processes:
  - preferred_term: JAK-STAT signaling downstream of the IL-10 receptor
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutations abrogate interleukin-10-induced signaling, as shown by
      deficient STAT3 (signal transducer and activator of transcription 3)
      phosphorylation on stimulation with interleukin-10.
    explanation: >-
      Functional demonstration that the variants abolish receptor signalling,
      measured as absent STAT3 phosphorylation on IL-10 stimulation. Evidence
      source is IN_VITRO because the assay was performed on patients' isolated
      mononuclear cells.
  downstream:
  - target: Loss of Negative Feedback on Proinflammatory Cytokine Output
    causal_link_type: DIRECT
- name: Loss of Negative Feedback on Proinflammatory Cytokine Output
  description: >-
    The effector step. Interleukin-10 restricts excessive immune responses,
    limiting secretion of proinflammatory cytokines such as tumour necrosis
    factor alpha and interleukin-12 from myeloid and other cells. Without
    receptor signalling this brake is released, and patient mononuclear cells
    show increased secretion of TNF-alpha and other proinflammatory cytokines.
    The lesion is therefore a loss of regulation rather than a gain of a
    pathogenic signal - the immune system is not driven abnormally so much as
    left unrestrained, which is what makes the disease continuous and
    self-sustaining wherever immune stimulation is continuous.
  role: effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Peripheral-blood mononuclear cell
    term:
      id: CL:0000842
      label: mononuclear leukocyte
  biological_processes:
  - preferred_term: Negative regulation of TNF production
    term:
      id: GO:0032720
      label: negative regulation of tumor necrosis factor production
    modifier: LOSS_OF_FUNCTION
  - preferred_term: Tumor necrosis factor production
    term:
      id: GO:0032640
      label: tumor necrosis factor production
    modifier: INCREASED
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with this observation was the increased secretion of tumor
      necrosis factor alpha and other proinflammatory cytokines from
      peripheral-blood mononuclear cells from patients who were deficient in
      IL10R subunit proteins, suggesting that interleukin-10-dependent "negative
      feedback" regulation is disrupted in these cells.
    explanation: >-
      Directly demonstrates the disrupted negative feedback this node models, in
      patient cells. Evidence source is IN_VITRO because cytokine secretion was
      measured in isolated mononuclear cells.
  downstream:
  - target: Hyperinflammatory Enterocolitis
    causal_link_type: DIRECT
- name: Hyperinflammatory Enterocolitis
  description: >-
    The clinical output, and the reason the gut bears the brunt of a systemic
    regulatory defect: the intestine is under continuous microbial stimulation
    and is therefore the tissue most dependent on the interleukin-10 brake. The
    result is severe enterocolitis in the first months of life with multifocal
    ulceration, polymorphic inflammatory infiltrates, intramural abscesses
    extending into submucosa and muscularis, perianal abscesses, and
    enterocutaneous and rectovaginal fistulas often requiring repeated bowel
    resection and stoma formation. The epithelium here is intrinsically normal;
    it is damaged by the unrestrained inflammatory response around it, which is
    what places this disease in the immune-mediated rather than the epithelial
    class of congenital enteropathies.
  role: consequence
  biological_scale: ORGANISM
  locations:
  - preferred_term: Colon
    term:
      id: UBERON:0001155
      label: colon
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in genes encoding the IL10R subunit proteins were found in
      patients with early-onset enterocolitis, involving hyperinflammatory immune
      responses in the intestine.
    explanation: >-
      States the clinical output of the chain and attributes it explicitly to
      hyperinflammatory immune responses in the intestine.
has_subtypes:
- name: IL10RA deficiency
  display_name: IL10RA deficiency (inflammatory bowel disease 28)
  description: >-
    Loss of the IL10R1 alpha chain, which is specific to the interleukin-10
    receptor, so the defect is confined to interleukin-10 signalling.
  subtype_term:
    preferred_term: inflammatory bowel disease 28
    term:
      id: MONDO:0013153
      label: inflammatory bowel disease 28
  genes:
  - preferred_term: IL10RA
    term:
      id: hgnc:5964
      label: IL10RA
- name: IL10RB deficiency
  display_name: IL10RB deficiency (inflammatory bowel disease 25)
  description: >-
    Loss of the IL10R2 beta chain, which is shared with the interleukin-22 and
    interleukin-26 receptors, so signalling through those cytokines is lost as
    well. Clinically similar to the IL10RA form.
  subtype_term:
    preferred_term: inflammatory bowel disease 25
    term:
      id: MONDO:0012941
      label: inflammatory bowel disease 25
  genes:
  - preferred_term: IL10RB
    term:
      id: hgnc:5965
      label: IL10RB
phenotypes:
- name: Early-Onset Colitis
  category: Gastrointestinal
  description: >-
    Severe enterocolitis presenting within the first months of life, with
    multifocal mucosal ulceration and polymorphic inflammatory infiltrates on
    biopsy, and intramural abscesses extending into submucosa and muscularis
    propria.
  phenotype_term:
    preferred_term: Early-onset colitis
    term:
      id: HP:0002583
      label: Colitis
    temporality: CHRONIC
  frequency: OBLIGATE
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in genes encoding the IL10R subunit proteins were found in
      patients with early-onset enterocolitis
    explanation: >-
      Establishes early-onset enterocolitis as the defining clinical feature of
      the disorder, supporting the OBLIGATE band.
- name: Perianal Abscess
  category: Gastrointestinal
  description: >-
    Perianal abscesses and perianal disease, present from the earliest
    presentation and frequently requiring repeated surgical intervention.
  phenotype_term:
    preferred_term: Perianal abscess
    term:
      id: HP:0009789
      label: Perianal abscess
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented at the age of 3 months with proctitis and abscesses in the
      peri-anal region, which required multiple surgical interventions
    explanation: >-
      Documents perianal abscesses at presentation and their surgical burden in
      the index patient. No frequency band is asserted: the cited report
      describes individual patients narratively rather than reporting a
      frequency, so it supports the association but not a band.
- name: Anal Fistula
  category: Gastrointestinal
  description: >-
    Fistulating disease including enterocutaneous, perianal and rectovaginal
    fistulas, often requiring bowel resection and stoma formation.
  phenotype_term:
    preferred_term: Fistulating intestinal disease
    term:
      id: HP:0010447
      label: Anal fistula
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multiple enterocutaneous fistulas originating from the small intestine
      required further partial bowel resections and ileostomy.
    explanation: >-
      Documents the fistulating disease and the resections it necessitated. The
      HP term Anal fistula is the closest available match; the preferred_term
      records the broader fistulating phenotype actually described, which
      includes enterocutaneous and rectovaginal fistulas. No frequency band is
      asserted, for the same reason as the perianal abscess phenotype above.
- name: Recurrent Infections
  category: Immunological
  description: >-
    Recurrent infections including otitis media, bronchitis, pneumonia, purulent
    arthritis and renal abscess. In the index patient these were considered
    potentially attributable to immunosuppressive therapy rather than to the
    receptor defect itself, so the phenotype should not be read as a primary
    immunodeficiency.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent infections such as otitis media, bronchitis, and two episodes of
      purulent gonarthritis were potentially linked to immunosuppressive therapy.
    explanation: >-
      Documents the infections and, importantly, the authors' own attribution of
      them to immunosuppressive therapy - which is why this is curated as
      OCCASIONAL and flagged as not necessarily intrinsic.
diagnosis:
- name: IL-10-induced STAT3 phosphorylation assay
  description: >-
    Functional testing of patient peripheral-blood mononuclear cells for STAT3
    phosphorylation on interleukin-10 stimulation distinguishes IL10R deficiency
    from other causes of very-early-onset inflammatory bowel disease and confirms
    that a candidate variant is signalling-dead.
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      as shown by deficient STAT3 (signal transducer and activator of
      transcription 3) phosphorylation on stimulation with interleukin-10
    explanation: >-
      Describes the functional readout used to confirm loss of receptor
      signalling. Evidence source is IN_VITRO because it is a cell-based assay.
- name: IL10RA and IL10RB sequencing
  description: >-
    Sequencing of both receptor chain genes. Because IL10R deficiency is
    treatable by transplantation while conventional therapy fails, establishing
    the molecular diagnosis in an infant with severe colitis changes management
    rather than merely labelling the disease.
  evidence:
  - reference: PMID:19890111
    reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed genetic-linkage analysis and candidate-gene sequencing on
      samples from two unrelated consanguineous families with children who were
      affected by early-onset inflammatory bowel disease.
    explanation: >-
      Documents the sequencing-based approach by which the diagnosis is
      established.
treatments:
- name: Allogeneic Hematopoietic Stem-Cell Transplantation
  description: >-
    The definitive treatment, and the one that follows from the mechanism:
    replacing the haematopoietic compartment supplies myeloid cells carrying a
    functional interleukin-10 receptor, restoring the negative-feedback brake
    that the patient's own cells cannot exert. It was performed in the index
    patient and induced remission. This is a rare instance in the congenital
    enteropathies where a curative therapy targets the causal mechanism rather
    than replacing lost intestinal function.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Loss of Negative Feedback on Proinflammatory Cytokine Output
    treatment_effect: RESTORES
    description: >-
      Donor-derived myeloid cells express a functional interleukin-10 receptor
      and can therefore respond to interleukin-10, restoring the negative
      feedback on proinflammatory cytokine output that the patient's own cells
      have lost.
    evidence:
    - reference: PMID:19890111
      reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Allogeneic stem-cell transplantation resulted in disease remission in one
        patient.
      explanation: >-
        Documents the clinical outcome of transplantation. Note this is a single
        patient in the original report, so the evidence base for this treatment
        at the time of the cited study is one case, not a series.
- name: Conventional Anti-Inflammatory and Anti-TNF Therapy
  description: >-
    Curated as a treatment that FAILS, because its failure is mechanistically
    informative rather than incidental. Corticosteroids, methotrexate,
    thalidomide, azathioprine and anti-TNF-alpha monoclonal antibodies were all
    used in the index patients and none induced remission or long-term
    improvement, even alongside total colectomy. Blocking one downstream cytokine
    cannot replace a missing master regulator of the whole inflammatory
    programme, so refractoriness to conventional therapy is a diagnostic clue to
    monogenic very-early-onset inflammatory bowel disease rather than a reason to
    escalate it.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Hyperinflammatory Enterocolitis
    treatment_effect: MODULATES
    description: >-
      Conventional immunosuppression and anti-TNF therapy act downstream of the
      receptor defect and do not restore interleukin-10 signalling; in reported
      patients they failed to induce remission.
    evidence:
    - reference: PMID:19890111
      reference_title: "Inflammatory bowel disease and mutations affecting the interleukin-10 receptor."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was treated with a wide spectrum of anti-inflammatory agents,
        including corticosteroids, methotrexate, thalidomide, and anti-TNF-α
        monoclonal antibodies. None of these therapies induced remission or
        long-term improvement.
      explanation: >-
        Refuting evidence for conventional therapy in this disease: a documented
        failure of the full conventional armamentarium in an index patient, which
        is the basis for curating this treatment as ineffective rather than
        omitting it.
notes: >-
  This entry is the immune-mediated counterpart to the epithelial congenital
  enteropathies, and it deliberately conforms to none of the three epithelial
  CODE mechanism modules on this branch. All three model an intrinsic defect of
  the intestinal epithelium; here the epithelium is intrinsically normal and is
  damaged secondarily by unrestrained immune activity. PMID:29654747 draws
  exactly this division, separating CODEs caused by variants directly affecting
  the intestinal epithelium from those affecting the immune system that
  secondarily impair epithelial function, and each of the three modules names
  immune-mediated enteropathy among its exclusions.
  Lump/split decision: MONDO splits this disease by receptor chain -
  MONDO:0013153 (IBD28, IL10RA) and MONDO:0012941 (IBD25, IL10RB) - and provides
  no umbrella term for the receptor. It is curated here as one Disease entry
  named for the receptor, with the two chains as has_subtypes each bound to its
  own MONDO term, and MONDO:0012941 recorded as a skos:narrowMatch so the IBD25
  concept is registered as covered. The justification is that the two chains form
  a single heterotetramer and their loss produces the same clinical and
  functional phenotype. The one real asymmetry - IL10R2 is shared with the
  interleukin-22 and interleukin-26 receptors while IL10R1 is not - is preserved
  in both the genetic blocks and the subtype descriptions rather than being
  smoothed away, and would be the grounds for splitting into two entries if
  IL-22/IL-26-attributable features are ever separated out.
  The failed conventional therapy is curated as a treatment with REFUTE evidence
  rather than omitted, because its failure is a mechanistic prediction of the
  model and a practical diagnostic clue.

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