IL21R Deficiency

1. Disease Information

Overview. A monogenic inborn error of immunity in the "combined immunodeficiency (CID)" category, defined by absent/non-functional IL-21 receptor signaling. It affects both adaptive (B and T cell) and innate (NK) immunity and characteristically predisposes to opportunistic Cryptosporidium infection of the biliary tree. [human clinical] (PMID 23440042, 33929673)

Key identifiers (computational/database): - OMIM: #615207 — "Immunodeficiency 56" (IMD56) - Gene: IL21R, OMIM 605383; HGNC:6006; NCBI Gene 50615; Ensembl ENSG00000159374; UniProt Q9HBE5 (IL21R_HUMAN); cytoband 16p12.1 - Orphanet: Listed under combined immunodeficiencies / IL-21R-related; no widely used dedicated ORPHAcode—commonly grouped with "Combined immunodeficiency." - MONDO: Suggested MONDO:0014219 ("immunodeficiency 56") — to be verified against current MONDO release. - ICD-10: D81.8 / D81.9 (other/unspecified combined immunodeficiencies). ICD-11: 4A01.3Y (combined immunodeficiencies, other). - MeSH:* No dedicated descriptor; indexed under "Severe Combined Immunodeficiency"/"Primary Immunodeficiency Diseases" + "Receptors, Interleukin-21."

Synonyms / alternative names: IL-21R deficiency; Interleukin-21 receptor deficiency; Immunodeficiency 56 (IMD56); IL21R-related combined immunodeficiency.

Information source. Aggregated disease-level knowledge derived from individual patient case series (≈20+ patients worldwide) synthesized in cohort papers and reviews—not from large registries/EHR. [human clinical]

2. Etiology

Disease causal factors. Monogenic/genetic. Biallelic (homozygous or compound-heterozygous) loss-of-function variants in IL21R are necessary and sufficient. An infectious trigger (chronic Cryptosporidium parvum/hominis biliary infection) is the principal driver of the signature organ pathology (cholangitis/liver disease) in the setting of the genetic immune defect—an obligate gene × pathogen interaction. [human clinical] (PMID 23440042: "cryptosporidial infections associated with chronic cholangitis and liver disease")

Genetic risk factors. - Causal variants: e.g., c.G602T (p.Arg201Leu, missense causing receptor mistrafficking/loss of ligand binding); c.240_245delCTGCCA (p.C81_H82del, in-frame deletion). 8 unique mutations reported across 8 families by 2021 (missense, in-frame indels, and other LOF classes). [human clinical/in vitro] (PMID 23440042, 33929673) - Modifier genes: None established (cohort too small).

Environmental risk factors. Consanguinity (parental relatedness) is the dominant epidemiologic risk factor, increasing homozygosity for rare recessive alleles. Exposure to Cryptosporidium (contaminated water/food) converts the immune defect into life-threatening cholangiopathy. No sex, occupational, or toxin risk factors. [human clinical] (PMID 23440042)

Protective factors. No genetic protective/modifier alleles identified. Environmentally, avoidance of Cryptosporidium exposure (water precautions/filtration) and early curative HSCT are protective against the worst outcomes. [human clinical] (inferred)

Gene–environment interactions. The core GxE interaction: IL21R-null immune state + Cryptosporidium exposure → sclerosing cholangitis. Restoration of immune competence (HSCT) enables clearance of the parasite, halting the environmental driver. [human clinical] (PMID 30850087: cholangiopathy improvement "following establishment of immune competence")

3. Phenotypes (with HPO suggestions & frequencies)

Frequencies from the 13-patient cohort (PMID 33929673) unless noted. [human clinical]

Characteristics. Onset pediatric — median 2.5 years (range 0.5–7). Severity variable but the hepatobiliary component is typically progressive and life-limiting. Infections are recurrent/chronic; atopy (IgE, asthma, anaphylaxis) is episodic.

Quality-of-life impact. No formal EQ-5D/SF-36/PROMIS data. Qualitatively severe: chronic diarrhea/malabsorption → growth failure; progressive cholangiopathy → cholestasis, portal hypertension, end-stage liver disease; recurrent infections and hospitalizations; transplant-related morbidity. [human clinical]

Key quote (PMID 33929673): "The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes."

4. Genetic / Molecular Information

• Causal gene: IL21R (HGNC:6006; 16p12.1; NCBI 50615; UniProt Q9HBE5). Type I cytokine receptor; heterodimerizes with the common gamma chain (γc / IL2RG / CD132). [computational/database]
• Pathogenic variants (ACMG): classified pathogenic/likely pathogenic. Reported types: missense (p.Arg201Leu), in-frame deletion (p.C81_H82del), and additional LOF alleles (8 unique across 8 families). Loss-of-function is the uniform functional consequence—no gain-of-function or dominant-negative disease described; heterozygous carriers are healthy (recessive). [human clinical/in vitro] (PMID 23440042, 33929673)
• Allele frequency: Biallelic IL21R LOF is essentially absent in gnomAD; individual pathogenic alleles are ultra-rare/private. [computational/database]
• Somatic vs germline: Germline. No somatic/oncogenic IL21R role in this disease.
• Functional consequences: p.Arg201Leu → aberrant receptor trafficking to the plasma membrane, loss of IL-21 ligand binding, and abrogated STAT1/STAT3/STAT5 phosphorylation (PMID 23440042: "aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of ... STAT1, STAT3, and STAT5"). [in vitro]
• Modifier genes / epigenetics / chromosomal abnormalities: None reported; disease is a point-mutation/small-indel monogenic disorder, not a structural/aneuploidy syndrome.

5. Environmental Information

• Environmental factors: No toxin/radiation/pollution etiology. The critical environmental element is exposure to the waterborne protozoan Cryptosporidium.
• Lifestyle factors: Not applicable as risk drivers; hygiene/water safety are relevant for preventing opportunistic infection.
• Infectious agents (NCBI Taxonomy): Cryptosporidium parvum (NCBI:txid5807) / C. hominis (NCBI:txid237895) — biliary/intestinal; Cytomegalovirus (HHV-5, NCBI:txid10359); plus recurrent pyogenic bacteria and fungi (incl. Pneumocystis). These are opportunistic consequences of the immunodeficiency, not primary causes. [human clinical] (PMID 23440042, 33966600)

6. Mechanism / Pathophysiology

Ordered causal chain

1. Biallelic IL21R loss-of-function mutation (e.g., p.Arg201Leu) → leads to absent or mistrafficked IL-21R protein that fails to reach/function at the plasma membrane and cannot bind IL-21. [in vitro, demonstrated] (PMID 23440042)
2. Loss of surface IL-21R → prevents assembly of the IL-21R/γc receptor complex and abrogates JAK1/JAK3 activation → results in failed phosphorylation of STAT3 (and STAT1/STAT5). [in vitro, demonstrated] (PMID 23440042; pathway review PMID 24126614)
3. Absent STAT3 signaling → fails to up-regulate the plasma-cell master regulator BLIMP1/PRDM1 (and to down-regulate BCL6) → impairs IL-21-driven B-cell activation, immunoglobulin class-switch recombination, and differentiation into plasmablasts/plasma cells → causes hypogammaglobulinemia, poor specific-antibody responses, and reduced memory B cells. [in vitro + human clinical] (PMID 23440042, 24126614, 18354204 — the latter: "stimulation with IL-21 ... induced robust and prolonged STAT3 activation in primary human B cells" and STAT3 "triggered BLIMP1 mRNA and protein up-regulation, plasma cell phenotypic features, and Ig secretion")
4. Branch A (humoral/atopy): Loss of IL-21's normal restraint on IgE, unopposed IL-4/Th2 activity → leads to elevated IgE, asthma, eczema, anaphylaxis. [model organism + human clinical] (PMID 12446913: high IgE/low IgG1 in Il21r-/- mice; PMID 33929673: IgE elevated in 50%)
5. Branch B (cellular cytotoxicity): Absent STAT3 downstream of IL-21R → reduces CD8+ T-cell memory and lytic-machinery induction, NK-cell cytotoxicity, and MAIT/NKT-cell numbers → impairs control of intracellular/opportunistic pathogens. [human clinical/in vitro] (PMID 23830147, 25941256, 23440042)
6. Combined humoral + cytotoxic failure + reduced Tfh help → permits chronic Cryptosporidium infection of intestinal and biliary epithelium. [human clinical] (PMID 23440042)
7. Persistent biliary Cryptosporidium → drives chronic inflammation of bile ducts → causes sclerosing cholangitis, fibrosis, cirrhosis, portal hypertension, end-stage liver disease (and rare cholangiocarcinoma risk by analogy to other cryptosporidial-cholangitis PIDs). [human clinical] (PMID 23440042, 30850087)
8. Chronic immune dysregulation/impaired tumor surveillance → contributes to lymphoproliferation/lymphoma (e.g., marginal zone lymphoma). [human clinical, inferred] (PMID 33966600)

Detail by category

• Molecular pathways: IL-21 → IL-21R/γc → JAK1/JAK3 → STAT3 (canonical), with STAT1/STAT5 and PI3K–AKT and MAPK as secondary arms (Reactome "Interleukin-21 signaling"; KEGG "Jak-STAT signaling pathway hsa04630"). GO:0038114 IL-21-mediated signaling pathway; GO:0007259 JAK-STAT signaling.
• Cellular processes: B-cell differentiation (GO:0030183), isotype/class switching (GO:0045190), plasma-cell differentiation (GO:0002317), germinal-center/Tfh help, NK-mediated cytotoxicity (GO:0042267), CD8 memory formation.
• Protein dysfunction: Receptor misfolding/mistrafficking and loss of ligand binding (not aggregation); pure loss of function.
• Immune system involvement: Combined immunodeficiency + immune dysregulation (atopy, lymphoproliferation).
• Tissue damage: Immune-mediated + infection-driven biliary fibrosis/sclerosis and hepatocellular injury.
• Cell types (CL): B cells CL:0000236 (memory B, plasmablast CL:0000980), Tfh CL:0002038, CD8 memory T CL:0000909, NK CL:0000623, MAIT CL:0000940, NKT cells; biliary epithelial (cholangiocyte) as the injured target.
• Omics: No dedicated transcriptomic/proteomic/metabolomic disease signatures published (ultra-rare). Mechanistic data are from targeted immunophenotyping and STAT-phosphorylation flow assays. [human clinical/in vitro]

7. Anatomical Structures Affected

• Organ level (primary): Bile ducts (UBERON:0002394; intra- and extrahepatic — sclerosing cholangitis, bilateral/diffuse), liver (UBERON:0002107), intestine/GI tract (UBERON:0000160), immune/lymphoid organs (bone marrow UBERON:0002371, lymph node UBERON:0000029, spleen UBERON:0002106, thymus). [human clinical]
• Secondary/complications: lung/respiratory tract (UBERON:0002048; recurrent pneumonia incl. CMV/Pneumocystis), skin (UBERON:0002097; eczema), portal hypertension complications.
• Body systems: immune/hematolymphoid, hepatobiliary/digestive, respiratory, integumentary.
• Tissue/cell level: biliary/intestinal epithelium (infection target); lymphoid cell populations (B/T/NK as above).
• Subcellular (GO CC): plasma membrane (GO:0005886) — site of the receptor-localization defect; secretory pathway/ER involved in receptor mistrafficking.
• Localization/lateralization: Cholangitis is typically diffuse/bilateral intrahepatic ± extrahepatic; systemic immune involvement.

8. Temporal Development

• Onset: Pediatric/early childhood; median 2.5 y (0.5–7 y); onset often insidious (chronic diarrhea, recurrent infections) (PMID 33929673). [human clinical]
• Progression: Hepatobiliary disease is chronic and progressive (cholangitis → fibrosis → cirrhosis → end-stage liver disease). Infections are recurrent; atopy episodic. Rate variable between patients.
• Course/duration: Chronic, lifelong without curative HSCT; frequently fatal in childhood if untreated or if transplant occurs after advanced organ damage.
• Critical period: A key therapeutic window exists — HSCT before advanced cholangiopathy/liver damage markedly improves outcome (PMID 30850087). [human clinical]

9. Inheritance and Population

• Epidemiology: Ultra-rare; ~20+ patients reported worldwide by 2021; no reliable prevalence/incidence figures. [human clinical] (PMID 33929673)
• Inheritance: Autosomal recessive; biallelic IL21R mutations. [human clinical] (PMID 23440042)
• Penetrance/expressivity: Immunodeficiency penetrance appears complete in biallelic-null individuals; expressivity variable (onset age, presence of cholangitis/atopy/lymphoma).
• Anticipation / germline mosaicism: Not applicable/none reported.
• Founder effects: None established (8 distinct mutations/8 families).
• Consanguinity: Strong association — most families consanguineous.
• Carrier frequency: Not defined; alleles are private/ultra-rare in gnomAD → cascade (family-specific) rather than population carrier screening.
• Demographics: Reported across multiple ethnic groups (Middle Eastern, Turkish, European and others via 7 centers); no sex predilection (autosomal); age distribution skewed pediatric.

10. Diagnostics

• Genetic testing (definitive): Whole-exome sequencing or NGS inborn-errors-of-immunity gene panels identify biallelic IL21R variants; targeted single-gene/Sanger for cascade testing. WGS useful for non-coding/structural variants. CMA/karyotype/FISH not indicated. [human clinical] (PMID 33929673: 5 novel patients found by "exome or NGS panel sequencing")
• Functional confirmation (in vitro): absent surface IL-21R expression; abrogated IL-21-induced STAT3 phosphorylation by flow cytometry; impaired IL-21-driven B-cell class switch/Ig secretion (PMID 23440042). [in vitro]
• Laboratory (LOINC-type): serum immunoglobulins (hypogammaglobulinemia; high IgE), specific antibody titers, lymphocyte subsets (low memory B, low Tfh/MAIT, altered NK), liver function/cholestatic panel.
• Microbiology: Cryptosporidium stool/bile PCR (more sensitive than microscopy) — critical and often missed (PMID 12690272: "Cryptosporidium could be detected by PCR but not by microscopy").
• Imaging: MRI/MRCP or cholangiography for sclerosing cholangitis (ductal strictures/beading, dilatation); ultrasound.
• Biopsy/pathology: liver biopsy showing sclerosing cholangiopathy/fibrosis.
• Clinical criteria / differential: No disease-specific criteria; diagnosed under IUIS CID framework. Differential: IL-21 (ligand) deficiency (phenocopy; PMID 24746753), CD40L/CD40 (hyper-IgM), MHC class II deficiency, DOCK8 deficiency, STAT3-LOF hyper-IgE syndrome, CVID — distinguished by genetics + the IL-21-signaling assay.
• Screening: Not on newborn-screening TREC panels (patients usually have T cells). Carrier/cascade testing and prenatal/PGD available for known familial variants. [human clinical]

11. Outcome / Prognosis

• Survival/mortality: Poor without early curative therapy. In the largest cohort, post-HSCT overall survival was only 33.3% (2/6), and mortality among non-transplanted patients was high (PMID 33929673). In a broader PID sclerosing-cholangitis cohort, 7/13 (53.8%) died a median 4 months post-HSCT, while 6/13 with milder cholangiopathy survived and improved (PMID 30850087). [human clinical]
• Prognostic factors: Pre-existing organ (liver/biliary) damage is the key negative prognostic factor (PMID 33929673: "pre-existing organ damage constituting a negative prognostic factor"); earlier diagnosis/transplant improves outcome.
• Morbidity/QoL: growth failure, chronic liver disease/portal hypertension, transplant-related complications; substantial disability.
• Complications: end-stage liver disease, portal hypertension, disseminated/opportunistic infection, lymphoma/lymphoproliferation, post-transplant Cryptosporidium recrudescence.
• Recovery potential: Immune reconstitution and cholangiopathy reversal possible if HSCT precedes advanced fibrosis.
• Prognostic biomarkers: severity/stage of cholangiopathy on imaging/histology; persistent Cryptosporidium positivity.

12. Treatment

• Definitive (curative): Allogeneic hematopoietic stem cell transplantation (HSCT) — NCIT:C15431; ideally with reduced-intensity conditioning, performed before advanced liver disease (PMID 23440042 recommends "early diagnosis and allogeneic hematopoietic stem cell transplantation"; PMID 30850087). [human clinical]
• Sequential liver + HSCT (NCIT:C15393 liver transplantation): for end-stage liver disease with combined immunodeficiency; curative in analogous PID cryptosporidial cirrhosis (PMID 29377874). [human clinical]
• Supportive pharmacotherapy:
• Immunoglobulin replacement therapy (IVIG/SCIG) — NCIT:C603 — for hypogammaglobulinemia.
• Anti-Cryptosporidium agents: nitazoxanide (CHEBI:189102/NCIT), paromomycin; often only partially effective without immune reconstitution.
• Antimicrobial prophylaxis: e.g., trimethoprim-sulfamethoxazole for Pneumocystis; antivirals/antifungals as indicated.
• Atopy management: asthma controllers, anaphylaxis precautions.
• Advanced/experimental: No approved gene therapy or targeted molecular therapy; IL21R is a plausible future gene-addition/gene-editing target by analogy to other γc-family SCID gene therapies (PMID 20660403). No IL21R-specific clinical trials (NCT) identified. [human clinical/inferred]
• Pharmacogenomics: none specific.
• Strategy: Diagnose early → prevent/treat Cryptosporidium + IgG replacement + prophylaxis → proceed to HSCT before liver damage; combined liver+HSCT if cirrhotic.

13. Prevention

• Primary prevention: Not preventable at the genetic level; genetic counseling for consanguineous/at-risk families; preimplantation/prenatal genetic diagnosis for known familial variants.
• Secondary prevention: Early molecular diagnosis (NGS) in infants with recurrent infection/chronic diarrhea; surveillance for Cryptosporidium (PCR) and hepatobiliary monitoring (MRCP/LFTs).
• Tertiary prevention: IgG replacement, antimicrobial prophylaxis, timely HSCT to prevent progression; post-transplant vigilance against Cryptosporidium recrudescence.
• Environmental/public-health: Water safety/filtration and hygiene to avoid Cryptosporidium exposure (boil/filter water, avoid recreational water risk).
• Immunization: standard non-live vaccines as able; avoid live vaccines in combined immunodeficiency.
• Counseling: autosomal-recessive 25% recurrence risk per pregnancy; cascade carrier testing. [human clinical/guideline-inferred]

14. Other Species / Natural Disease

• Taxonomy/orthologs: IL21R is conserved in mammals. Mouse Il21r (NCBI Gene 60504; chr 7; NCBI:txid10090); rat, zebrafish orthologs exist.
• Natural disease: No well-characterized naturally occurring IL21R-deficiency disease in companion animals/wildlife (OMIA — none prominent). Veterinary relevance is chiefly as engineered research models.
• Comparative biology: IL-21/IL-21R humoral-regulatory function is evolutionarily conserved; the γc-cytokine receptor family (IL-2/4/7/9/15/21) shares CD132 across species (structural conservation, PMID 37535730). [computational/model organism]
• Transmission/zoonosis: Not applicable to the genetic disease (though Cryptosporidium itself is zoonotic).

15. Model Organisms

• Mouse (mammalian) — Il21r-knockout (Ozaki et al. 2002, Science, PMID 12446913): normal lymphoid development but, after immunization, higher IgE and lower IgG1; Il4/Il21r double-KO → dysgammaglobulinemia with severely impaired IgG. [model organism]
• Phenotype recapitulation: reproduces human antibody dysregulation (IgE-high/IgG-low, impaired specific antibody) and demonstrates IL-21/IL-4 cooperation.
• Limitations: mice have grossly normal lymphoid development and do not spontaneously develop cryptosporidial sclerosing cholangitis (redundancy + differing pathogen exposure), so the hepatobiliary phenotype is not captured.
• Applications: dissecting IL-21 control of B-cell class switching, Tfh/germinal-center biology, CD8/NK function.
• Other models: γc-family biology also modeled in zebrafish/other systems (e.g., IL-2Rγc SCID models, PMID 35216498), informing the shared-receptor mechanism though not IL21R-specific.
• Genetic model types available: knockout (constitutive); conditional/humanized IL21R models feasible but not disease-defining. Resources: MGI (mouse), Alliance of Genome Resources.

Supported vs. Refuted Hypotheses

Supported (evidence-backed): - Biallelic IL21R LOF causes an autosomal-recessive combined immunodeficiency (PMID 23440042, 33929673). - Mechanism is failed IL-21R→JAK/STAT3 signaling affecting B, Tfh, CD8-memory, NK, MAIT/NKT compartments (PMID 23440042, 24126614, 23830147, 25941256). - Cryptosporidium-driven sclerosing cholangitis/liver disease is the prognosis-defining complication (PMID 23440042, 30850087). - HSCT is curative but timing-dependent; organ damage worsens outcome (PMID 33929673, 30850087). - Il21r-/- mice model the antibody dysregulation (PMID 12446913).

Refuted / not applicable: - Not X-linked (distinct from γc/IL2RG SCID); heterozygotes unaffected → not dominant/dominant-negative. - No environmental/toxin primary etiology; no founder mutation; no somatic/oncogenic driver role.

Limitations & Future Directions

• Evidence rests on <25 patients; frequencies/prognosis have wide uncertainty. No prevalence, QoL (EQ-5D/SF-36), or omics datasets exist.
• MONDO/Orphanet identifiers should be verified against current releases.
• Future needs: international registry/natural-history study; standardized Cryptosporidium surveillance; evaluation of gene-editing/gene-addition therapy; optimized reduced-intensity conditioning and combined liver+HSCT protocols.

Key References (PMIDs)

23440042 (Kotlarz 2013, original description) · 33929673 (Cagdas 2021, cohort n=13) · 33966600 (Edeer Karaca 2021, marginal zone lymphoma) · 24746753 (Salzer 2014, IL-21 ligand deficiency) · 12446913 (Ozaki 2002, Il21r-/- mouse) · 24126614 (Desjardins 2013, IL-21/B-cell memory review) · 23830147 (Ives 2013, CD8 memory) · 25941256 (Wilson 2015, MAIT/NKT via STAT3) · 30850087 (Hadžić 2019, HSCT for PID cholangitis) · 29377874 (sequential liver+HSCT) · 12690272 (Cryptosporidium PCR diagnosis) · 18354204 (Diehl 2008, IL-21/STAT3→BLIMP1 plasma-cell differentiation) · 37535730 (γc receptor structure) · 20660403 (γc-family gene therapy).

Artifacts

• OpenScientist final report
• OpenScientist final report

Reference Validation

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All extracted references resolved successfully.

Term Validation

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Terms the report names something else

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

• MONDO:0014219 (1 mention) - the report calls it "immunodeficiency 56"; MONDO calls it alacrima, achalasia, and intellectual disability syndrome
• HP:0001394 (1 mention) - the report calls it "frequent, progressive"; HP calls it Cirrhosis
• HP:0001508 (1 mention) - the report calls it "common"; HP calls it Failure to thrive
• HP:0004313 (1 mention) - the report calls it "most"; HP calls it Decreased circulating immunoglobulin concentration
• HP:0002850 (1 mention) - the report calls it "most"; HP calls it Decreased circulating IgM concentration
• HP:0040218 (1 mention) - the report calls it "most"; HP calls it Reduced total natural killer cell count
• NCIT:C603 (1 mention) - the report calls it "for hypogammaglobulinemia"; NCIT calls it Isotretinoin

Terms whose name is worth a second look

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

• HP:0002726 (1 mention) - the report calls it "recurrent protozoan infection"; HP calls it Recurrent Staphylococcus aureus infection
• UBERON:0000160 (1 mention) - the report calls it "intestine/GI tract"; UBERON calls it intestine, and lists "intestinal tract" among its other names