Autoimmune Enteropathy

Definition

Autoimmune enteropathy (AIE) is an immune‑mediated condition in which loss of immune tolerance targets intestinal epithelial cells, producing intractable secretory diarrhea, malabsorption, protein‑losing enteropathy, and failure to thrive. AIE ranges from gut‑limited disease to syndromic, multisystem immune dysregulation and most often presents in infancy or early childhood but can present at any age.

Classification (practical)

• IPEX: X‑linked FOXP3 deficiency causing classic syndromic disease in males (Immune dysregulation, Polyendocrinopathy, Enteropathy, X‑linked).
• IPEX‑like: Monogenic immune dysregulation syndromes (examples include CTLA4, LRBA, IL2RA, STAT1/3 variants) affecting both sexes with enteropathy and systemic autoimmunity.
• GI‑limited AIE: Autoimmune enteropathy confined mainly to the gut without clear systemic monogenic cause.
• AIRE/APS1‑associated enteropathy: Enteropathy occurring in the context of autoimmune polyendocrine syndrome type 1 due to pathogenic variants in the AIRE gene (see glossary below).

Pathogenesis

Central mechanism is breakdown of peripheral tolerance with autoreactive T‑cell activity directed at epithelial antigens.

• FOXP3 mutations (IPEX) → defective regulatory T cells (Tregs) causing widespread autoimmunity targeted to gut epithelium and other organs.
• Other monogenic defects disrupt immune checkpoints, Treg survival/function, or cytokine signaling and produce IPEX‑like phenotypes.
• Autoantibodies against enterocytes, goblet cells, and a reported ~75 kDa gut/kidney antigen are described; pathogenic roles vary and assays are not standardized.
• Tissue changes include epithelial apoptosis, villous atrophy, crypt alterations, goblet/Paneth cell depletion, and dense lamina propria T‑cell infiltrates.

Epidemiology

AIE is rare; precise incidence is unknown. Syndromic forms such as IPEX are uncommon and X‑linked, predominantly affecting males. IPEX‑like and sporadic forms occur in both sexes and across ages.

Clinical features

Core intestinal manifestations

• Persistent secretory diarrhea (often high volume), malabsorption, and protein‑losing enteropathy causing hypoalbuminemia and failure to thrive.
• Stools may be watery, mucoid, or bloody; severe cases frequently need parenteral nutrition.

Extraintestinal manifestations (subtype dependent)

• IPEX: early insulin‑dependent diabetes mellitus, severe eczema/dermatitis, autoimmune thyroid disease, autoimmune cytopenias, hepatopathy, nephritis, interstitial lung disease, lymphadenopathy, and splenomegaly.
• IPEX‑like: variable multisystem autoimmunity driven by the underlying gene defect.
• GI‑limited AIE: primarily intestinal disease without significant extraintestinal autoimmunity.
• AIRE/APS1‑associated enteropathy: often targets enteroendocrine cells producing a distinct phenotype (see glossary and pathology below).

Laboratory signals

• Hypoalbuminemia, electrolyte disturbances, and anemia (from loss or autoimmune hemolysis).
• Markedly elevated IgE and peripheral eosinophilia are common in many pediatric cases, particularly IPEX.
• Autoantibodies (anti‑enterocyte, anti‑goblet cell, and anti‑75 kDa antigen) are supportive but not definitive.

Endoscopy and histopathology

• Endoscopic appearance ranges from near normal mucosa to diffuse erythema, granularity, erosions, and loss of vascular pattern; biopsies are essential.
• Characteristic histology: villous blunting/atrophy, crypt hyperplasia, prominent lamina propria mononuclear (T cell) infiltrate, increased epithelial apoptosis (apoptotic bodies), and variable loss of goblet and Paneth cells.
• Key distinction from celiac disease: AIE typically shows lamina propria T‑cell predominance and epithelial apoptosis rather than dominant intraepithelial lymphocytosis.
• In AIRE/APS1‑associated disease, immune targeting often preferentially affects enteroendocrine cells producing a distinct pattern with relatively milder absorptive cell loss.

Diagnosis — stepwise approach

1. Stabilize fluids, electrolytes, and nutrition; institute TPN if severe protein loss or failure to thrive.
2. Laboratory evaluation: CMP, albumin, CBC/differential, IgE, immunoglobulins, eosinophils; stool studies to exclude infection.
3. Serology: anti‑enterocyte and anti‑goblet cell antibodies; anti‑75 kDa antigen is reported in some pediatric series (limited availability).
4. Endoscopy with targeted biopsies of duodenum and colon for histopathology and apoptosis assessment.
5. Immunophenotyping: Treg (FOXP3+) numbers/function where available; T‑cell activation markers.
6. Genetic testing: FOXP3 sequencing in suspected IPEX; immune dysregulation gene panels or whole‑exome sequencing for IPEX‑like or unexplained presentations.
7. Exclude other causes: celiac disease (serology and histology), congenital diarrheal disorders, eosinophilic GI disease, inflammatory bowel disease, and infections.

Management

Supportive care

• Aggressive fluid and electrolyte repletion, albumin replacement as needed, and nutritional rehabilitation; TPN is often required while enteropathy is severe.

Immunosuppression

• Systemic corticosteroids for rapid control of inflammation.
• Steroid‑sparing agents: calcineurin inhibitors (tacrolimus, cyclosporine), sirolimus, mycophenolate mofetil, azathioprine as clinically appropriate.
• Biologic agents (rituximab, anti‑TNF, others) have been used for refractory cases with variable success.

Targeted therapy

• In IPEX‑like disorders, genotype‑directed agents can be effective: abatacept for CTLA4/LRBA pathway defects, JAK inhibitors for STAT gain‑of‑function disorders, and other targeted approaches based on molecular mechanism.

Curative therapy

Hematopoietic stem cell transplantation (HSCT) is the only established curative therapy for FOXP3‑deficient IPEX and can restore immune tolerance. Early HSCT before irreversible organ damage yields better outcomes. HSCT may also be considered for severe refractory IPEX‑like disease based on genotype and center experience. Established endocrine damage (for example, insulin‑dependent diabetes) often persists after transplant.

Long‑term follow‑up

• Multidisciplinary lifelong follow‑up with gastroenterology, immunology, endocrinology, nutrition, and transplant teams.
• Monitor growth, infections, immune function, endocrine sequelae, and complications of chronic immunosuppression or HSCT.

Prognosis

• Historically poor in untreated infants; modern supportive care, immunosuppression, and early HSCT have improved survival and long‑term outcomes.
• Prognosis depends on age at diagnosis, severity, genotype, timing of HSCT, and extent of irreversible organ damage prior to definitive therapy.

Autoantibodies and diagnostic nuance

• Anti‑enterocyte and anti‑goblet cell antibodies support AIE diagnosis but are not diagnostic alone; assay availability and standardization vary.
• An antibody against a ~75 kDa gut/kidney antigen has been reported in pediatric AIE cohorts but is not universally available clinically and should be interpreted in context.
• Genetic confirmation remains the most definitive diagnostic evidence for syndromic forms (e.g., FOXP3 in IPEX).

Practical clinical points

• Suspect AIE in infants and children with refractory secretory diarrhea plus autoimmune features; stabilize and involve specialists early.
• Obtain endoscopic biopsies early; histology guides differentiation from other enteropathies such as celiac disease.
• Request FOXP3 testing promptly for suspected IPEX; expand to immune dysregulation gene panels if FOXP3 is negative or presentation is atypical.
• Consider HSCT early in FOXP3‑deficient IPEX and in selected severe IPEX‑like cases; coordinate multidisciplinary care and genetic counseling.

Areas of ongoing research and future directions

• Standardization and pathogenic characterization of serologic markers (anti‑enterocyte, anti‑goblet cell, anti‑75 kDa).
• Expanded genotype–phenotype mapping for IPEX‑like disorders and understanding variable expressivity.
• Development of precision therapies targeted to specific molecular defects and optimization of HSCT timing and conditioning.
• Longitudinal registries to define natural history, long‑term outcomes, and best practices across centers.

Glossary: AIRE/APS1 and related acronyms, spelled out and synonyms

• AIRE — Autoimmune Regulator (gene). The AIRE gene encodes a transcription factor required for thymic expression of peripheral tissue antigens that promotes central tolerance.
• APS1 — Autoimmune Polyendocrine Syndrome Type 1. Synonyms: Autoimmune Polyendocrinopathy Syndrome Type 1; formerly also called Autoimmune Polyendocrinopathy‑Candidiasis‑Ectodermal Dystrophy (APECED).
• APECED — Autoimmune Polyendocrinopathy‑Candidiasis‑Ectodermal Dystrophy. Synonyms: APS‑1; classic triad includes chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, and some patients develop enteropathy.
• IPEX — Immune dysregulation, Polyendocrinopathy, Enteropathy, X‑linked. Caused by pathogenic variants in FOXP3; classic syndrome of early enteropathy, dermatitis, and endocrinopathy in males.
• FOXP3 — Forkhead box P3 (gene and protein). A lineage‑defining transcription factor for regulatory T cells; pathogenic variants cause IPEX.
• LRBA — Lipopolysaccharide‑responsive and beige‑like anchor protein. LRBA deficiency can produce CTLA4 dysregulation and an IPEX‑like phenotype; abatacept may be effective.
• CTLA4 — Cytotoxic T‑lymphocyte‑associated protein 4. Haploinsufficiency leads to immune dysregulation and IPEX‑like disease; abatacept replaces CTLA4 inhibitory signaling.
• STAT‑GOF — Signal Transducer and Activator of Transcription gain‑of‑function (e.g., STAT1 or STAT3 GOF mutations). These can cause immune dysregulation with enteropathy and are sometimes treated with JAK inhibitors.