AIRE Autoimmune Polyendocrinopathy

AIRE autoimmune polyendocrinopathy—the classic disorder caused by changes (variants) in the AIRE gene and widely known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) or Autoimmune Polyendocrine Syndrome type 1 (APS-1).  AIRE autoimmune polyendocrinopathy is a rare, inherited immune system disease. Because of a faulty AIRE gene, the thymus (an immune training organ) fails to properly “teach” young T-cells to ignore the body’s own tissues. As a result, the immune system attacks several glands and body parts, causing lifelong problems such as chronic yeast (Candida) infections, low blood calcium from underactive parathyroid glands, and adrenal gland failure. Doctors often call this combination APECED or APS-1. The disease usually begins in childhood or the teen years and can involve many organs over time. PMC+2NCBI+2

APECED / APS-1 is a rare, inherited immune system disease caused by harmful changes in the AIRE gene. AIRE helps “train” young immune cells in the thymus so they learn not to attack the body. When AIRE doesn’t work, the immune system mistakenly targets many organs (especially endocrine glands) and also loses protection against Candida infections. Classic early problems are chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease (primary adrenal insufficiency). Other issues can involve teeth enamel, thyroid, pancreas (type 1 diabetes), liver, lungs, gut, eyes, and skin. Doctors use the names APECED, APS-1, and autoimmune polyendocrinopathy for the same condition. Frontiers+1

In the thymus, special cells (medullary thymic epithelial cells) show “self” proteins to developing T cells; AIRE is a key switch that turns on many of these self-proteins. If AIRE is faulty, too many self-reactive T cells escape into the body and later attack organs. People with APS-1 also form autoantibodies that block IL-17/IL-22 (weakening antifungal defenses) and type I interferons (IFN-α/ω), which can worsen viral infections; this explains the frequent Candida infections and some severe infections. PMC+2Cell+2

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Other names

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED); Autoimmune Polyendocrine Syndrome type 1 (APS-1); Polyglandular Autoimmune Syndrome type 1 (PAS-1). All these names describe the same condition caused by harmful variants in the AIRE gene, which controls immune tolerance in the thymus. PMC+1

The AIRE protein tells thymus cells to briefly display “self-antigens” from many tissues. This teaches T-cells what not to attack. When AIRE is missing or dysfunctional, many self-reactive T-cells slip through training, survive, and later attack the body. This breakdown of central tolerance explains the many autoimmune problems in APS-1. PMC+1

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Types

There aren’t “types” in the same way as some diseases, but doctors often group APS-1 by what is affected and when:

1) Classic triad–dominant APS-1. People mainly show the classic three: (a) chronic mucocutaneous candidiasis (CMC), (b) hypoparathyroidism, and (c) primary adrenal insufficiency (Addison disease). Two out of these three or a proven AIRE variant make the diagnosis very likely. NCBI+1

2) Multisystem APS-1. In addition to (or instead of) the triad, a person develops several other autoimmune or inflammatory problems, such as thyroid disease, type 1 diabetes, gonadal failure, alopecia, vitiligo, hepatitis, pneumonitis, gastritis/pernicious anemia, intestinal dysfunction, nephritis, or asplenia. PubMed

3) Late-onset/atypical APS-1. Some individuals present in adulthood or have unusual first signs (e.g., liver, lung, skin, or GI disease) before the classic triad appears; careful testing finds AIRE variants. PMC

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Causes

In APS-1, the root cause is almost always changes in the AIRE gene. The items below explain how and why disease develops or worsens—genetics, immune pathways, and modifiers. Each short paragraph gives one cause in simple words.

1. Loss-of-function AIRE variants. Harmful (often recessive) variants stop AIRE from switching on “self-antigen” teaching in the thymus. Autoreactive T-cells then survive and later attack glands and tissues. PMC

2. Failed central tolerance in the thymus. Without AIRE-guided “lessons,” young T-cells do not learn the difference between self and non-self, so autoimmunity becomes likely. PMC

3. Autoantibodies against IL-17/IL-22. Most people with APS-1 make antibodies that block IL-17A, IL-17F, and IL-22. These cytokines defend against Candida, so blocking them leads to chronic yeast infections. PMC+1

4. Excess type-1 interferon activity and neutralizing IFN-autoantibodies. APS-1 serum often contains strong interferon-related autoantibodies; this abnormal cytokine environment shapes infections and autoimmunity risk. PMC

5. Th17 pathway imbalance. APS-1 disturbs IL-17 biology, impairing mucosal antifungal defenses and fueling CMC. PMC

6. Ectopic antigen display defects. AIRE drives “tissue-restricted antigen” expression in thymic epithelial cells; when this fails, too many self-reactive T-cells escape. ScienceDirect

7. mTEC development and adhesion abnormalities. AIRE also helps thymic epithelial cells mature and organize; defects alter the training niche for T-cells. RUPress+1

8. Founder variants in isolated populations. Certain countries or founder groups show higher APS-1 rates due to shared AIRE variants. PubMed

9. Consanguinity (autosomal recessive pattern). Because two non-working AIRE copies are usually needed, consanguinity can increase risk in families. PMC

10. Dominant-negative AIRE variants (rare). Some AIRE changes act in a dominant way and can present later with milder or different features. PMC

11. Genetic modifiers beyond AIRE. Other genes may alter when and how organs are affected, explaining variable severity among patients. Nature

12. Molecular mimicry/infections as triggers. Intercurrent infections can “wake up” autoreactive cells that already escaped tolerance, unmasking disease. PMC

13. Microbiome influences. Imbalanced mucosal immunity (including IL-17 pathways) may shift the microbiome and sustain candidiasis and inflammation. PMC

14. B-cell/autoantibody cascades. Once T-cell tolerance fails, B-cells produce organ-specific autoantibodies (e.g., against parathyroid, adrenal, or other targets) that amplify damage. PMC

15. Cytokine network skewing (IFN-γ). Excess type-1 immunity, especially IFN-γ activity, increases tissue inflammation and candidiasis risk. Science

16. Environmental stressors. Illness, surgery, or major stress can unmask adrenal failure or low calcium in people with silent disease. Frontiers

17. Autoimmunity to endocrine enzymes and receptors. Organ-specific targets in the adrenals, parathyroids, thyroid, and gonads become immune targets after tolerance failure. PubMed

18. Ectodermal dysplasia components. Skin, enamel, and nail changes reflect chronic autoimmunity and epithelial barrier dysfunction linked to AIRE defects. PMC

19. Pulmonary and hepatic autoimmunity. The same mechanisms can affect lung (pneumonitis) and liver (hepatitis) tissues. PubMed

20. Renal/other organ involvement. Kidneys and GI tract can be affected; careful monitoring prevents long-term complications. BioMed Central

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Common symptoms and signs

1. Chronic yeast infections of mouth, skin, or nails. Ongoing thrush, sore mouth, or nail infections caused by Candida—often the earliest sign. PMC+1

2. Tingling, cramps, or seizures from low calcium. Underactive parathyroids (hypoparathyroidism) cause low calcium that triggers muscle cramps, numb lips/fingers, or even seizures. NCBI

3. Fatigue, weight loss, low blood pressure. Primary adrenal failure (Addison disease) leads to salt loss, dizziness, fainting, and severe fatigue. NCBI

4. Skin changes. Vitiligo (white patches), alopecia (hair loss), dry skin, or painful mouth angles. PubMed

5. Thyroid problems. Slowed body functions (hypothyroidism) or, less often, overactive thyroid. PubMed

6. Delayed puberty or infertility. Gonadal failure can cause absent/irregular periods or low testosterone symptoms. PubMed

7. Stomach and blood issues. Autoimmune gastritis/pernicious anemia leads to B12 deficiency, pallor, and weakness. PubMed

8. Liver inflammation. Autoimmune hepatitis with tiredness, jaundice, or abnormal liver tests. PubMed

9. Lung symptoms. Chronic cough or breathlessness from autoimmune pneumonitis. PubMed

10. Asplenia or poor spleen function. Increases infection risk. PubMed

11. Diarrhea or malabsorption. Intestinal involvement causes weight loss and nutrient deficits. PubMed

12. Kidney issues. Protein in urine or swelling when renal involvement occurs. BioMed Central

13. Eye and enamel problems. Dry eyes, keratitis, or thin tooth enamel (enamel hypoplasia). PMC

14. General infections or unusual reactions to viruses. Cytokine autoantibodies can change infection patterns. PMC

15. Psychosocial stress. Chronic illness burden, fatigue, and frequent appointments affect daily life. PMC

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Diagnostic tests

A) Physical examination

1) Full skin–nail–mouth exam. Doctors look for thrush, angular cheilitis, nail dystrophy, vitiligo, alopecia, and enamel changes—clues to APS-1. PMC

2) Vital signs and hydration status. Low blood pressure, weight loss, and skin pigmentation may point to adrenal failure; muscle cramps suggest low calcium. NCBI

3) Puberty/thyroid checks. Absent periods, small testes, or thyroid enlargement prompt endocrine testing. PubMed

B) Manual/bedside tests

4) Chvostek and Trousseau signs. Gentle tapping or a blood-pressure cuff can trigger facial twitch or hand spasm in hypocalcemia, supporting hypoparathyroidism. NCBI

5) Orthostatic BP test. A drop in blood pressure upon standing suggests salt-wasting in Addison disease. NCBI

6) Simple oral exam for candidiasis. Removable white plaques and sore mouth indicate mucocutaneous candidiasis. PMC

C) Laboratory and pathological tests

7) Serum calcium, phosphorus, magnesium, and PTH. Low calcium with inappropriately low PTH confirms hypoparathyroidism. NCBI

8) Morning cortisol and ACTH; ± ACTH stimulation test. Low cortisol with high ACTH indicates primary adrenal failure. NCBI

9) Thyroid panel (TSH, free T4) and thyroid antibodies. Detects autoimmune thyroid disease common in APS-1. PubMed

10) B12 level, intrinsic factor/parietal cell antibodies, CBC. Screens for pernicious anemia and gastritis. PubMed

11) Liver chemistries and autoimmune hepatitis antibodies. Evaluates hepatic involvement. PubMed

12) Gonadal hormones (FSH/LH, estradiol/testosterone). Assesses primary ovarian/testicular failure. PubMed

13) Glucose/HbA1c and islet antibodies. Checks for type 1 diabetes. PubMed

14) Serum electrolytes and renin/aldosterone. Helps stage adrenal failure and salt balance. NCBI

15) Broad autoantibody profile. APS-1 often includes cytokine autoantibodies (e.g., against IL-17, IL-22; sometimes type I interferons) and organ-specific autoantibodies. PMC+1

16) Fungal culture or PCR from lesions (when unclear). Confirms Candida species in resistant or atypical cases. PMC

17) AIRE genetic testing (sequencing). A disease-causing AIRE variant confirms APS-1 even if the full triad is not yet present. NCBI

D) Electrodiagnostic tests

18) ECG for QT prolongation in hypocalcemia. Low calcium from hypoparathyroidism can lengthen the QT interval and predispose to arrhythmia; ECG helps monitor risk. NCBI

E) Imaging tests

19) Chest CT or MRI (as needed). Assesses autoimmune pneumonitis or lung scarring when people have cough or breathlessness. PubMed

20) Abdominal ultrasound or MRI. Helps evaluate liver disease and, when indicated, kidneys or adrenals for complications; imaging complements lab data.

Non-pharmacological treatments

1. Multidisciplinary care & regular screening — Coordinate care among endocrinology, infectious disease, dentistry, pulmonology, hepatology, gastroenterology, ophthalmology, and genetics. Routine screening (hormones, oral health, lung checks) catches problems early and prevents complications like bronchiectasis or strictures. NCBI+1

2. Candida hygiene & triggers — Good oral/skin care, denture hygiene, avoiding smoking and high-sugar foods reduce Candida load and oral cancer risk linked to chronic Candida. PMC

3. “Steroid sick-day” education (for Addison’s) — Learn when and how to increase hydrocortisone during fever, vomiting, surgery, or trauma; carry a steroid emergency card and injectable hydrocortisone. This prevents adrenal crisis. Society for Endocrinology+1

4. Calcium crisis prevention (for hypoparathyroidism) — Education on maintaining target calcium, recognizing tingling/cramps, taking meds with food as advised, and not missing doses, to avoid emergency hypocalcemia. Wiley Online Library

5. Lung-protective plan — Early evaluation of chronic cough; airway clearance training; vaccinations per standard schedules; timely antibiotics for bronchiectasis flares; and referral to a bronchiectasis program if needed. PMC+1

6. Dental prevention program — Fluoride varnish, sealants, remineralizing therapy, minimally invasive restorations, and regular dental visits combat enamel hypoplasia and caries common in APS-1. PMC+1

7. Eye surface care — Lubrication, lid hygiene, and specialist follow-up for APECED keratopathy; early management may avert scarring and reduce need for transplants. Lippincott Journals

8. Nutrition support in enteropathy — Dietitian-guided nutrition (adequate calories, electrolytes, fat-soluble vitamins) during autoimmune enteropathy flares helps reduce hospitalizations and speeds recovery alongside medical therapy. PMC

9. Education on infection risks — Because interferon-blocking autoantibodies can worsen some viral infections, families should seek care early for serious fevers/viral illnesses and share APS-1 info with clinicians. PMC

10. Genetic counseling — APS-1 is usually autosomal recessive; counseling helps families plan testing of siblings and future pregnancies. NCBI

Drug treatments

1. Fluconazole for chronic mucocutaneous candidiasis — An oral azole antifungal used as first-line for mucosal Candida if species is susceptible; dosing depends on site/severity (typical adult oral/esophageal 100–200 mg daily; duration varies). Purpose: clear infections and prevent strictures. Side effects: liver enzyme elevations, drug interactions. Oxford Academic+1

2. Hydrocortisone for primary adrenal insufficiency — A glucocorticoid (often 15–25 mg/day split doses) replaces missing cortisol; fludrocortisone (a mineralocorticoid) treats salt loss. Purpose: normalize energy, blood pressure, and stress response. Teach stress-dosing and emergency injection. Side effects: weight gain, hypertension if over-replaced. PubMed+1

3. Fludrocortisone — A mineralocorticoid (commonly 0.05–0.2 mg/day) to control potassium and maintain blood pressure in Addison’s. Monitor blood pressure, potassium, and renin. Side effects: edema, hypertension, hypokalemia. e-EnM

4. Calcitriol plus oral calcium for hypoparathyroidism — Active vitamin D (e.g., calcitriol 0.25–1.0 µg/day) with divided elemental calcium maintains low-normal serum calcium and reduces symptoms. Purpose: replace missing PTH effect. Side effects: hypercalciuria, kidney stones if over-treated. Wiley Online Library+1

5. Levothyroxine for hypothyroidism — A thyroid hormone; typical start ~1.6 µg/kg/day in healthy adults with dose titration to normalize TSH. Purpose: restore normal metabolism. Side effects (if over-treated): palpitations, bone loss. PMC+1

6. Insulin for type 1 diabetes — Basal-bolus injections or pumps; insulin is essential when pancreatic autoimmunity causes insulin deficiency. Purpose: control glucose and prevent ketoacidosis. Side effects: hypoglycemia if dosing not matched to intake/activity. Diabetes Journals

7. Immunosuppression for autoimmune hepatitis — Prednisone/prednisolone (often 0.5–1 mg/kg/day) ± azathioprine (e.g., 50 mg/day then weight-based) is guideline-supported first-line; mycophenolate if AZA not tolerated. Purpose: stop liver damage. Risks: infection, cytopenias, liver toxicity—monitor closely. SPGP+2PMC+2

8. Combination immunotherapy for APECED pneumonitis — Case-series support azathioprine or mycophenolate plus rituximab for autoimmune lung inflammation to prevent progression to bronchiectasis; dosing individualized in specialty centers. Side effects: infusion reactions, infection risk. PMC+1

9. Topical ophthalmic immunomodulators for keratopathy — Specialist-directed topical cyclosporine A may help chronic inflammatory keratitis and reduce scarring risk; monitor for burning/irritation. ScienceDirect

10. Budesonide / systemic steroids for autoimmune enteropathy — Budesonide (locally acting steroid) or systemic corticosteroids induce remission; thiopurines or biologics considered if refractory, per specialist. Purpose: control diarrhea and malabsorption. PMC+1

Dietary & molecular supplements

1. Cholecalciferol (vitamin D3) — Maintains 25-OH vitamin D sufficiency to optimize calcium absorption alongside calcitriol; dosing individualized (often 800–2000 IU/day, higher if deficient). Function: supports bone and calcium balance in hypoparathyroidism. Wiley Online Library

2. Elemental calcium (carbonate or citrate) — Divided doses with meals (typical 1–3 g/day elemental, tailored) to maintain target serum calcium when PTH is low. Function: reduces cramps/tingling and protects bone. Wiley Online Library

3. Magnesium — Correcting low magnesium helps PTH secretion/action and stabilizes calcium; dose per labs and tolerance. Function: supports neuromuscular stability. Wiley Online Library

4. Phosphate moderation — Not a pill, but a nutrition point: avoid excess phosphate additives; helps keep calcium-phosphate product in safe range. Function: protects kidneys and soft tissues. Wiley Online Library

5. Fat-soluble vitamins in malabsorption — In autoimmune enteropathy, vitamins A/E/K supplementation may be needed to correct deficiencies and support vision, nerves, and clotting. Function: prevents deficiency complications. PMC

6. Electrolyte replacement during diarrheal flares — Oral rehydration with sodium/potassium solutions prevents dehydration and helps maintain adrenal/thyroid medication absorption. Function: stabilizes volume and electrolytes. PMC

Immunity-/regeneration-oriented” hormone therapies

1. rhPTH(1-84) (parathyroid hormone) — For chronic hypoparathyroidism not well-controlled on standard care, once-daily rhPTH(1-84) can reduce calcium/calcitriol needs and smooth calcium levels; dosing is individualized in endocrinology care. Oxford Academic+1

2. Teriparatide [PTH(1-34)] — Off-label alternative in difficult hypoparathyroidism; often 20 µg twice daily works better than once daily. Pumps (continuous infusion) have been used in refractory cases. SpringerLink+1

3. Palopegteriparatide (long-acting PTH prodrug) — Real-world data show use with dose titration alongside conventional therapy; availability varies by region and program. ScienceDirect

4. Rituximab (B-cell depleter) in specific organ autoimmunity — In APS-1 pneumonitis, adding rituximab to a steroid-sparing agent can lead to remission in specialized centers. PMC

Procedures & surgeries

1. Endoscopic dilation for Candida-related esophageal strictures — Recurrent esophageal Candidiasis can cause narrowing; serial dilations plus antifungals restore swallowing. Frontiers

2. Ocular surface surgery / keratoplasty — Severe scarring keratitis may require corneal transplantation; rejection risk and recurrence demand close specialist care. PubMed+1

3. Comprehensive dental rehabilitation — Severe enamel hypoplasia may need staged restorations/veneers/implants to restore function and reduce infections. PMC

Prevention tips

1. Carry emergency hydrocortisone and a steroid card if you have Addison’s; teach family how to use it. Society for Endocrinology
2. Have a personal action plan for fever, vomiting, or surgery (stress dosing). PMC
3. Address Candida early (mouth rinses, prompt antifungals) to prevent strictures. Oxford Academic
4. Routine lung checks for chronic cough to catch pneumonitis before bronchiectasis. PMC
5. Regular dental and eye visits to prevent long-term damage. PMC+1
6. Vaccinations per standard schedules and early medical attention for severe viral illness (due to anti-interferon antibodies). PMC
7. Medication adherence (calcium/calcitriol/thyroid/adrenal) to avoid crises. Wiley Online Library
8. Genetic counseling/testing for siblings where appropriate. NCBI

When to see a doctor urgently

Go now if you have any of these: new severe vomiting, fainting, very low blood pressure, or confusion (possible adrenal crisis); tingling around mouth, muscle cramps, or spasms that don’t stop (possible hypocalcemia); chest pain or painful swallowing (possible esophageal candidiasis/stricture); daily/night cough, breathlessness, or fever (possible pneumonitis/bronchiectasis); eye pain/light sensitivity (possible keratitis). Lippincott Journals+4Society for Endocrinology+4Wiley Online Library+4

What to eat & what to avoid

Aim for balanced meals with adequate calcium (as prescribed), normal magnesium, and not too much phosphate (avoid cola/phosphate-additive processed foods) if you have hypoparathyroidism. Maintain stable carbohydrate intake if you have diabetes and coordinate with insulin. Limit high-sugar foods/drinks that fuel Candida, and keep excellent oral hygiene. Keep good hydration—especially during illness—to support adrenal and kidney function. Wiley Online Library

FAQ

1) Is APS-1 contagious?
No. It’s a genetic immune disorder from AIRE variants (usually autosomal recessive). NCBI

2) Can APS-1 be cured?
There’s no single cure, but organ-specific treatments and timely immunosuppression can control disease and prevent complications. NCBI

3) Why do I get so many Candida infections?
Autoantibodies that block IL-17/IL-22 weaken antifungal defenses, so Candida persists on skin and mucosa. MDPI

4) Why are viral illnesses sometimes severe?
Some patients have neutralizing antibodies to type I interferons, key early antiviral proteins. PMC

5) What’s the role of genetic testing?
Confirming AIRE mutations supports diagnosis, guides family screening, and may enroll you in research. NCBI

6) What’s the best antifungal for me?
Fluconazole is first choice for many mucosal infections if the strain is susceptible; therapy and duration are individualized. Oxford Academic

7) How do I prevent an adrenal crisis?
Know sick-day rules, carry a steroid card, and have emergency hydrocortisone available. Society for Endocrinology

8) Are PTH injections an option?
Yes—rhPTH(1-84) (and sometimes teriparatide) can help hard-to-control hypoparathyroidism under specialist care. Oxford Academic+1

9) Why is my dentist part of the team?
Enamel hypoplasia and oral Candida are frequent; proactive dental care prevents pain, infections, and tooth loss. PMC

10) I have a chronic cough—is that part of APS-1?
It can be. APECED pneumonitis is under-recognized; early lung evaluation and immunosuppression can prevent bronchiectasis. PMC

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: September 29, 2025.

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