GeneticsTier 2Medical Sciences concept

Autoimmune polyendocrine syndromes - genetics (AIRE, FOXP3)

Core concept

Two monogenic syndromes that map onto the two arms of immune tolerance, plus a common polygenic syndrome
APS-1 / APECED = failure of CENTRAL tolerance
- AIRE (autoimmune regulator, 21q22.3), autosomal recessive
- AIRE is a transcriptional regulator in thymic medullary epithelial cells driving promiscuous expression of tissue-specific self-antigens (insulin, thyroglobulin, CYP enzymes)
- -> autoreactive thymocytes are never shown their target -> escape negative selection
IPEX = failure of PERIPHERAL tolerance
- FOXP3 (Xp11.23), X-linked recessive -> males
- FOXP3 is the master transcription factor of CD4+CD25+ regulatory T cells -> no functional Tregs -> unchecked effector T cells
APS-2 = polygenic, HLA-DR3/DR4 (DQ2/DQ8), CTLA-4, PTPN22 - far commoner than either monogenic form, and the one actually seen on the wards

	APS-1 (APECED)	APS-2 (Schmidt)	IPEX
Gene	AIRE	Polygenic, HLA-DR3/DR4	FOXP3
Inheritance	AR	Polygenic	X-linked
Onset	Childhood	Adulthood, F>M	Neonatal/infancy
Classic triad	Chronic mucocutaneous candidiasis + hypoparathyroidism + Addison's (2 of 3 = diagnosis)	Addison's + autoimmune thyroid disease and/or T1DM	Enteropathy + T1DM + eczema
Other	Ectodermal dystrophy (nail/enamel), keratoconjunctivitis, autoimmune hepatitis, pernicious anaemia, hypogonadism, alopecia, vitiligo, asplenia	Coeliac, vitiligo, pernicious anaemia, alopecia, myasthenia	Autoimmune cytopenias, thyroiditis, nephritis, severe infections
Hallmark antibody	Anti-interferon-alpha and anti-interferon-omega (present in ~100%, even before disease)	Organ-specific (21-hydroxylase, TPO, GAD65)	-
Prognosis	Lifelong sequential organ failure	Good with replacement	Fatal in infancy without HSCT

APS-1 order of appearance: candidiasis (~age 5) -> hypoparathyroidism (~age 9) -> Addison's (~age 14); new components keep appearing for decades - the surveillance never stops
Anti-IL-17A/IL-17F/IL-22 autoantibodies explain the mucocutaneous candidiasis in APS-1 - a phenocopy of the IL-17 pathway defects
Anti-21-hydroxylase antibody predicts progression to Addison's in APS-2
Hypoparathyroidism essentially never occurs in APS-2 - it is the discriminator

One autoimmune endocrinopathy mandates looking for the others - the classic exam trap is treating new hypothyroidism in a patient with undiagnosed Addison's; thyroxine accelerates cortisol clearance and can precipitate adrenal crisis**
- Always replace glucocorticoid before thyroxine
Screen periodically in a diagnosed proband: morning cortisol/ACTH (or Synacthen), TSH, HbA1c/glucose, B12, calcium/PTH, coeliac serology, FBC
Falling insulin requirement or unexplained hypoglycaemia in type 1 diabetes -> think coeliac disease or new Addison's
APS-1 pointers: hypoparathyroidism in a child, unexplained mucocutaneous candidiasis, or a combination of endocrine and non-endocrine autoimmunity -> AIRE sequencing and anti-interferon-omega antibodies
- Consider oesophageal squamous carcinoma surveillance in long-standing candidiasis, and hyposplenism vaccination
IPEX - intractable neonatal enteropathy with T1DM in a boy -> FOXP3 testing; bridge with sirolimus/immunosuppression, definitive treatment is allogeneic HSCT
*CTLA-4 haploinsufficiency and LRBA deficiency produce an IPEX-like picture with hypogammaglobulinaemia and lymphoproliferation - treated with abatacept* (CTLA-4-Ig)
Checkpoint inhibitor therapy is the acquired phenocopy - blocking CTLA-4 or PD-1 removes the same peripheral tolerance and causes thyroiditis, hypophysitis, T1DM and adrenalitis

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.