Monique Lee

APECED & IPEX Discuss the laboratory, clinical genetic and pathophysiological aspects of

1) APECED 2) IPEX

APECED

• Autoimmune polyendocrine syndrome type 1 (APS1) Genetics & pathophysiology

• Autosomal recessive, AIRE gene on 21q22.3 • More prevalent in Finns, Norwegians, Sardinians, Iranian Jews • Mutations in autoimmune regulator gene (AIRE), a transcription regulator highly expressed in

medullary thymus epithelial cells (mTEC) o AIRE induces ectopic expression of self-­antigens, presented to developing T cells in

the thymus (high affinity binding results in negative T cell selection) o Lack of AIRE: self-­reactive T cells escape thymic deletion, cause multiorgan

autoimmunity in periphery Clinical Usually a triad of mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure.

• Multiorgan autoimmunity o Addison’s, ovarian failure (primary hypogonadism in 60%), hypothyroidism, type 1

diabetes, pernicious anaemia, vitiligo, autoimmune hepatitis, Sjogren’s • Chronic mucocutaneous candiasis

o Usually first symptom in childhood or early adolescence, often recurrent and difficult to treat

• Hypoparathyroidism o Usually first endocrine manifestation (often before school age)

• Adrenocortical failure Usually develops later at 10-­15yrs

• Others o Enamel hypoplasia, alopecia, nail dystrophy, malabsorption & GI disorders,

keratopathy, IgA deficiency, asplenia Laboratory

• Autoantibodies: majority of APECED patients have a variety of autoantibodies which may predate disease

o IL17A, IL17F, IL22: may cause CMC;; detected in all APECED patients o IFN-­alpha: high titre neutralising IgG to IFN alpha and omega have been detected.

Highly specific (otherwise only in myasthenia gravis or thymoma patients) o 21-­hydroxylase: 75% of those with Addison’s o GAD65: frequently detected in intestinal dysfunction o SOX10: often detected in cutaneous autoimmune manifestations e.g. alopecia, vitiligo

• Genetic analysis: required for confirmation of diagnosis IPEX Genetics & pathophysiology

• X-­linked recessive, FOXP3 • FOXP3:

o Expressed mainly in lymphoid tissues, particularly CD4+ CD25bright regulatory T cells o Critical differentiation switch of Tregs. Once activated, forms homodimer and

transcriptionally represses cytokine promotors e.g. NF-­kB and NFAT o Represses production of multiple proinflammatory cytokines e.g. IL-­2, IL-­4, IFN-­

gamma o Deficiency: impaired ability to suppress immune activation

Monique Lee

Clinical • Onset within 1st year of life with severe watery or mucoid-­bloody diarrhoea, FTT, early onset

diabetes mellitus, thyroid disease, autoimmune cytopenia, variable skin lesions (erythroderma, exfoliative dermatitis, eczema, psoriasis-­like), renal disease (GN, interstitial nephritis)

• Increased susceptibility to infections o Sepsis, meningitis, pneumonia, osteomyelitis o Common pathogens: enterococcus, staphylococcus, CMV, candida

• Female carriers asymptomatic Laboratory

• Marked elevation of IgE • Elevated IgA in 60% • Eosinophilia • Elevated liver enzymes • Autoantibodies

o Islet cell Ab: most frequent o Also anti-­GAD, anti-­microsomal, anti-­thyroglobulin, anti-­smooth muscle, anti-­

enterocyte, anti-­pplatelet, anti-­neutrophil • Absence of T regulatory cells on FC (CD4+ CD25+ intracellular FOXP3) • Villous atrophy & lymphocyte infiltrates in small bowel mucosa • FOXP3 gene analysis • NOTE: normal specific antibody responses and lymphocyte prolifereation tests