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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
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