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APECED: monogenic autoimmune disease

APECED: monogenic autoimmune disease. Pärt Peterson. University of Tampere, Finland University of Tartu, Estonia. APS1 or APECED. APS1 (autoimmune polyendocrine syndrome type 1) or APECED ( autoimmune polyendocrinopathy candidiasis ectodermal dystrophy ). Autosomal recessive inheritance

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APECED: monogenic autoimmune disease

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  1. APECED: monogenic autoimmune disease Pärt Peterson University of Tampere, Finland University of Tartu, Estonia

  2. APS1 or APECED • APS1 (autoimmune polyendocrine syndrome type 1) or APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) • Autosomal recessive inheritance • More prevalent in some populations such asFinns (1:25000), Iranian Jews (1:9000) and Sardinians (1:14400). Very high incidence (1/4400) reported in a small town Bassa del Grappa, in Northern Italy • No HLA association Autoimmune regulator (AIRE) is a gene mutated in APECED

  3. Clinical Features • Endocrinopathies • Hypoparathyreoidism • Addison’s disease • Gonadal dysfunction • Type 1 diabetes mellitus • Autoimmune thyroiditis • Autoimmune gastritis • Chronic mucocutaneous candidiasis • Ectodermal dystrophies • dental enamel • nails • alopecia • vitiligo • Autoimmune hepatitis • Keratopathy

  4. Candida infection and vitiligo of APS1 patient From Prof. Olle Kämpe, Uppsala University

  5. APS1/APECED and APS2 are two different syndromes

  6. Autoantigens in Addison’sdisease • Steroid 17a-hydroxylase, P450c17 • Steroid 21-hydroxylase, P450c21 • Side-chain cleavage enzyme, P450scc Thomas Addison All three P450 enzymes are active in steroidogenesis in adrenal cortex. P450c21 is expressed only in adrenal cortex, P450c17 and P450scc are also expressed in gonads Krohn et al. Lancet 339: 770, 1992 Uibo et al. JCEM 78: 323, 1994

  7. APS1/APECED autoantigens

  8. AIRE protein • N-terminal HSR domain: homodimerisation • SAND domain: putative DNA binding • PHD finger: transcriptional regulation • Proline rich region • LXXLL motif: binding to nuclear receptors Nagamine et al. Nat Genetics 17: 393, 1997 The Finnish-German Consortium. Nat Genetics 17: 399, 1997

  9. Similarity to Nuclear Proteins Mi-2: helicase, involved in chromatin remodelling, autoantigen in dermatomyositis TIF1: transcriptional coactivator Sp100: interferon responsive, transcription activator, autoantigen in PBC, lymphoid restricted Sp140: homologous protein to Sp100, autoantigen in PBC

  10. in situ hybridisation Anti-AIRE ab Expression in the Thymus • The major AIRE expressing tissue is the thymus • Lower levels of expression are seen in the fetal liver, spleen and lymph nodes • In the thymus, AIRE is seen in a distinct subset of cells Heino et al. BBRC 257: 821, 1999

  11. Subcellular localization Aire localizes to nuclear dots in thymus medulla and in transfected Cos cells

  12. aa 11 7 100 189 516 63 67 280 299 340 350 430 434 475 520 545 AIRE L L NLS SAND PHD PRR L PHD L HSR/ASS (23.5%) aa 12 8 188 301 64 68 99 342 352 430 434 475 520 524 552 279 Aire HSR/ASS L L NLS SAND PHD PRR L PHD L (16%) ASS L L NLS SAND PHD L L PHD Human and Mouse AIRE proteins are 77% identical Mittaz et al. BBRC, 255: 483, 1999

  13. MTS5 MTS10 Aire co-localizes with epithelial cell markers in thymus medulla

  14. Spl macroph. Spl CD4+8-DC Thy CD8lo/-DC Spl CD4-8+DC Thy CD8+ DC Spl CD4-8-DC Thymocytes Aire b-actin AIRE is expressed in Dendritic cells Several subclasses of mouse dendriticcells express Aire AIRE mRNA is upregulated in vitro stimulated human DCs

  15. Thymocyte differentiation Cortex Double negative CD4- CD8- No T-cell receptor Double positive CD4+ CD8+ T-cell receptor Medulla Single positive CD4+ CD8- or CD4- CD8+ T-cell receptor

  16. Thymocytes are selected differentially according to their reactivity TCR reactive to non-self antigens Cells survive and when meeting pathogen will proliferate T-cell precursor Cell death TCR reactive to self antigens

  17. Autoimmune diseases and autoantigens Addison’s disease steroid P450 cytochromes Autoimmune gastritis H+/K+ ATPase Pernicious anemia intrinsic factor Hashimoto thyroiditis thyroid peroxidase, thyroglobulin Graves disease thyroid receptor Myasthenia gravis Acetylcholine receptor Type 1 diabetes insulin, GAD65 Vitiligo tyrosinase, MART Rheumatoid arthritis type 2 collagen Multiple sclerosis myelin basic protein

  18. Ectopic (promiscuous) expression of self antigens in thymus Many tissue specific autoantigens are expressed in thymus. During negativeselection, T-cells to these antigens are deleted. If antigen is not expressed in thymus or is expressed in a different way, this may cause autoimmunity From Gotter et al. 2004

  19. Diverse genes expressed in thymic epithelial cells Tissues specific antigens (pancreas, stomach, brain, eye, liver, muscle, kidney specific genes) Expression of genes expressed during fetal stages, pregnancy-associated genes Expression of male specific genes in females and vice versa Expression of cancer specific antigens Conserved in mice and humans Estimation of 3000 genes (5-10% of known genes) in addition to basal expression of thymic epithelial cells

  20. AIRE (autoimmune regulator) gene is central in expressing tissue specific antigens

  21. Aire deficient mice have autoantibodies and lymphocytic infiltration in multiple tissues Anderson et al. Science, 2002

  22. Microarray analysis of gene expression in wild-type and Aire deficient mouse The expression of tissue specific genes is lower or non-existing in Aire deficient mouse Anderson et al. Science, 2002

  23. HSR NLS SAND PHD PRR PHD The PHD zinc fingers form the activation domain of AIRE

  24. AIRE Interacts with CBP • AIRE binds CBP at its CH1 and CH3 domains by far western and yeast two-hybrid assays • CH1 also binds STAT2 and HIF-1a; CH3 binds E1A and TFIIB

  25. CBP: cAMP response element binding (CREB) protein binding protein CBP is implicated in various transcriptional responses regulating growth, differen- tiation or apoptosis Belongs to the class of transcription co-activators possessing histone acetyl- transferase activity (HAT) and thus have the potential to regulate the chromatin structure From Hottiger and Nabel, 2000 CBP/p300 interacts with many transcription activators and coactivators

  26. AIRE CBP merge AIRE Colocalises with CBP

  27. 3D picture of AIRE dots Nuclear Bodies • Most prominent nuclear bodies are promyelocytic leukemia (PML) nuclear body or POD (PML oncogenic domain) • Approximately 0.3 to 1 micrometers in diameter • Other proteins in nuclear dots are involved in transcription or suspected in chromatin binding (Sp100, CBP, BLM, p53) • Function unknown, activation or degradation site? • Some of the proteins like CBP move in and out.

  28. AIRE Function AIRE induces the expression of autoantigens that lead to the elimination of the autoreactive T cells Thymus T cell autoreactive to APECED autoantigen AIRE Thymic epithelial cell expressing autoantigens

  29. Loss of Function When AIRE is defective, autoreactive T cells escape selection, and autoimmunity develops Thymus T cell autoreactive to APECED autoantigen No AIRE Thymic epithelial cell expressing autoantigens

  30. University of Tampere Jukka Pitkänen Camelia Magureanu Ulla Aapola Niko Sillanpää Astrid Murumägi Maarit Heino Pärt Peterson Kai Krohn WEHI, Melbourne Hamish Scott Li Wu Keio University, Tokyo Jun Kudoh Nobuyoshi Shimizu University of Geneva Laureane Mittaz Stylianos Antonarakis University of Tokushima Mitsuru Matsumoto University of Würzburg Philipp Ströbel Alex Marx University of Birmingham Graham Anderson Eric Jenkinson

  31. University of Tartu Ana Rebane Vivian Kont Kaidi Möll Tõnis Org Ingrid Liiv Eneli Õis Annika Reimets Rainis Venta Mario Saare

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