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Role of AIRE in Thymoma-associated Myasthenia Gravis ? University Medical Centre Mannheim Thymoma AIRE-PHD1 AIRE in mTEC Alexander Marx, MD University.

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Presentation on theme: "Role of AIRE in Thymoma-associated Myasthenia Gravis ? University Medical Centre Mannheim Thymoma AIRE-PHD1 AIRE in mTEC Alexander Marx, MD University."— Presentation transcript:

1 Role of AIRE in Thymoma-associated Myasthenia Gravis ? University Medical Centre Mannheim Thymoma AIRE-PHD1 AIRE in mTEC Alexander Marx, MD University of Heidelberg EuroMG Paris,

2 APECED/APS-1 and AIRE The Autoimmune regulator (AIRE) is a gene mutated in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy or APECED Several autoimmune (endocrine) diseases (highly variable) Hypoparathyroidism & Addison’s disease Type 1 diabetes mellitus Gonadal dysfunction (e.g. premature ovarian failure) Autoimmune hepatitis, Alocecia, Autoimmune Thyroid Disease... Mucocutaneous Candidiasis (often first & leading symptom) Thymus EuroMG, Paris Virtually 100% of patients have auto-Ab to type I interferons

3 AIRE is mainly expressed in keratin-positive medullary thymic epithelial cells (mTEC), less commonly in dendritic cells Aire Pan- Cytokeratin (mTEC) EuroMG, Paris Regulation of > 1000 genes

4 Aire Thyroglobulin Aire p450_c17 Pärt Peterson Aire drives „promiscuous“ expression of „tissue-specific antigens“ (TSA) and some other genes mainly in medully thymic epithelial cells AIRE-dependent TSA: Insulin, TPO, casein ,  -subunit of AChR, p450, S100 A8 EuroMG, Paris

5 Mathis & Bennoit, ARI, 2009 Functional effect of AIRE-driven autoantigen expression in medullary thymic epithelial cells (mTECs) mTEC Cross-presentation by dendritic cells (DC) Promiscuous expression and improved prentation of autoantigens & MHCII DC Apoptotic mTEC Tolerance Induction EuroMG, Paris

6 Significant Correlation between Prevalence of HCs and Prevalenve of AIRE+ Cells in Normal Human Thymus r = 0.81 p< EuroMG, Paris

7 Age-dependent decline of Hassall‘s Corpuscles and AIRE+ cells in normal human thymus Age, Decades Hassall‘s Corpuscles & Aire+ Cells per Area HCs Aire+ Cells Mean HCs per area NT Outlier (HCs) Mean Aire+ per area NT Outlier (Aire+) Aire/HCs ~ (0 - 40y) ~ (41- 90y) EuroMG, Paris

8 AABB1B2B3„C“ „Medullary“Mixed„Cortical“TSCC Among WHO-defined Thymomas Hassall‘s Corpuscles are common only in Type B1 Thymomas („predominantly cortical“) WHO-Classification: 1999, 2004 Histogenetic Classification: Marino & Müller-Hermelink, 1985; Kirchner, 1992 EuroMG, Paris

9 >95% of thymomas, including all type A & AB thymomas do not express AIRE* (Ströbel, 2007) AIRE --- Thymus Type B1 § § ~50% of type B1 thymomas are Aire + *AIRE, Autoimmune Regulator

10 Loss of AIRE and AIRE-related self-antigen expression in >95 of thymomas Ströbel et al. J Pathol 2007

11 Mathis & Bennoit, ARI, 2009 Does AIRE-deficiency in thymomas elicit autoimmune diseases, including APECED ? mTEC Cross-presentation by dendritic cells (DC) Promiscuous expression and improved presentation of autoantigens & MHCII DC Apoptotic mTEC Autoimmunity NO Impaired Clonal Deletion EuroMG, Paris

12 Minimal overlap of clinical and serological autoimmune features in APS-1 patients and patients with AIRE(-) thymomas anti-insulin anti-GAD65 anti-Cyp1a2 anti-Cyp17 anti-Cyp21 ANA anti-AChR anti-striational anti-TPO overlap: anti-IFN type I MG EuroMG, Paris

13 Generation and export of CD4+ T-Cells is the „sine qua non“ of MG development in type AB and B Thymomas (Ströbel; Buckley) CD45 RA FITC NT / Thymitis CD4 RA 16,0 % 26,7 %2,5 % CD 8 PE 18,3 % CD8 RA 25,3 % CD8 RA 4,5 % CD8 RA CD 4 QR MG-negative Thymoma (AIRE----) CD4 RA MG+ Thymoma (Aire ----)

14 Production of Regulatory T-cells is Impaired in Type Ab and B Thymomas (Ströbel, Ann Neurol, 2004) EuroMG, Paris

15 Thymomas as an human model to study the relationship between AIRE expression and generation of FOXP3+ regulatory T cells Expression /  -Actin FOXP3 NTMG(+) MG(-) - * * Ströbel et al. Ann N Y Acad Sci, 2008 EuroMG, Paris

16 AIRE+AIRE- Hassall Hassall P< AIRE & HC Status of Medullary Islands in B1 Thymomas H+A+ H--A+ H+A-- H--A-- AIRE Expression and Hassall‘s Corpuscles are correlated in B1 Thymoma Hassall+ B1 Thymoma Hassall--- B1 Thymoma EuroMG, Paris

17 In B1 Thymomas the number of FoxP3+ cells (likely Tregs) is NOT correlated with the presence of Aire+ cells FoxP3 per Aire+ cell FoxP3 per Aire-- cell Case # AIRE is probably NOT involved in the generation of Tregs in humans EuroMG, Paris

18 Why is AIRE Expression Reduced in Thymomas? EuroMG, Paris

19 Factors known to be associated with thymic Aire deficiency in thymic epithelial cells (TECs) Germ line mutation of Aire gene (APS I, APECED) Abnormal hyper-methylation of Aire promoter Lack of LT  RANK/RANKL, TRAF, RelB / NFkB signalling Defective T-cell maturation in various SCIDs, Omen Syndrome, chronic cyclosporine treatment (> secondary defects of TECs) Defective TEC maturation in thymoma ? EuroMG, Paris NO !

20 Phenotypic Markers of Thymic Epithelial Cell Subsets MHC-II lo Aire MHC-II hi Aire +/- Kyewski, 2007 Anderson, 2009 MHC-II lo DEC205+ MHC-II hi DEC205+

21 Medullary GenesCortical Genes Genes on OncoChip 443 „Compartment-specific“ gene expression profiling of thymomas compared to purified cortical and medullary normal TECs 162 Gotter et al. 2004

22 Hypothetical „Developmental Concept“ of the WHO Thymoma Classification MHC-II lo Aire ---- MHC-II hi Aire + Mutation B1 ThymomaOther MG+Thymoma Types EuroMG, Paris B1 Thymoma Oversize of Cortex

23 Summary AIRE deficiency in thymomas does not correlate with the MG Status of thymoma patients the efficiency of intrathymomatous CD4+ thymopoiesis the capacity to generate FoxP3+ Tregs AIRE deficiency in thymomas is an indicator of TEC immaturity and likely of functional insufficiency of TECs in A, AB, B2 and B3 thymomas The massively increased cortex/medulla ratio in B1 thymomas might be a structural basis for tolerance failure in AIRE+ B1 thymomas

24 Mannheim: Philipp Ströbel Wen-Yu Chuang Christian Sauer Djeda Belharazem Li Norbert Gretz Alexander Marx Würzburg etc. Bei Huang Andreas Zettl Andreas Rosenwald Mannheim: Philipp Ströbel Wen-Yu Chuang Christian Sauer Djeda Belharazem Li Norbert Gretz Alexander Marx Würzburg etc. Bei Huang Andreas Zettl Andreas Rosenwald Acknowledgments


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