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Role of AIRE in Thymoma-associated

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Presentation on theme: "Role of AIRE in Thymoma-associated"— Presentation transcript:

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

2 APECED/APS-1 and AIRE The Autoimmune regulator (AIRE)
is a gene mutated in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy or APECED Thymus 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) Virtually 100% of patients have auto-Ab to type I interferons EuroMG, Paris

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

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

5 Functional effect of AIRE-driven autoantigen expression
in medullary thymic epithelial cells (mTECs) Apoptotic mTEC mTEC DC Cross-presentation by dendritic cells (DC) Promiscuous expression and improved prentation of autoantigens & MHCII Tolerance Induction Mathis & Bennoit, ARI, 2009 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 HCs Aire+ Cells Aire/HCs ~ (0 - 40y) ~ (41- 90y) Hassall‘s Corpuscles & Aire+ Cells per Area Mean HCs per area NT Outlier (HCs) Mean Aire+ per area NT Outlier (Aire+) Age, Decades EuroMG, Paris

8 Among WHO-defined Thymomas Hassall‘s Corpuscles are common
only in Type B1 Thymomas („predominantly cortical“) WHO-Classification: 1999, 2004 A AB B1 B2 B3 „C“ „Medullary“ Mixed „Cortical“ TSCC Histogenetic Classification: Marino & Müller-Hermelink, 1985; Kirchner, 1992 EuroMG, Paris

9 AIRE--- >95% of thymomas, including all type A & AB
thymomas do not express AIRE* (Ströbel, 2007) Thymus Type B1§ § ~50% of type B1 thymomas are Aire+ 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 Does AIRE-deficiency in thymomas elicit autoimmune
diseases, including APECED ? Apoptotic mTEC mTEC NO DC Cross-presentation by dendritic cells (DC) NO Promiscuous expression and improved presentation of autoantigens & MHCII Impaired Clonal Deletion Autoimmunity Mathis & Bennoit, ARI, 2009 EuroMG, Paris

12 MG overlap: anti-IFN type I
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 overlap: anti-IFN type I MG ANA anti-AChR anti-striational anti-TPO 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) MG+ Thymoma (Aire ----) MG-negative Thymoma (AIRE----) NT / Thymitis CD4 RA CD4 RA CD4 RA 16,0 % 26,7 % 2,5 % CD45 RA FITC CD 4 QR 18,3 % CD8 RA 25,3 % 4,5 % CD45 RA FITC CD 8 PE

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 Ströbel et al. Ann N Y Acad Sci, 2008 Expression / b-Actin 2 4 FOXP3 NT MG(+) MG(-) - * EuroMG, Paris

16 AIRE Expression and Hassall‘s Corpuscles are correlated in B1 Thymoma
Hassall+ B1 Thymoma AIRE & HC Status of Medullary Islands in B1 Thymomas Hassall--- B1 Thymoma AIRE+ AIRE- Hassall + 343 222 Hassall --- 34 123 P<0.0001 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 NO ! 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 LTb, 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 ? NO ! EuroMG, Paris

20 Phenotypic Markers of Thymic Epithelial Cell Subsets
MHC-IIlo DEC205+ MHC-IIhi DEC205+ MHC-IIlo Aire ----- MHC-IIhi Aire +/- Kyewski, 2007 Anderson, 2009

21 „Compartment-specific“ gene expression profiling of thymomas
compared to purified cortical and medullary normal TECs 4606 Genes on OncoChip 153 53 Gotter et al. 2004 162 443 Cortical Genes Medullary Genes

22 Hypothetical „Developmental Concept“ of the WHO Thymoma Classification
Mutation Other MG+Thymoma Types B1 Thymoma B1 Thymoma Oversize of Cortex MHC-IIlo Aire ---- MHC-IIhi Aire + EuroMG, Paris

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

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