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Nature Reviews Immunology, Volume 8, December 2008

Nature Reviews Immunology, Volume 8, December 2008. Self Tolerance. “Ability to distinguish self-reactive from nonself-reactive lymphocytes”. Central Tolerance/Negative Selection. Negative selection of self-reactive thymocytes mTECs expressing TSA

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Nature Reviews Immunology, Volume 8, December 2008

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  1. Nature Reviews Immunology, Volume 8, December 2008

  2. Self Tolerance • “Ability to distinguish self-reactive from nonself-reactive lymphocytes”

  3. Central Tolerance/Negative Selection • Negative selection of self-reactive thymocytes • mTECs expressing TSA • AIRE turns on (peripheral) genes in the thymus • Deletion of self-reactiveT cells

  4. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; (APS-1) Monogenic autoimmune syndrome; mutations in the AIRE gene More common in certain population; Finnish & Sardinians Presence of autoantibodies specific for multiple self antigens  structural & functional similarities Lymphocytic infiltration of endocrine glands Autoantibodies can be used as diagnostic markers Most common mutation of AIRE: R257X in exon 6 / 13 base-pair deletion in exon 8 AIRE-deficient mice not susceptible to candidiasis APECED

  5. Common autoimmune diseases

  6. What is the molecular mechanism of AIRE to prevent autoimmunity?

  7. Infiltration of Peripheral tissues in AIRE -/- mice by mononuclear cells mTECs in AIRE-/- mice express less peripheral TSAs  Ins2 & Spt1 Other factors are also necessary for the efficient TSA expression AIRE-/- mice expressing transgenic HEL & TCRs developed diabetes AIRE-/- develop AI uveitis (IRBP) and gastritis (MUC6) AIRE-/- mice reacted also against AIRE-independent expressed proteins AIRE deficiency results in autoimmunity • AIRE might have other roles in negative selection chemokine or antigen presentation downregulated • AIRE deficiency leads to an accumulation of imma. CD4+ Liston et al., 2003

  8. mTEC subpopulations express AIRE in the thymus  CD80, CD86, CD40 and MHC class IIhi Two subsets of mTECs in the thymic medulla CD80lowMHC classIIlow & CD80hiMHC classIIhi AIRE expression activates the promiscuous expression of TSAs in mature mTECs (CD80hiMHC classIIhi) AIRE directs mTECs differentiation High level of heterogeneity between mTEC subpopulations mTEC differentiation: CD80lowAIRE- CD80hiAIRE- CD80hiAIRE+ Defects in alternative NFkB pathways disturb AIRE expression RANK is needed for differentiation of mTECs from AIRE- to AIRE+ cells AIRE expression by mTECs

  9. Functional domains of AIRE • Domains characteristic of transcriptional regulators & chromatin-binding proteins • Nuclear protein; fibrillar structures in the cytoplasm • Functional domains are highly conserved between mammalian AIRE homologues COS-1 Pitkanen et al., 2001

  10. Localization of nuclear bodies COS-1 • AIRE locates in dot-like structures • AIRE nuclear body localization depends on the CARD domain • PML nuclear bodies contain AIRE interacting proteins • PML and AIRE Nuclear bodies are associated with the nuclear matrix • AIRE nuclear bodies might influence nuclear organization of chromatin • AIRE also in the nucleoplasm HeLa Bjorses et al., 1999

  11. AIRE is a potent transcriptional activator PHD zinc fingers, CARD and SAND participate in transcriptional activation of AIRE AIRE does not seems to act as a specific DNA binding transcription factor, but rather have a more general function AIRE binds directly to CBP  promotes the transcription PIAS1 and DNA-PK identified as protein partners of AIRE  interaction are needed for the formation of AIRE associated nuclear structures and for the regulation of AIRE-mediated gene expression PIAS1 and AIRE might interact via different nuclear bodies DNA-PK phosphorylates N-terminal region of AIRE Transcriptional activation

  12. Transcriptional elongation and histone binding • AIRE promotes transcriptional elongation  via P-TEFb • P-TEFb forms a complex with RNA-Pol. II & removes N-TEF • PHD zinc fingers binds to N-terminal tail of unmythyl. H3K4 • AIRE functions as a transcription activator and initiator of gene expression • Trimethylated H3K4 genes are active and trimethylated H3K27 are silent; both modification are poised for transcription • TSA genes lacking trimethylated H3K4  silent genes • AIRE preferentially binds to unmodified histones

  13. Coordinated gene regulation? • AIRE might function as an activator & repressor • AIRE functions as a co-regulator of genomic clusters • Together with transcriptional regulators AIRE functions in protein complexes

  14. Stochastic gene regulation? • AIRE activates genes in a stochastic manner  identical cell clones show variations in protein expression between individual cells • Influencing factors are varying amounts of gene regulators, availability of chromosomal positions etc. • AIRE regulated genes are expressed in mTECs in random combination and at relatively low levels

  15. Thank you for your attention!

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