Transcript The role of autophagy on the replication of Herpes Simplex

Nature Reviews Immunology, Volume 8, December 2008
Self Tolerance
• “Ability to distinguish self-reactive from nonselfreactive lymphocytes”
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
APECED
• 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
Common autoimmune diseases
What is the molecular
mechanism of AIRE to prevent
autoimmunity?
AIRE deficiency results in
autoimmunity
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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 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
AIRE expression by mTECs
• 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
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
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
Transcriptional activation
• 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 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 Nterminal 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
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
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
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