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Autoimmunity, Autoimmunity Genetic/Environmental Basis Females more predisposed to dzs, Autoimmunity Tx NSAIDS Corticosteroids, immunosupps -both dampen inflammation Biological Tx -anti-TNF-a for rhem arth -mABs for MS, Crohn's -block VLA-4 integrin ->prevent MS relapse, Autoimmunity Genetic/Environmental Basis Familial -IDDM runs in families -more HLA-DR3 and 4-linked to HLA-DQ ->HLA-DQb lnked to IDDM -HLA-DR2 is IDDM-protective -more IDDM siblings share 2 HLA haplotypes ->IDDM prob due to HLA haplotypes (all refer to MHC Class II) -Identical twin SLE concordance=25-50%, Checkpoint 1: Central tolerance Clonal deletion/anergy of immature lymphos if autoreactive -in thymus, marrow AIRE-promotes expression of tissue-spec Ags from periphery to thymus ->central del. of autoreactive imm. cells (like self-Ags from retina, ovaries) Mutated AIRE->APECED->destroy endocrine tissues Checkpoint 2 Peripheral inactivation -self-reactive but not strong enough for central deletion -not as imp't if NL 1st checkpoint Somatic Hypermutation in Germinal Center -B cells make various ABs -if reactive to Ag in GC, likely "self" ->apoptosis (destroy Ag if outside GC), Autoimmunity Rogue Process Due to ubiquitous nature of self-Ag ->can't rid body of Ag ->positive feedback loop of ABs ->inflammation, more cell injury ->release sequestered self-Ags -from attraction of non-spec cells (macs, PMNs from cytokines) -can have 2ndary auto-Ags ->presented by B to local T cells ->immune response against 2nd (epitope spreading) (multiple diff BCRs bind same complex at diff points->present same Ag to T ->T activates multiple B for many ABs), Autoimmunity Rogue Process All Parts of Immune System can be auto-immune: -auto-ABs-can be transferred to mouse->cause dz -pregnancy-IgG cross placenta->transfer dz -auto-reactive T cells can transfer dz too (EAE~MS) -only if they share MHC molecules Mostly mediated by both parts, Peripheral inactivation -self-reactive but not strong enough for central deletion -not as imp't if NL 1st checkpoint Somatic Hypermutation in Germinal Center -B cells make various ABs -if reactive to Ag in GC, likely "self" ->apoptosis (destroy Ag if outside GC) Regulatory T cells -express CD-25, develop in thymus -initial response to weak self-Ag -in periph, if encounter self-Ag ->release IL-10, TGF-b ->inhibit surr. autoreactive T cells ->Extrinsic back-up reg for cells w/ broken tolerance -added to thymectomized mice ->cured autoimmune dz -body says "you're not dangerous but you could be, look out for me", Checkpoint 1: Central tolerance Clonal deletion/anergy of immature lymphos if autoreactive -in thymus, marrow AIRE-promotes expression of tissue-spec Ags from periphery to thymus ->central del. of autoreactive imm. cells (like self-Ags from retina, ovaries) Mutated AIRE->APECED->destroy endocrine tissues If Mature Ag bind receptor -if inflamm->activate T -if non-inflam->anergy/deletion, Autoimmunity Genetic/Environmental Basis Infections- In mice, grow transgenic viral protein in beta cells -infect w/ virus->attack beta cells ->molecular mimicry -but MM w/ "self" that resembles viral -cross-reactive T cells/ABs->autoimmune -continues even when pathogen eliminated, Autoimmunity NL Tolerance Mechs Immune Privilege (brain, fetus, testes, eye): 1.Unconventional drainage -Naive lymphos excluded from tissue (BBB) 2.Humoral factors skew towards Th2 via TGF-b -less damaging to tissue 3.FasL on tissues->apop of lyphos w/ Fas -Can still be targets of autoimmune attake -MS-Myelin Basic Protein