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This Concept Map, created with IHMC CmapTools, has information related to: autoimmunity, 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, 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 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 Genetic/Environmental Basis Females more predisposed to dzs, Autoimmunity NL Tolerance Mechs 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, 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, Autoimmunity Hypersensitivity Type IV IDDM-CD8 T cell-mediated beta-cell destuction -does clear Ag, 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", Autoimmunity Distinguish self from nonself Lymphocyte thinks "self" when: -encounters ligand while still immature -high, constant concentration of ligand -binding of ligand in absence of co-stims -usually dependent on innate system firing, Autoimmunity Hypersensitivity Type II AI Hemolytic Anemia-Rh, I Ags ->destroy RBCs by complement -taken up by FcR+ phagos AI thrombocytopenic purpura -platelet integrin->abnl bleeding Goodpasture's-bsmt memb collagen ->kidney dz, pulm hemorrhage Graves'-TSHR->excess TH production Myasthenia Gravis-ACh receptors ->internalized-weaker mm. activity, 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%, 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 Rogue Process Auto-ABs clear "self" -thus, no "self" left for T,B cell tolerizing, Autoimmunity NL Tolerance Mechs IgG-monomeric auto-Ag -large qties in blood ->can't cross-link BCR -BUT if lots of immune complexes ->enough multivalent IgG to cross link ->ignorant B cells make response -make "rheumatoid factor" autoAB, 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 Sympathetic Ophthalmia Trauma of one eye ->Released intraocular Ag to LN ->activate T cell->to both eyes ->attack both eyes, 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 Ignorant Mature Naive T cells -low affinity for self-Ag -can be activated w/ high co-stim ->like infection eg.TLR-9 binds CpG->co-stim -after DNA had been taken up -autoreactive B cells Tissue death/inflam can release self-Ags ->activate ignorant T, B cells eg-MI->releas cardiac antigens, -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" CD4+CD25+ Reg T cells Suppress autoimmune dz -depletion->dz moderate affinity to self in thymus -start as CD4 T cells->receive signal Colitis Tx w/ CD4 CD25 T cells -to lamina propria of colon ->prolif & secrete reg. cytokines -reduce activation of DCs, auto T cells -Treg remain in lam prop after colitis, Autoimmunity Types of Dzs: -cluster in families Systemic: -auto-ABs to more ubiquitous self-Ags Rheum. Arthritis Scleroderma SLE-targets chromatin Sjogren's Syn Polymyositis Auto. hemolytic anemia 2ndary to above, 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), 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% HLA-DRbeta Contains Asp at position 57 -forms salt bridge to Arg on DRalpha IDDM pts have Val, Ser, or Ala ->thus no salt bridge, poor binding ->poor intrathal. negative selection