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Immuno Outline Test #3 Lectures 19/20: Mechanisms of Tolerance and Autoimmune Disease B cell Central Tolerance Negative Selection o BM stromal cells express self-Ag on surface o If strong binding to the multi-valent self-Ags as BCR’s crosslink apoptosis o If strong linking to soluble self-Ags w/o crosslinking of BCR anergy o Strong binding maintains activation of RAG 1/ 2 rearranges L chain (receptor editing) o No recognition of self-Ags survival (cells enter periphery as IgM+IgD+ *different than T cells o Surviving B cells go to follicles, anergic B cells do NOT go to follicle *diff than T cells Positive Selection B cell Peripheral Tolerance 4 Mechanisms to prevent against auto-immunity: o Signal 1 anergy o CTLA-4 anergy o Fas/FasL pathway apoptosis o Tregs reside in lymph, infected site Follicular Exclusion: CXCR5- anergic B cells encounter self-Ag in T cell zone If B cells react to self-reactive Ag aptoptosis (Fas expression) Apoptosis of Anergic Self-Reactive B cells (especially in Germinal Center) will die!! *not a method of autoimmunity T cells Central Tolerance Thymus- eliminates self-reactive T cells o Positive Selection: cortex Positive selection for T cell who’s TCR binds MHC on thympic epithelial cell survives, becomes single-positive, upregulates CD3 If no MHC interaction (defect) apoptosis o Negative Selection Test TCR for self-reactivity Surviving SP T cell interacts with Medullary Thympic Epethial cells (MTEC) produce AIRE (self-Ags) can also interact w/ DCS and Macs If strong MHC binding to self-Ag apoptosis If weak MHC binding to self-Ag survival (only 10%) Surviving T cells (Naïve Mature) reside in T cell zone T cell Peripheral Tolerance The surviving T cells (Naïve Mature) need 3 signals from mature DC* critical to immune response o Signal 1: microbe peptide o Signal 2: PRR (innate receptor) and cytokine receptor expresses B7 on APC o Signal 3: cytokines o T cell receives 3 signals Activated (effector Tcell) TCL or Th1 o If only get signal 1 T cell anergy o T cells can differentiate into CD4 cells and CD8 cells (based on cytokine secretion) IL-12 TH1, secretes IFN-gamma Tc1 IL-4 Th2, secretes IL-4, IL-13 If Self-Ag is presented on mature MHC o T cell gets activated, must be inhibted by CTLA-4, Fas/FasL(tissues) o CTLA-4 gets expressed on self-reactive T cell, binds B7 (instead of CD28) blocks TCR or cytokine signals apoptosis o Fas/FasL gets expressed on self-reactive T cells kill each other o * potential for autoimmunity= breakdown of CTLA-4 or Fas/FasL o Immunosuppression Natural T regs (Lymphoid): express CD25 early and FOXP3+ Use NFkB, and IL-2 for Treg developement FOXP3 expression Contact dependent, supressors Induced T regs (Tissues) Secrete TGFbeta, upregulates Fox3P suppressor cell Secrete IL-10 no Fox3P expression, secretes IL-10 Treg 1 (Tr1) Secrete mucosal Ag or immature DC and low dose Ag Th3, secretes IL-10 and TGF beta. Cytokine dependent suppressors, secrete cytokies Diabetes T cells destroy beta cells B cells produce autoantibodies (diagnostic marker for high risk diabetes85% predictor, can intervene with drug Population of beta cells decreases, at 10% left, plasma glucose increases and beta cells enter “honeymoon” phase and proliferate/grow If not given insulin, beta cells population will then continue to decrease Fas/FasL, MHC, perforin/granzyme, TNF-alpha and TNF receptor all involved in beta destruction Self reactive T cells in the pancreas lymph nodes MHC connection (IDDM1- insulin dependent diabetes mellitus o If strong interactions between HLA, Ag, and TCR, then self-reactive T cell eliminated o If floppy binding, weak TCR signal, reactive T cell survives and escapes central tolerance Activation of self-reactive T cells o “molecular mimicry”- microbes can elicit signals 2 &3 (B7, innate receptor, cytokines) o Other sources: Ag source: Wheat (gluten), cow’s milk (insulin) o Ag and TNF source: viral components, wheat (gluten) Self Reactive T cell escapes methods of tolerance by: o 1- have mature APC (already have signal 1), don’t see anergy o 2- susceptibility of allele (IDDM!2), CTLA 4 is diminished/defective o 3- deficiency in Tregs (IDDM10) IL-10 levels, not enough IL-10 for suppression, provokes immune response CD80/CD86 Other Auto-immune Diseases Autoantibodies mediate disease by recognizing self-Ag, forming immune complex, complexes build up compliment (vasculitits, nephrititis) Activation of Self-Reactive B cells o Reside in T cell zone, encounter self-Ag (nothing to rescue cell) apoptosis o Activated Self-reactive CD4+ T cells rescue self-reactive anergic B cells (CD40 Ligand signaling) o **No method of rescuing T cells** o Rescued Self-Reactive B cell expresses CXCR5, enters follicle Immunotherapy for Autoimmunity HLA-DQ/DR: Class II MHC Vitamin D sways response from inflammatory (Th1, Th17, beta cell destruction) to Th2 anti-inflammatory response (Tregs, IL-10) suppress disease onset Oral Tolerance in mucosa- dose dependent o High Dose Tolerance: Several peptides expressed on APC, bind TCR (w/o costimulation) anergy o Low Dose Tolerance: TGF beta stimulates DC’s to activate Tregs (Ag w/o co-stimulation), suppression of T cell Potential for systemic tolerance o So in the oral tolerance, it’s always w/o co-stimulation? Gluten Tolerance o If gluten is improperly digested to gliaden peptides, they become negative charged and bind strongly to MHC (HLA DQ w/ Celiac Disease) generates inflammatory response o IEL’s also secrete cytokines (IFNgamma) Th1 (inflammation) Ag-Coupled Cell-Induced Tolerance o Crosslink chemicals w/ peptides on splenocytes direct tolerance anergy o MBP peptides + ECDI-fixed PBL prevents onset of EAE o If Ag coupled cell undergoes apoptosis indirect tolerance peptide on apoptotic bodies induced anergy (Prevents epitope spreading?) o EAE , autoreactive CD4+ T cell enters tissue, releases cytokines destroys myelin produce more Ag leaky BBB activate other peptide, activates more T cells (reason for relapsing, remitting) in MS Anti-CD20 Antibody o Rituximab: inhibits B cell function (reduces amount of auto antibody) Antigen-Specific Immunotherapy o Main goal: attack certain group of targeted cells cell death/anergy o Problem: allergies against soluble peptide o High doses of soluble peptides anergy o T cell-reactivation w/ peptide activation induced cell death Hypersensitivities Type I “immediate hypersensitivity” rapid degranulation of mast cells wheal and flare- blotches of raised lesions effects skin, respiratory, GI, systemic allergen exposure induces Th2 (instead of Th1) response isotype switching (IgE) instead of IgG Aptopic (predisposition for allergic response) increased affinity of mast cell FceR, higher affinity for IgE, and remains on surface longer Allergen binds B cell activates Th2 cell produces IgE IgE binds FceR on Mast cell Second exposure to Allergen allergen binds IgE on mast cell allergen cross-linkage of IgE activates mast cell degranulation Immediate response: premade granules Late phase response: cytokines Epinephrine: primary treatment for anaphylaxis cAMP, PKA, in mast cells (prevents mast cell degranulation) Type II Antibody-mediated hypersensitivity Against Cell surface Ags Complement – classical pathway, “frustrated phagocytosis”, release digestive enymes and ROS onto tissue Fc receptor mediated recruitment and activation of inflammatory cells Opsonization & phagocytosis: circulating cells coated with Abs against cell surface Ags neutrophils, macs capture coated cells (phagocytosis) – NO frustrated phagocyosis o Ex: ABO group, Rh factor Ab-mediated cell dysfunction o Binding of Ab to cell surface Ags impair normal function (no inflammation) ex: hyperthyroidism, Myasthenia gravis Type III Immune Complex Mediated Hypersensitivity Abs against soluble Ags ICs deposit in kidney, blood vessels, Joints Compliment activation activates Neutrophils, bind to Fc frustrated phagocytosis Normal IC clearance: C1q binds to ICC3b binds to Agbound C3b binds to receptor CR1 on RBC RBC goes to liver, spleen, Factor I loosens IC from RBC gets phagocytosed Persistant Ags (infection, autoimmunity, inhaled Ag-mold) persistant IC complexes SLE (Systemic Lupus Erythematosus) Normal Clearance of Apoptotic cells o Opsonized by Macrophages, non-inflammatory, tolerance Impaired Clearance of Apoptosis o Deficiency in (or AutoAb against) one of opsonization factors apoptotic body not clearned undergoes necrosis stimulates inflammation Type IV T cell Mediated Hypersensitivity Abnormal T cell responses to Ags Autoimmune disease (Lupus) Delayed Type Hypersensitivity (CD4+ Tcells) o Granulomatous Hypersensitivity Chronic T cell response to chronic Ag, IFN gamma activates macs to create granulomas TNFalpha: recruitment of macs to granuloma (maintain) Sensitization step: CD4 T cell memory o Contact Dermatitis (T cell mediated allergic response) Poison Oak, small Ags, conjugate w/ self protein 1. Sensitization Step: initial contact w/ Ag (skin allergens), small amount contact Ag T cell memory (2 weeks) first encounter: no reaction w/in 2 weeks 2. Elicitation Step Re-exposure to contact Ag Memory response, macrophage inflammatory cytokines clinical symptoms (localized inflammation) T cell Mediated cytolysis (CD8+ T cells) o FasL-Fas Pathway apoptosis Target cells= Fas + (fas on stressed cell) Effector= FasLigand o Peforin/Granzyme Activate caspase pathwayapoptosis Blood Group Ags and Transfusions Blood Transfusions o Used to treat hemorrhage, RBC destruction (hemolytic anemia), inadequate blood cell production in bone marrow o Requires cross-matching Red cells: ABO group, Rh factor, Minor red cell Ags White cells: MHC matching Blood Types o Inherited antigenic proteins, carbs, glycoproteins on RBC surface o AA or AO: A antigens on RBCs, anti-B antibodies, receive B or O blood o BB or BO: B antigen on RBC’s; anti-A antibodies, receive A or O blood o AB: A and B antigens on RBCS; neither anti-A nor anti-B Ab, receive A, B, AB, O blood (universal recipient) o O: neither A nor B Ag on RBC; anti-B and Anti-A Abs; receive O blood (universal donor) o True recpient: AB+ o True Donor: ORh Factor o Hemolytic Disease of the Newborn: o Problem when mom is Rh-, o During delivery of Rh+ baby, blood is transferred, and Mom makes Abs against Rh+ (first baby okay) o If second baby is Rh+, Mom will attack baby with her Ab(IgG) against Rh+ o Treatment: Rhogam: doesn’t allow mom to make Ab against Rh+ (immunosuppressor) Transfusion o Needed when Hb(hemoglobin) <8 g/dL o Cross Matching Major cross match: tests patients serum for Ab directed against RBC to be transfused Minor Cross match: test donors serum for Ab directed against recipient’s RBC Drop of donor RBC mixed w/ patient plasma If patient has Ab against donor red cells, agglutination Acetominophen and benedryl given prior to transusion (reduces minor transfusion reactions) Coomb’s Test Direct:: used for anemias (looking for Abs bound to RBC’s), can be caused by certain meds Indirect: used for testing reaction for blood transfusion o Add Ab’s from patients sample to donors RBC’s= Ab’s bind to RBC o Add anti-Human IgG binds to Ab’s bound to RBC agglutination = not compatable o Transfusion Reactions Clinical Symptoms: fever, chills, dark urine, chest pains, dyspnea, shock, flank pain, oliguria, anuria, blooding/hypotension during surgery Non-immune reactions: contaminated blood, causes immune response Immune reactions: RBC incompatability, Platelet/Leukocyte incompatability, anti-allotypic Abs Acute Hemolytic Reaction Most frequent case of transfusion reaction due to ABO incompatability- Clerical Error!! Fever, chills, flushing, hypotension/hypertension, tachycardia, nausea, burning, bleeding at IV site Recipient IgM against donor A/B antigens hemolysis of donor RBC’s, compliment, form clots, anaphylaxis, shock, death Diagnosis: o serum of patient appears pink (hemoglobinemia) o serum biliruben elevated o dark patient urine (hemoglobinuria) Transfusion-Related Acute Lung Injury Occurs w/in 6 hours Symptoms resemble respiratory distress syndrome Nonproductive cough, dyspnea, tachypnea, hypotension, tachycardia, fever, chills, bilateral nodular infiltrates on CXR, pulmonary edema Immune complexes enter pulmonary vascular bed vasodilation pulmonary edema Allergic Reactions/Anaphylaxis Occurs when a person has been pre-sensitized to allergen, and receives same allergen in transfusion Transplantation Immunology Autologous graft- self graft Synthetic graft- graft into different member of same strain Xenographic graft- graft into different species Allographic graft- different member of same species (different strain) o Alloantigens- molecules on allograft seen as foreign alloreactive immune response o Direct recognition of Alloantigens TCR can see allogenic MHC as self, recognizes foreign peptide Or TCR can view allogenic MHC and foreign peptide Because all cells have MHC IUsually occurs in CD8+ cells direct lysis Strong rejection because of numerous MHC’s on graft, greater opportunity for APC binding readily activate T cells o Indirect recognition of Alloantigens APC of recipient (DCs) take up allogenic tissue cell processes peptide presents to alloreactive T cells by APC CD4+ more common, also CD8+ (cross-presentation) o Graft vs Host Disease (GVHD): donor tissue that has T cells in itrecognizes recipient molecules as foreign graft attacks tissues of host o Non-MHC Alloantigens Minor histocompatability antigens (mHA) Allograft Rejection o Hyperacute rejection: Occurs w/in minutes to hours after transplantion Pre-existing antibodies bind to graft endothelial cell Ags (sell surface) – same as Type II hypersensivity Complement activated, recruits neutrophils, macs o Chronic Rejection T cells Chronic IFNgamma smooth muscle proliferation (hyperplasia) vessel occlusion (causes damage) o Acute Rejection Involves CD4+, CD8+, and B cells Activates complement same response Immunosuppression and Rejection Cyclosporine: inhibits activation of NFAT transcription factor blocks T cell cytokine production Rapamycin: inhibits IL-2 signaling blocks lymphocyte proliferation (no clonal expansion) Immunodeficiency Primary Immunodeficiency Diseases o Humoral Immunodeficiencies Infantile hypogammaglobulinemia (Bruton-Janeway syndrome) lack of Bcell tyrosine kinase gene, lack of follicles, lack of B cells, few circulating Igs, bacterial infections Common Variable Immunodeficiency (CVID) Normal B cell numbers, defective differentiation/maturation (Heavy chain gene deletion) Abnormal function of T cells (inadequate T cell help) Excessive Treg activity Low Igs Bacterial, fungal, parasitic infections Adult onset agammaglobulinemia o High prevalence of autoimmune disease o Neoplasmic conditions, GI lymphomas Hyper IgM Syndrome Lack of CD40L on T cells (no isotype switching) IgG, IgA, high IgM bacterial infections IgA deficiency Anti-IgA antibodies, antibodies to milk, other food antigens Bacterial, parasitic (Giardia) o Cellular (T cell) immunodeficiencies Thympic Aplasia (DiGeorge’s Syndrome) Depletion of T cell areas T cells Normal B cell #’s, deficient function Igs (IgG) viral, bacterial Neonatal tetany (hypocalcemia from hypoparathyroidism) Abnormalities of heart, vessels Facial dysmorphism, mental subnormality o Combined Immunodeficiencies Severe Combined Immunodeficiencies (SCID) “bubble boy” thympic apasia, atrophy of lymphoid organs T cells, variable B cells IgG all types of infection, chronic/persistant Therapies: Bone marrow transplantation, gene thearpy MHC deficiencies Lack of expression of MHC class I or class II Normal/low T cells B cell # normal, deficient function IgG all types of infections Ataxia-Telangiesctasia rare Deficiency of DNA repair enzymes Capillary abnormalities (visible in superficial areas) Cerebellar ataxia, telangeictasia of skin, conjunctiva Thymic hypoplasia, T cell deficiency, Ig’s (IgA) Wiskott-Aldrich Syndrome rare WASP abnormal Hematopoetic cells have abnormal shape, size, fxn IgM, failure to respond to polysaccharide vaccines hemorrhage o Phagocytic deficiencies Chronic Granulomatous Disease Mutation in NADPH oxidase (respiratory burst) defective killing by macs Granuloma formation pneumonia, lymphadenitis, abscesses in skin, liver, etc. Chediak-Higashi Syndrome Neutrophil disorder defective intracellular killing Recurrent bacterial infections in lungs, skin, mucous membranes Leukocyte Adhesion Deficiency Deficient selectin/ligand on endothelium neutrophils cannot leave bloodstream Recurrent infections, impaired healing, lack of pus formation Secondary Immunodeficiency Diseases o More common than primary immune diseases o Can be caused by: Malnutrition Aging: B, T cells, innate immunity, tolerance Chemotherapeutic agents: impacts ALL cells (immunosuppression) especially rapidly dividing cells treatment: transfusions, transplantations, immunotherapy Alcohol: triggers Cortociotrophin releasing hormone glucocorticoids downregulates phagocytes, B,T cells Reduces estrogen levels, reduce cytokine production Infections AIDS