2Immunological (hypersensitivity) diseases Diseases caused by aberrant (excessive or uncontrolled) immune reactionsReactions against self antigens (autoimmunity)Uncontrolled or excessive reactions against foreign antigensUnderlying problem may be failure of self-tolerance and control mechanismsThe nature of the disease is determined by the type of immune responseDiseases are classified based on immune mechanisms: useful for understanding pathogenesis, but many diseases involve multiple mechanisms
3Types of hypersensitivity disease Type of hyper-sensitivityPathogenic immuneresponseMechanism oftissue injuryImmediate hyper-sensitivity (Type I)IgE antibody,mast cellsMast cell mediatorsPhagocytosisComplementInterference withcell functionsIgM and IgG antibodiesagainst cell and matrixantigensAntibody mediated(Type II)Complexes of circulatingantigens and IgM orIgG antibodiesComplement and Fcreceptor mediatedinflammationImmune complexmediated (Type III)Cytokine-mediated inflammationKilling by CTLsT cell mediated(Type IV)CD4 and CD8 T cells
7Actions of mast cell mediators Mast cell products are responsible for the manifestations ofimmediate hypersensitivity
8Clinical manifestations of immediate hypersensitivity
9Treatment of immediate hypersensitivity disorders
10Genetic susceptibility for immediate hypersensitivity Allergic diseases run in familiesDifferent members of the same family may show different manifestations of immediate hypersensitivity (“atopy”)Multiple susceptibility genes have been identified by gene mapping and family studiesGenes may influence TH2 responses, IgE production, mast cell activation, end-organ sensitivitySusceptibility loci identified include: HLA (immune responsiveness); cytokine gene cluster; others
12How antibodies cause disease -- 1 Neutrophils (and monocytes) are recruited by complementproducts (generated by the classical pathway) and binding to Fctails of deposited antibodies, and are activated.Leukocyte recruitment and activation are part of inflammation.
13Experimental models of immune complex diseases Serum sicknessSystemic immunization with large dose of protein antigen --> circulating immune complexes --> complexes deposit in vessels and cause inflammation (Fc receptor and complement-mediated)Arthritis, vasculitis, glomerulonephritisArthus reactionSubcutaneous administration of antigen in previously immunized individual --> formation and deposition of local immune complexesCutaneous vasculitis
16How antibodies cause disease -- 2 Antibody and/or complement (C3b) are deposited on cell andare recognized by receptors for Fc or C3b on phagocytes -->coated (opsonized) cell is ingested and destroyed.Basis of autoantibody-mediated depletion of RBCs, platelets
18Causes of antibody-mediated diseases Autoimmunity (production of autoantibodies)May be due to failure of self-tolerance in autoreactive B cells or helper T cellsAntibody responses to foreign antigensAntibodies against hepatitis B form immune complexes --> vasculitis (polyarteritis nodosa)Post-streptococcal glomerulonephritis: immune complexes of Strep antigen + anti-Strep antibodies; formed in circulation or GBMNot known why immune complex diseases develop in rare individuals after common infections
19How T cells injure tissues -- 1 CD4+ T cells respond to self (or microbial) antigens, produce cytokines that recruit and activate macrophages and neutrophils, and the products of these leukocytes damage tissues.Recall that the same reaction destroys phagocytosed microbes (cell-mediated immunity, one arm of host defense)
20Delayed type hypersensitivity (DTH) reaction Detectable reaction to an antigen in a sensitized (previously exposed) individualCaused mainly by CD4+ T cells cytokine secretion inflammation, macrophage activation
21Morphology of a delayed type hypersensitivity (DTH) reactionClassically attributed to Th1 response; may include Th17.
22How T cells injure tissues -- 2 Cytotoxic T lymphocytes (CTLs) react against antigensin host tissues and kill (“lyse”) the host cells.
23Causes of T cell-mediated hypersensitivity diseases AutoimmunityType 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasisReaction to microbes and other foreign antigensContact sensitivity (DTH) to chemicals (poison ivy)Tuberculosis (granulomatous inflammation in response to a persistent microbe: chronic DTH)Crohn’s disease (excessive Th1 and Th17 responses to gut commensals?)Viral hepatitis (CTLs kill virus-infected hepatocytes); not considered an example of “hypersensitivity”
24Immune-mediated inflammatory diseases Chronic diseases in which inflammation is a prominent component and the immune system reacts excessively against one or more tissuesMajor role of CD4+ T cells and cytokines; antibodies may contribute to diseaseSame therapies work in many of these diseasesThese diseases develop because the normal controls on immune responses fail; typically due to autoimmunity but may be excessive reactions to microbesMS, type 1 diabetes, RA: autoimmunityCrohn’s: reaction against gut microbes?
25Chronicity of immune-mediated inflammatory diseases Many of these hypersensitivity diseases are chronic and even self-perpetuating because:The initiating stimuli cannot be removed (self or environmental antigens, persistent microbes)The immune response tends to amplify itself (normally, enables few antigen-specific lymphocytes to deal with infections)
26Amplification loop in DTH reactions Cytokines arepowerfulamplifiers ofimmune reactions
27Therapy of immune diseases: the current way Block the production or counteract the actions of effector molecules that cause tissue injuryAnti-inflammatory drugs, e.g. steroidsBlock T cell activation (immunosuppressive drugs, e.g. cyclosporine)Deplete pathogenic antibodies (plasmapheresis), B or T lymphocytes (depleting antibodies)EmpiricalDesensitization for allergyIntravenous IgG (IVIg): engages inhibitory FcR on B cells?
28Therapy of immune disorders: rational approaches target lymphocyte activation and subsequent inflammationCTLA-4.Ig(block costimulation)Inhibitors of calcineurin, various kinases(inhibit signaling)CD28IL-2TCRAPCAnti-IL-2R(block cytokine receptor)T cellIL-12, IL-23(p40)TNF, IL-1,IL-6Rantagonists(block cytokines)TNF, IL-1,IL-6IL-17AAnti-IL-17AAnti-p40Anti-integrin antibodies(block adhesion)Inflammation
29Molecularly targeted therapies for immunological diseases: the rational approach Target the molecular basis of lymphocyte activation and effector functions: rationally designed therapiesBased on understanding of lymphocyte biologyRisks -- reactivation of infectionsInduce antigen-specific immunological tolerance: requires identification of target antigensBeing tried in MS, type 1 diabetes (in which the major autoantigens are known)