Lecture outline Types of hypersensitivity reactions Immediate hypersensitivity, allergy Antibody-mediated diseases T cell-mediated diseases Therapeutic approaches

Immunological (hypersensitivity) diseases Diseases caused by aberrant (excessive or uncontrolled) immune reactions Reactions against self antigens (autoimmunity) Uncontrolled or excessive reactions against foreign antigens Underlying problem may be failure of self-tolerance and control mechanisms The nature of the disease is determined by the type of immune response Diseases are classified based on immune mechanisms: useful for understanding pathogenesis, but many diseases involve multiple mechanisms

Types of hypersensitivity disease Type of hyper- sensitivity Pathogenic immune response Mechanism of tissue injury Immediate hyper- sensitivity (Type I) IgE antibody, mast cells Mast cell mediators Phagocytosis Complement Interference with cell functions IgM and IgG antibodies against cell and matrix antigens Antibody mediated (Type II) Complexes of circulating antigens and IgM or IgG antibodies Complement and Fc receptor mediated inflammation Immune complex mediated (Type III) Cytokine-mediated inflammation Killing by CTLs T cell mediated (Type IV) CD4 and CD8 T cells

Immediate hypersensitivity reaction

Stages of immediate hypersensitivity reactions

Sequence of events in immediate hypersensitivity

Actions of mast cell mediators Mast cell products are responsible for the manifestations of immediate hypersensitivity

Clinical manifestations of immediate hypersensitivity

Treatment of immediate hypersensitivity disorders

Genetic susceptibility for immediate hypersensitivity Allergic diseases run in families Different members of the same family may show different manifestations of immediate hypersensitivity (“atopy”) Multiple susceptibility genes have been identified by gene mapping and family studies Genes may influence TH2 responses, IgE production, mast cell activation, end-organ sensitivity Susceptibility loci identified include: HLA (immune responsiveness); cytokine gene cluster; others

How antibodies deposit in tissues Antibody is specific for tissue antigen (typically self): disease is target tissue Antibody reacts with circulating antigen (self or foreign), and complexes tend to deposit in small vessels; not specific for any tissue

How antibodies cause disease -- 1 Neutrophils (and monocytes) are recruited by complement products (generated by the classical pathway) and binding to Fc tails of deposited antibodies, and are activated. Leukocyte recruitment and activation are part of inflammation.

Experimental models of immune complex diseases Serum sickness Systemic immunization with large dose of protein antigen --> circulating immune complexes --> complexes deposit in vessels and cause inflammation (Fc receptor and complement-mediated) Arthritis, vasculitis, glomerulonephritis Arthus reaction Subcutaneous administration of antigen in previously immunized individual --> formation and deposition of local immune complexes Cutaneous vasculitis

Immune complex-mediated glomerulonephritis

Anti-basement membrane antibody- mediated glomerulonephritis

How antibodies cause disease -- 2 Antibody and/or complement (C3b) are deposited on cell and are recognized by receptors for Fc or C3b on phagocytes --> coated (opsonized) cell is ingested and destroyed. Basis of autoantibody-mediated depletion of RBCs, platelets

How antibodies cause disease -- 3

Causes of antibody-mediated diseases Autoimmunity (production of autoantibodies) May be due to failure of self-tolerance in autoreactive B cells or helper T cells Antibody responses to foreign antigens Antibodies against hepatitis B form immune complexes --> vasculitis (polyarteritis nodosa) Post-streptococcal glomerulonephritis: immune complexes of Strep antigen + anti-Strep antibodies; formed in circulation or GBM Not known why immune complex diseases develop in rare individuals after common infections

How 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)

Delayed type hypersensitivity (DTH) reaction Detectable reaction to an antigen in a sensitized (previously exposed) individual Caused mainly by CD4+ T cells  cytokine secretion  inflammation, macrophage activation

Morphology of a delayed type hypersensitivity (DTH) reaction Classically attributed to Th1 response; may include Th17.

How T cells injure tissues -- 2 Cytotoxic T lymphocytes (CTLs) react against antigens in host tissues and kill (“lyse”) the host cells.

Causes of T cell-mediated hypersensitivity diseases Autoimmunity Type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis Reaction to microbes and other foreign antigens Contact 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”

Immune-mediated inflammatory diseases Chronic diseases in which inflammation is a prominent component and the immune system reacts excessively against one or more tissues Major role of CD4+ T cells and cytokines; antibodies may contribute to disease Same therapies work in many of these diseases These diseases develop because the normal controls on immune responses fail; typically due to autoimmunity but may be excessive reactions to microbes MS, type 1 diabetes, RA: autoimmunity Crohn’s: reaction against gut microbes?

Chronicity 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)

Amplification loop in DTH reactions Cytokines are powerful amplifiers of immune reactions

Therapy of immune diseases: the current way Block the production or counteract the actions of effector molecules that cause tissue injury Anti-inflammatory drugs, e.g. steroids Block T cell activation (immunosuppressive drugs, e.g. cyclosporine) Deplete pathogenic antibodies (plasmapheresis), B or T lymphocytes (depleting antibodies) Empirical Desensitization for allergy Intravenous IgG (IVIg): engages inhibitory FcR on B cells?

Therapy of immune disorders: rational approaches target lymphocyte activation and subsequent inflammation CTLA-4.Ig (block costimulation) Inhibitors of calcineurin, various kinases (inhibit signaling) CD28 IL-2 TCR APC Anti-IL-2R (block cytokine receptor) T cell IL-12, IL-23 (p40) TNF, IL-1, IL-6R antagonists (block cytokines) TNF, IL-1, IL-6 IL-17A Anti-IL-17A Anti-p40 Anti-integrin antibodies (block adhesion) Inflammation

Molecularly targeted therapies for immunological diseases: the rational approach Target the molecular basis of lymphocyte activation and effector functions: rationally designed therapies Based on understanding of lymphocyte biology Risks -- reactivation of infections Induce antigen-specific immunological tolerance: requires identification of target antigens Being tried in MS, type 1 diabetes (in which the major autoantigens are known)