Hypersensitive reaction

Several important general features of hypersensitivity disorders : Both exogenous and endogenous antigens may elicit hypersensitivity reactions. The development of hypersensitivity diseases (both allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes. A general principle that has emerged is that hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses. 1.Immediate (Type 1) Hypersensitivity Mediated by immunoglobulin E (IgE) antibodies directed against specific antigens Many local type I hypersensitivity reactions have two well-defined phases The immediate or initial reaction 1. Characterized by vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions. 2. become evident within 5 to 30 minutes after exposure to an allergen and tend to subside in 60 minutes late-phase reaction o sets in 2 to 24 hours later without additional exposure to antigen and may last for several days. o characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal epithelial cell damage. Most immediate hypersensitivity reactions are mediated by IgE antibodydependent activation of mast cells and other leukocytes. - Mast cells are bone marrow-derived cells that are widely distributed in the tissues and activated by the cross-linking of high-affinity IgE Fc receptors - Basophils are similar to mast cells in many respects, including the presence of cell surface IgE Fc receptors as wellas cytoplasmic granules, and not normally present in tissues but rather circulate in the blood in extremely small numbers.

TH2 cells play a central role in the initiation and propagation of immediate hypersensitivity reactions by stimulating IgE production and promoting inflammation

Mediator - Preformed (Primary) Mediator stored in the granules, and de novo synthesis 3 categories of prefored (Primary) Mediator 1. Vasoactive amines. The most important mast cellderived amine is histamine 2. Enzymes, cause tissue damage and lead to the generation of kinins and activated components of complement by acting on their precursor proteins 3. Proteoglycans, serve to package and store the amines in the granules.(e.g : Heparin) Lipid (Secondary) Mediator synthesized by sequential reactions in the mast cell membranes that lead to activation of phospholipase Component of secondary Mediator 1. Leukotrienes 2. Prostaglandin D2 3. Platelet-activating factor (PAF Condition important example of IgE mediated disease 1. Systemic Anaphylaxis - Follows parenteral or oral administration of an allergen (drugs, food) - sign and symptom : pruritus, urticaria and erithema occur minutes after exposure followed by bronchoconstriction and laryngeal edema obstruction 2. Local Immediated Hypersensitive Reactions - These reactions are exemplified by atopic allergies - local type response to common inhaled or ingested allergen - symptom : urticaria, angioedema, rhinitis and asthma 2. Antibody-Mediated (Type II) Hypersensitive This type of hypersensitivity is caused by antibodies that react with antigens present on cell surfaces or in the extracellular matrix..There are 3 mechanism of antibodymediated injury. a. Opsonization and Phagocytosis - Cells opsonized by IgG antibodies are recognized by phagocyte Fc receptors, which are specific for the Fc portions of some IgG subclasses. - The net result is phagocytosis of the opsonized cells and their Destruction - Antibody-mediated destruction of cells may occur by another process called antibodydependent cellular cytotoxicity (ADCC). Its mediated by monocytes, neutrophils, eosinophils, and NK cells - antibody-mediated cell destruction and phagocytosis occur in the following situations : o transfusion reactions, o hemolytic disease of the newborn (erythroblastosis fetalis), o autoimmune hemolytic anemia ,agranulocytosis, and thrombocytopenia

o certain drug reactions b. Inflammation - When antibodies deposit in fixed tissues, such as basement membranes and extracellular matrix, the resultant injury is due to inflammation - due to both complement- and Fc receptordependent reactions - Antibody-mediated inflammation is the mechanism responsible for tissue injury in some forms of glomerulonephritis, vascular rejection in organ grafts, and other disorders

c. Cellular Dysfunction - In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation

3. Immune Complex-Mediated (Type III) Hypersensitivity - Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition - can be systemic, if immune complexes are formed in the circulation and are deposited in many organs, or localized to particular organs, such as the kidney (glomerulonephritis),joints (arthritis), or the small blood vessels of the skin if the complexes are deposited or formed in these tissues

The pathogenesis of systemic immune complex disease can be divided into three phases : 1. Formation of antigen-antibody complexes in the circulation The introduction of a protein antigen triggers an immune response that results in the formation of antibodies, typically about a week after the injection of the protein 2. deposition of the immune complexes in various tissues, thus initiating 3. an inflammatory reaction at the sites of immune complex deposition

Local Immune Complex Disease (Arthus Reaction) is a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally. These complexes precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed thrombosis worsens the ischemic injury

4. T-Cell Mediated (Type IV) Hypersensitivity - initiated by antigen-activated (sensitized) T lymphocytes,including CD4+ and CD8+ T cells - induced by environmental and self-antigens can be a cause of chronic inflammatory disease. - Reactions of CD4+ T Cells: Delayed-Type Hypersensitivity and Immune Inflammation o The same immunological events are responsible for chronic inflammatory reactions against self-tissues o Lead to granuloma formation - Reactions of CD8+ T Cells: Cell-Mediated Cytotoxicity o In this type of T cellmediated reaction, CD8+ CTLs kill antigen-bearing target cells o The killing of infected cells leads to the elimination of the infection, and is responsible for cell damage that accompanies the infection (e.g., in viral hepatitis) o Lead to apoptosis

Summary Table

Autoimmune Disease
at least three requirements should be met before a disorder is categorized as truly due to autoimmunity: (1) the presence of an immune reaction specific for some self-antigen or self-tissue; (2) evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance; and (3) the absence of another well-defined cause of the disease The diseases can be organ spesific disease or systemic or generalized disease

Immunological Tolerance
Immunological tolerance is the phenomenon of unresponsiveness to an antigen as a result of exposure of lymphocytes to that antigen. Self-tolerance refers to lack of responsiveness to an individual's own antigens, and it underlies our ability to live in harmony with our cells and tissues. The mechanisms of self-tolerance can be broadly classified into two groups: central tolerance and peripheral tolerance : a. Central Tolerance In this process, immature self-reactive T- and B-lymphocyte clones that recognize selfantigens during their maturation in the central (or generative) lymphoid organs (the thymus for T cells and the bone marrow for B cells) are killed or rendered harmless b. Peripheral Tolerance Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues; these are best defined for T cells - Anergy: This refers to prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens under certain conditions. - Suppression by regulatory T cells - Deletion by activation-induced cell death

Mechanism of Autoimmunity
Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes - Role of Susceptibility Genes Several autoimmune disease are linked with the HLA locus, especially class II alleles (HLA-DR, -DQ) - Role of Infection Two mechanisms have been postulated to explain the link between infections and autoimmunity o Induction of costimulators on APCs :If these cells are presenting selfantigens, the result may be a breakdown of anergy and activation of T cells specific for the self-antigens. o Molecular Mimicry: some microbes may express antigens that have the same amino acid sequences as self-antigens.may result in the activation of self-reactive lymphocytes