Immunologyعلم المناعة

Hypersensitivity Reactions 2 2الحساسية تفاعالت فرط

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Antibody-Mediated Cytotoxicityباالضداد المتواسطالسمية

Antibody-Mediated Diseases (Type II Hypersensitivity)

• Caused by High-affinity autoantibodies capable of activating complement and binding to the Fc receptors of phagocytes

• Antibodies are directed against target antigens on the surface of cells (circulating or fixed cells) or other tissue components.

• The antigens may be normal molecules intrinsic to cell membranes or in the extracellular matrix, or they may be adsorbed exogenous antigens (e.g., a drug metabolite)

• It causes several important diseases.

Mechanisms of Type II Hypersensitivity 1- Opsonization and phagocytosis: When circulating

cells, such as red blood cells or platelets, are coated (opsonized) with autoantibodies, with or without complement proteins, the cells become targets for phagocytosis by neutrophils and macrophages

Opsonization of cells by antibodies and complement components and ingestion by phagocytes

• Opsonized cells are usually eliminated in the spleen, and this is why splenectomy is of clinical benefit in some antibody-mediated diseases.

• Diseases: e.g.

(1) transfusion reactions, in which cells from an incompatible donor react with preformed antibody in the host

(2) hemolytic disease of the newborn (erythroblastosis fetalis), in which IgG anti–red blood cell antibodies from the mother cross the placenta and cause destruction of fetal red blood cells

Hemolytic disease of the fetus and newborn, HDN, HDFN

2- Inflammation: Antibodies bound to cellular or tissue antigens activate the complement system by the classical pathway • Antibody-mediated inflammation is responsible for

tissue injury • Diseases: e.g. 1. some forms of glomerulonephritis 2. vascular rejection in organ grafts

Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products

3- Antibody-mediated cellular dysfunction: antibodies directed against a host protein impair or dysregulate important functions without directly causing cell injury or inflammation • Diseases: e.g. 1. In myasthenia gravis, antibodies against

acetylcholine receptors in the motor end plates of skeletal muscles inhibit neuromuscular transmission, with resultant muscle weakness.

Anti-receptor antibodies disturb the normal function of receptors. In this example antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis

2. In Graves disease antibodies can stimulate cellular responses excessively., antibodies against the thyroid-stimulating hormone receptor stimulate thyroid epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism.

antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease.

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• Antigen–antibody (immune) complexes are often formed in the circulation, then may deposit in blood vessels, leading to complement activation and acute inflammation

• the complexes may be formed at sites where antigen has been planted previously (in situ immune complexes).

• The antigens may be exogenous, such as a foreign protein that is injected or produced by an infectious microbe, or endogenous, if the individual produces antibody against self antigens (autoimmunity).

Type III Hypersensitivity: Immune Complex–Mediated Diseases

Immune complex–mediated diseases tend be systemic, but often preferentially involve the kidney (glomerulonephritis), joints (arthritis), and small blood vessels (vasculitis)

Systemic Immune Complex Disease

Acute serum sickness: was a frequent sequel to the administration of large amounts of foreign serum e.g., serum from immunized horses used for protection against diphtheria.

In modern times, the disease is infrequent and usually seen in individuals who receive antibodies from other individuals or species e.g. horse or rabbit antithymocyte globulin used to deplete T cells in recipients of organ grafts.

Systemic immune complex disease can be divided into 3 phases: 1- Formation of Immune Complexes: about 1 week after the injection of the protein. 2- Deposition of Immune Complexes: The factors that lead to tissue deposition and disease are not fully understood. Organs where blood is filtered at high pressure to form other fluids, like urine (kidney) and synovial fluid (joints), are sites where immune complexes become concentrated and deposit. 3- Inflammation and Tissue Injury: about 10 days after antigen administration. • Complement activation and engagement of leukocyte Fc

receptors. • Antibodies are IgG or IgM. • Consumption of complement decreases serum levels of C3 (can be

used as a marker for disease activity) • Clinical features: fever, urticaria, joint pain (arthralgia), lymph

node enlargement, and proteinuria.

Morphology:

Acute vasculitis with fibrinoid necrosis + intense neutrophilic infiltration.

When deposited in the kidney, the complexes can be seen on immunofluorescence microscopy as granular deposits of mmunoglobulin and complement and on electron microscopy as electron-dense deposits along the glomerular basement membrane

Acute serum sickness is induced by administration of a single large dose of antigen. The lesions tend to resolve as a result of phagocytosis and degradation of the immune complexes

Chronic serum sickness results from repeated or prolonged exposure to an antigen. This occurs in several diseases, such as systemic lupus erythematosus.

Acute and Chronic Serum Sickness

Local Immune Complex Disease (Arthus Reaction)

o The reaction is produced experimentally by injecting an antigen in the dermis of a previously immunized animal with preformed antibody.

o Immune complexes form as the antigen diffuses into the vascular wall at the site of injection, triggering an inflammatory reaction and histologic appearance as in systemic immune complex disease.

o Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after injection and begin to resolve after about 48h.

o Edema and hemorrhage, in the injection site, occasionally followed by ulceration and area of tissue necrosis as a result of local acute immune complex vasculitis.

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بالخاليا المتواسطفرط الحساسية

T Cell–Mediated Diseases (Type IV Hypersensitivity)

Includes several autoimmune disorders and pathologic reactions to environmental chemicals and persistent microbes. Two types of T cell reactions are capable of causing tissue injury and disease: (1) cytokine-mediated inflammation, in which the

cytokines are produced mainly by CD4+ T cells. (2) Direct cell cytotoxicity, mediated by CD8+ T cells.

T cells are increasingly recognized as the basis of chronic inflammatory diseases, and many of the new designed therapies for these diseases have been developed to target the abnormal T cell reactions.

CD4+ T Cell–Mediated Inflammation

cytokines produced by the T cells induce inflammation

that may be chronic and destructive.

The prototype of T cell–mediated inflammation is delayed-type hypersensitivity(DTH), a tissue reaction to antigens given to immune individuals. In this reaction, an antigen administered into the skin of a previously immunized individual

A detectable cutaneous reaction appears within 24 to 48 hours.

• Naïve T cells are activated in secondary lymphoid organs by recognition of peptide antigens displayed by dendritic cells.

• The T cells differentiate into TH1 effector cells under the influence of various cytokines.

• TH17 cells also may contribute to the reaction, especially when neutrophils are prominent in the inflammatory infiltrate.

• TH1 cells secrete cytokines, mainly IFN-γ >> activate macrophages >> produce substances that destroy microbes and damage tissues, and mediators that promote inflammation

• Activated TH17 cells secrete cytokines that recruit neutrophils and monocytes.

Clinical Examples of CD4+ T Cell–Mediated Inflammatory Reactions:

Tuberculin reaction: The classic example of DTH, known in clinical medicine as the PPD skin test. It is produced accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular “cuffing”.

Granulomatous inflammation:

• A chronic form of TH1-mediated inflammation and macrophage activation by prolonged DTH reactions against persistent microbes or other stimuli may result in.

• The initial perivascular CD4+ T cell infiltrate is progressively replaced by macrophages over a period of 2 to 3 weeks.

• These accumulated macrophages exhibit morphologic evidence of activation and become epithelioid cells. The epithelioid cells occasionally fuse under the influence of cytokines to form multinucleate giant cells. An aggregate of epithelioid cells, typically surrounded by a collar of lymphocytes, is called a granuloma.

Contact dermatitis: presents as a vesicular dermatitis. the environmental chemical binds to and structurally modifies self proteins, and peptides derived from these modified proteins are recognized by T cells and elicit the reaction.

Drug reactions: Many of them are among this type of hypersensitivity reactions of humans. The responsible drug alters self proteins, including MHC molecules, and these neoantigens are recognized as foreign by T cells, leading to presents as a vesicular dermatitis. It is thought that in these reactions, the environmental chemical binds to and structurally modifies self proteins, and peptides derived from these modified proteins are recognized as foreign by T cells and elicit the reaction. Drug reactions often manifest as skin rashes.

Systemic autoimmune diseases: such as rheumatoid arthritis and multiple sclerosis, and diseases probably caused by uncontrolled reactions to bacterial commensals, such as inflammatory bowel disease

CD8+ T Cell–Mediated Cytotoxicity In this type of T cell–mediated reaction, CD8+ CTLs (cytotoxic T

lymphocytes) kill antigen-expressing target cells >> tissue destruction. Clinical examples:

• Type 1 diabetes

• Graft rejection: CTLs directed against cell surface MHC antigens

• Reactions against viruses: viral peptides are displayed by class I MHC molecules and the complex is recognized by the TCR of CD8+ T lymphocytes >> elimination of the infection, but in some cases, it is responsible for cell damage (e.g., in viral hepatitis). CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in inflammatory reactions resembling DTH, especially following virus infections and exposure to some contact sensitizing agents.