Immunologyعلم المناعة

Hypersensitivity Reactions 1 1الحساسية تفاعالت فرط

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Hypersensitivity Reactions تفاعالت فرط الحساسية

• Immune responses that normally are protective sometimes are capable of causing tissue injury

• immune responses may be:

Inadequately controlled

Or directed against normally harmless antigens

Or inappropriately targeted to host tissues

• Pathologic immune responses may be directed against different types of antigens and may result from various underlying abnormalities.

Causes of Hypersensitivity Reactions

أسبابها

Autoimmunity: reactions against self antigens.

>>>autoimmune diseases

Reactions against microbes: the reaction appears to be excessive or the microbial antigen is unusually persistent

Reactions against environmental antigens: genetic predisposition

Classification of Hypersensitivity Reactions

o Hypersensitivity reactions can be subdivided into 4 types based on the principal immune mechanism responsible for injury:

-Three are variations on antibody-mediated injury

-The fourth is T-cell mediated reaction

o Several immune reactions may coexist in any disease

األرجية( =IgEبـ المتواسط)فرط الحساسية الفوري

IgMعادة وقد تكون IgG: االضداد المثبتة للمتممة•

يحدث انحالل أو بلعمة للخلية الهدف او اضطراب عملها •

Antibody-Mediated Cytotoxicityباالضداد المتواسطالسمية

T8السامة التائيةتفعيل الخاليا •

بالخاليا المتواسطفرط الحساسية

Immediate (Type I) Hypersensitivity= Allergy

األرجية • Occurs rapidly (within minutes)

• Allergens may be introduced by inhalation, ingestion, or injection

• The injury is caused by TH2 cells: The TH2 cells that are induced secrete several cytokines, including IL-4 and IL-5.

• IL-4 stimulates B cells specific for the allergen to undergo heavy-chain class switching to IgE

• IgE antibodies>>mast cells >> release mediators that act on blood vessels and smooth muscle as well as cytokines that recruit and activate inflammatory cells including eosinophils

Variables that probably contribute to the strong TH2 responses to allergens include the route of entry, dose, and chronicity of antigen exposure, and the genetic profile of the host

Mediators in Immediate (Type I) Hypersensitivity Three Groups of mediators are important in this type:

1. Rapidly released mediators:

-Vasoactive amines: granules of mast cells contain histamine>>>vasodilation, increased vascular permeability, smooth muscle contraction, and increased secretion of mucus.

-Chemotactic factors for neutrophils and eosinophils.

2. Newly synthesized lipid mediators: Mast cells synthesize and secrete prostaglandins >>>causes intense bronchospasm and increased mucus secretion. Leukotrienes>>> LTC4 and LTD4 are the most potent vasoactive and spasmogenic agents known; LTB4 is highly chemotactic for neutrophils, eosinophils, and monocytes

3. Cytokines: important for the late-phase reaction. These include TNF and chemokines>> recruit and activate leukocytes, IL-4 and IL-5>>amplify the TH2-initiated immune reaction.

Predisposing Factors

• Genetic factors: Susceptibility to immediate hypersensitivity reactions is genetically determined. A positive family history of allergy in 50% of atopic individuals.

• An increased ability to develop immediate hypersensitivity reactions= atopy تأتب ( التأهب لألرجية)

• Higher serum IgE levels and more IL-4–producing TH2 cells

• Environmental factors: Exposure to environmental pollutants, domestic animals, infections

• hygiene hypothesis: too much hygiene in childhood may increase allergies later in life

Clinical and Pathologic Manifestations

IgE-triggered reaction has two well-defined phases:

(1) The immediate response: stimulated by mast cell granule contents and lipid mediators and is characterized by vasodilation, vascular leakage, and smooth muscle spasm, usually evident within 5 to 30 minutes after exposure to an allergen and subsiding by 60 minutes. • Local: when the antigen is confined to a particular site,

such as the skin (atopic dermatitis), the gastrointestinal tract (food allergies), or the lung (certain forms of asthma)

• Systemic = anaphylaxis تأق : Systemic exposure to protein antigens (e.g., bee venom) or drugs (e.g., penicillin)

(2) Late-phase reaction stimulated mainly by cytokines, which usually sets in 2 to 8 hours later, may last for several days, and is characterized by inflammation as well as tissue destruction.

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.