Immunopathology Lecture Notes 2024-2025 PDF

Nineveh university - College of medicine Immunopathology 2024-2025 Dr. Hadeel. T. Ali. AL-Obaidy College of medicine, Nineveh university M.B.Ch.B, MS...

Nineveh university - College of medicine Immunopathology 2024-2025 Dr. Hadeel. T. Ali. AL-Obaidy College of medicine, Nineveh university M.B.Ch.B, MSc., (Path.) C.A.B. (Path.) Hypersensitivity reaction Hypersensitivity reaction Definition: it is a pathological, hyperfunction, and injurious immune response to antigen leading to tissue injury, disease or sometimes death in a sensitized individual. Or in other word: is defined an exaggerated response of the immune system to an antigen. General Features of Hypersensitivity Disorders: ❖ Priming or sensitization The person must have become sensitized to the allergen by a prior exposure. ❖ Almost any substance capable of inducing an immune response is a potential allergen (antigen). ❖ Genetic susceptibility: Hypersensitivity diseases are usually associated with the inheritance of particular susceptibility genes (e.g. HLA genes). ❖ Development of hypersensitivity to any particular allergen is due to a complex interaction of genetic susceptibility & exposure. Nature of antigens: It may be exogenous or endogenous origin. ❖ Exogenous antigens: Examples, antigens in dust, pollens, foods, drugs, microbes, chemicals, and few blood products. ❖ Endogenous antigens: Self antigens.  Classification of hypersensitivity reactions Type I (immediate) hypersensitivity. Type II hypersensitivity ( antibody-mediated disorder) Type III hypersensitivity ( immune complex mediated disorders) Type IV hypersensitivity ( cell-mediated or delayed type).  TYPE I (IMMEDIATE) HYPERSENSITIVITY REACTIONS Usually known as allergic or atopic disorders and the environmental antigens that elicit these reactions are known as allergens. Definition: Type I hypersensitivity reaction is a type of immunological tissue reaction, which occurs rapidly (within 5-10 minute) after the interaction of antigen (allergen) with an IgE antibody bound to the mast cells in a sensitized person  Characteristics ❑ Type I HSR occurs in 10-20% of the population ❑Immediate reaction occurring within minutes (5–10 minutes). ❑Antibodies: Mediated by IgE antibody. Atopic individuals thus exhibit elevated levels of serum IgE ❑Develops after the interaction of an antigen with IgE antibodies bound to mast cells. ❑Genetic susceptibility: Occurs in genetically susceptible individuals previously sensitized to the antigen, who are said to be atopic. ❑Antigens (allergens): Many allergens (e.g. house-dust mite, pollens, animal danders or moulds) in the environment are harmless for majority of individuals. E.g. Bronchial asthma, hay fever, food allergies. Mechanism of HSR I A. During Initial Exposure to Antigen (Sensitization) In a genetically susceptible individual, the following events occur: 1. Exposure to sensitizing antigen: either by: 1) inhalation, 2) ingestion or 3) injection. 2. Presentation of the antigen: The sensitizing antigen (allergen) is presented to T cells. by the antigen presenting cells APC(macrophages) & T cell then differentiates into TH2 cell. 3. Activation of TH2 cells: In genetically susceptible individual, antigens (allergens) activates TH2 (subset of CD4+ helper T cells) to secret cytokines (e.g. IL-4, IL-5 and IL-13). 4. Production of IgE antibody: IL-4 secreted by TH2 cells stimulates B cells to secrete cytotropic IgE antibodies. IL-5 activates eosinophils and IL-13 stimulates epithelial cells to secrete mucus. 5. Sensitization of mast cells by IgE antibody: ❑ Mast cells are mainly concentrated near blood vessels and nerves and in subepithelial tissues (common sites of type I hypersensitivity). ❑ Mast cells possess Fc- receptor, which have high affinity for IgE antibodies. ❑ IgE antibodies attach to the Fc-R on the mast cells and the circulating basophils. This takes a time to develop. ❑So in the first meeting between the allergen and the immune system, no reaction will happen. The mast cell/Basophil is the effector cell in this response. B. During re-exposure to Antigen On re-exposure to the allergen, it will cross link the IgE molecules on the surface of the mast cells or the basophils and this will lead to activation of the cells and degranulation in which mast cells and basophils will release the contents of their granules to the exterior. These granules are mediators. including histamine, cytokines, prostaglandins, and leukotrienes; they are responsible for the immediate features of atopy like vasodilatation, increased vascular permeability, increased glandular secretion and smooth muscle contraction.  IgE triggered reactions can be divided into two phases: 1. Immediate phase response : Develops within 5 to 30 minutes after exposure to an allergen and subside in 60 minutes. there is release of preformed mediators of histamine, proteases and chemotactic factors Characterized by vasodilation, vascular leakage, and smooth muscle spasm or glandular secretions. 2. Late-phase reaction: Develops in 2 to 8 hours after the exposure to antigen which may last for several days. release of secondary mediators from the mast cells that include prostaglandins, leukotrienes, cytokines and platelet activating factor (PAF). Characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and TH2 cells. It also shows mucosal epithelial cell damage. Examples of type I hypersensitivity includes Localized type I HSR the commonest examples are hay fever and extrinsic asthma both tend to run in families and often preceded by atopic eczema in infancy or childhood. Patients with hay fever develop acute inflammation of the nasal & conjunctival mucosae with sneezing and hypersecretion minutes (immediate) after exposure to the allergen like the grass pollen, food. Similarly, patients with bronchial asthma develop wheezes & acute respiratory distress due to bronchospasm and increased mucus secretion after exposure to house dust or animal dander. IMMUNOPATHOLOGY Systemic type I HSR this is called anaphylactic reaction, which may result in anaphylactic shock characterized by hypotension, wide spread urticaria and dyspnea. Such shock may be seen following injection of a drug (like penicillin) to a sensitive patient and constitutes a medical emergency, which may be fatal. Inflammation due to type I hypersensitivity reaction: Nasal mass with edematous stroma with inflammatory cell infiltrate ( mainly eosinophils) covered by ciliated columnar epithelium allergic nasal polyp 2_ANTIBODY-MEDIATED (TYPE II) HYPERSENSITIVITY REACTIONS Definition: it is a reaction by antibodies directed toward specific antigens fixed on cell surfaces cause lysis of target cells. Characteristics: ▪ Antibodies: IgG (usually) and IgM (rarely). ▪ Antigen: ❑ Endogenous antigens: ❑ Exogenous antigens: These antigens may get adsorbed on a cell surface or extracellular matrix may cause altered surface antigen (e.g. drug metabolite). The antigen is on the surface of cells + Ab →→ Ag-Ab reaction may be one of three effects: 1- Complement dependent HSR (opsonization & phagocytosis) 2- Antibody dependent cellular cytotoxicity 3-Antibody mediated cellular dysfunction 1. Complement dependent HS-reactions Complement activation and lysis of the target cells after opsonization & phagocytosis. The complement here is C3b, the Ig is IgG, IgM Type II HSR phagocytosis Mechanisms of Injury a. Cell lysis (antibody dependent) o Antibody directed against antigen on the cell membrane activates the complement system, leading to lysis of the cell. Example: Transfusion reaction, incompatible blood transfusion for either ABO or Rh incompatibility when RBCs from incompatible donor enter the recipient circulation, they become coated with antibodies directed against RBC antigen of the donor and are lysed. b. Phagocytosis When circulating cells, such as erythrocytes or platelets, are coated (opsonized) with autoantibodies, with or without complement proteins, the cells become targets for phagocytosis (opsonization) which is phagocytosis of cells coated with antibodies) by macrophages Example: penicillin attaches to RBCs → IgG antibodies are made against penicillin → splenic macrophages phagocytose the RBCs (hemolytic anemia). 2. Antibody dependent cellular cytotoxicity in which the antibody molecule provides a link between the natural killer cell or macrophage and the Ag on the surface of the target cell without phagocytosis & without activation of complement →Drilling holes by perforin & granzyme. phagocytosis 3. Ab- mediated cellular dysfunction Antibody directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation.. e.g.. A. Sometimes antibodies are formed against specific receptor & block its effect as in Hashimoto thyroiditis: Ab formed are against TSH receptor of thyroid epithelial cells, locking the site of TSH action, resulting in hypothyroidism. B: Grave’s disease Here the antibodies formed against TSH receptor of thyroid epithelial cells themselves act as TSH leading to continuous thyroid stimulation with a resultant thyrotoxicosis. EXAMPLES OF TYPE II HSR Examples of type II reaction are mainly on blood cells and some other body cells and tissues. 1. Antibodies to blood cells e.g. i) Autoimmune haemolytic anaemia ii) Transfusion reactions iii) Haemolytic disease of the newborn (erythroblastosis foetalis) iv) Idiopathic thrombocytopenic purpura (ITP) v) Drug-induced cytotoxic antibodies 2. Antibodies to tissue components e.g. i) Graves’ disease (primary hyperthyroidism) ii) myasthenia gravis iii) type 1 diabetes mellitus, islet cell autoantibodies are formed iv) In hyperacute rejection reaction, antibodies are formed against donor antigen.