Lec. 3 - Type III HSR (Complex HSR) 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.)  Type III HSR (Immune Complex HSR) Characterized by: immune complex formation either: locally in certain tissue or circulating in the blood & deposition in various tissues. Antibodies: Complement-fixing antibodies namely IgG, IgM, and occasionally IgA Antigen: Exogenous: Various foreign proteins, e.g. foreign serum protein injected (e.g. diphtheria antitoxin, horse anti-thymocyte globulin) or produced by an infectious microbe. Endogenous: DNA Ag Mechanism of type III HSR EXAMPLES OF TYPE III REACTION Clinical examples of localized HSR III Arthus Reaction 1-Arthus reaction is a local area of tissue necrosis usually in the skin, resulting from acute immune complex vasculitis. 2-Arthus reaction can be experimentally produced by intracutaneous injection of an antigen to a previously immunized animal (with circulating antibodies against the antigen). As the antigen diffuses into the vascular wall, it locally binds to the antibody, and form large immune complexes at the site of injection. Immune complexes deposited in the vessel walls, cause fibrinoid necrosis, and thrombosis leading to ischemic injury. The Arthus reaction is a rare adverse reaction that usually occurs after vaccination with large and more severe local reactions. This reaction is characterized by pain, swelling, induration and edema, even accompanied by severe necrosis or ulceration at the injection sites. However, most of mild cases generally can be cured without treatment, and only severe cases need to be treated with anti-allergy. Therefore, this adverse reaction is often ignored by people*. *https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930064/ Examples of systemic HSR III A- Serum sickness C_Acute post-streptococcal glomerulonephritis B- SLE Systemic lupus erythematosus It results from auto-antibodies against nuclear components (DNA, histones, etc.). These are normally sequestered inside the nucleus where they are hidden from the immune system (antibodies), but they are released following tissue injury; e.g., a viral infection and are quickly bound by the patient own antibodies. The antigen-antibody complexes will deposit in the basement membranes of the glomeruli, lungs, joints, skin, lymph nodes…etc, where they induce complement fixation, inflammation & tissue damage Clinical Features of Systemic Lupus Erythematosus ❑ Acute post-streptococcal glomerulonephritis ❑ which develops 1-2 weeks following throat infection. ❑ The streptococcal antigens pass into the blood. ❑ then antibodies develop against them and react to form the ag-ab complexes ❑ which precipitate on the basement membrane of the glomerular capillaries. ❑ These complexes will activate complement components and cause the inflammation (vasculitis) & endothelial damage. ❑ The patient presents clinically with hematuria and oliguria. Serum Sickness This was a frequent sequel to the administration of old vaccines from other species (e.g. serum horses and rabbits). Nowadays it is infrequent, and usually seen in individuals who receive antibodies from other individuals or species, e.g. horse or rabbit antithymocyte globulin administered to deplete T cells in recipients of organ grafts Pathogenesis Divided into three phases: 1. Formation of immune complexes:. o after Formation of antibody: which usually forms a week (7 to 12 days) after the injection of the foreign protein and are secreted into the blood. 2. Deposition of immune complexes: Sites of deposition: – Blood vessels: It causes vasculitis. – Renal glomeruli: It causes glomerulonephritis. – Joints: It causes arthritis. 3. Inflammatory reaction and tissue injury Clinical features ❑ Fever ❑urticaria ❑ joint pain (arthralgias) ❑lymph node enlargement ❑ and proteinuria appear during this phase. Immune Complex mediated Diseases  Type IV hypersensitivity Type IV hypersensitivity is characterized by cell-mediated response rather than antibodies. Specifically T lymphocytes including CD4+ and CD8+ T cells are involved in the development of the sensitivity, hence called cell-mediated hypersensitivity. Reaction is delayed by 48 to 72 hours after exposure to antigen. Hence also called as delayed-type hypersensitivity (DTH). T lymphocytes (CD4+) are activated by a variety of non-degradable agents like bacteria, fungi and protozoa…etc.  Delayed HSR (Type IV HSR) Mechanism The activated macrophages give rise to epithelioid cells and these cells surrounded by a collar of lymphocytes all around lead to formation of a granuloma. Granuloma Prolonged DTH reaction against persistent microbes (e.g. tubercle bacilli) or other nondegradable (foreign bodies) injurious agent may produce a special microscopic reaction known as granulomatous inflammation. The granuloma is composed of localized collection of epithelioid cells surrounded by lymphocytes with langhans type giant cell. Clinical Examples of CD4+ T Cell–Mediated Inflammatory Reactions Tuberculin Reaction (Mantoux Test) Tuberculin reaction is a classical example for delayed-type hypersensitivity. ❑It is produced by the intracutaneous injection of purified protein derivative (PPD, also called tuberculin), a protein-containing antigen of the tubercle bacillus. ❑In a previously sensitized individual, the injection site becomes red and indurated in 8 to 12 hours, reaches a peak (usually 1 to 2 cm in diameter) in 24 to 72 hours, and thereafter slowly subsides. ❑Microscopically, the injected site shows perivascular accumulation “cuffing” of CD4+ T cells and macrophages.  Contact dermatitis is a common example of tissue injury resulting from DTH reactions. It may be evoked by contact With chemical substances, and presents as a vesicular dermatitis. It is thought that in these reactions, the environmental chemical binds to and structurally modifies self proteins, which are recognized by T cells and elicit the reaction. The same mechanism is responsible for many drug reactions, among the most common hypersensitivity reactions of humans. The responsible drug (often a reactive chemical) alters self proteins, including MHC molecules, and these neoantigens are recognized as foreign by T cells, leading to cytokine production and inflammation. Drug reactions often manifest as skin rashes. CD4+ T cell–mediated inflammation is the basis of tissue injury in many organ- specific and systemic autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis 2. Direct Cell Toxicity Mediated By CD8+ T Cells It is a type of T-cell mediated tissue injury due to CD8+ T lymphocytes (also called as cytotoxic T lymphocytes- CTLs), which kill antigen-bearing target cells. Example—killing of virus infected cells and some tumor cells. Mechanism of Cytotoxic T Cell–Mediated Killing Perforin-granzymes system Through Fas ligand  EXAMPLES OF TYPE IV REACTION These are as follows: 1. Reaction against mycobacterial infection e.g. tuberculin reaction, granulomatous reaction in tuberculosis, leprosy. 2. Reaction against organ transplantation e.g. transplant rejection, graft versus host reaction 3. Reaction against virally infected cells. 4. Reaction against malignant cells in the body.