Immune System Disorders PDF

General Pathology, 15-18 / 12 / 2024 Immune system disorders Immune system disorders They include: 1. Immune deficiency 2. Hypersensitivity reactions 3. Autoimmune diseases...

General Pathology, 15-18 / 12 / 2024 Immune system disorders Immune system disorders They include: 1. Immune deficiency 2. Hypersensitivity reactions 3. Autoimmune diseases Immune deficiency A. Primary immune deficiency Rare in general and genetically predisposed. Manifest themselves in infancy, between 6 months and 2 years of life, and they are detected when the affected infants undergo recurrent infections. Includes: 1. Primary antibody deficiencies in which the affected infants suffer from recurrent bacterial infections of the respiratory tract, such as: a. Acute and chronic pharyngitis b. Otitis media c. Sinusitis d. Bronchitis and pneumonia 2. Primary T-cells deficiencies in which the affected patients show a poor immune defense against fungal and viral infections. B. Secondary (acquired) immune deficiency Acquired immune deficiencies take place due to: 1. Aging 2. Malnutrition 3. Immune-suppressive drugs 4. Radiotherapy and chemotherapy of cancers 5. Viral infections e.g., acquired immunodeficiency syndrome (AIDS) which is caused by the human immunodeficiency virus (HIV) and characterized by profound immunosuppression that leads to opportunistic infections, neoplasms, and neurologic manifestations. Hypersensitivity reactions Hypersensitivity reactions are characterized by an excessive immune response against harmless antigens resulting in cell and tissue damage. Types of hypersensitivity reaction Type I hypersensitivity reactions (immediate hypersensitivity reactions) Also known as allergic reactions or allergies. Occur rapidly (typically within minutes) after the exposure of previously sensitized individuals to exogenous environmental antigens (known as allergens). May take place as a local reaction that is merely annoying (e.g., seasonal rhinitis), severely debilitating (e.g., atopic asthma), or systemic and fatal (anaphylaxis). The exposure to allergens may take place through the skin contact (e.g., dust mites and bacterial infections), ingestion (e.g., eggs, peanuts, hazelnut and shellfish), inhalation (e.g., the pollen, mold and pet dander), or injection (e.g., drugs). 1  General Pathology, 15-18 / 12 / 2024 Immune system disorders The reaction is mediated by an IgE antibodies-immune response. ❖ The allergens interact with IgE antibodies causing them to bind to and activate mast cells. ❖ Activated mast cells degranulate and release histamine and leukotrienes which are responsible for the clinical manifestation of this type of hypersensitivity reaction. Development of Allergies 1. Genetic predisposition The susceptibility to type 1 immediate hypersensitivity reactions is genetically determined. Genetically-predisposed, higher tendency to develop immediate hypersensitivity reactions is called atopy. ❖ Atopic individuals have high levels of IgE antibodies in the blood. 2. Exposure to exogenous environmental factors Exposure to exogenous environmental pollutants is also an important predisposing factor for the development of allergic reactions. 3. Non-antigenic stimuli It is estimated that 20% to 30% of immediate hypersensitivity reactions are triggered by non- antigenic stimuli such as temperature extremes and exercise, and do not involve IgE response. It is believed that in these cases mast cells are abnormally sensitive to activation by non- immune stimuli. Anaphylaxis Life-threatening reaction taking place after systemic exposure of previously sensitized individuals to exogenous protein allergens e.g., bee venom, and drugs such as penicillin. Less commonly, the ingestion or inhalation of exogenous allergens also can trigger systemic anaphylaxis e.g., ingestion of allergic food such as shellfish. Clinical findings of anaphylaxis 1. It is the most severe form of the hypersensitivity reactions. 2. Itching, erythema and urticaria (hives) appear within minutes next to the exposure of a sensitized person to the allergen. 3. Followed shortly by profound respiratory difficulty caused by upper airway obstruction (due laryngeal edema & bronchospasm) and accentuated by hypersecretion of mucus. 4. Without immediate (emergent) intervention, there may be systemic vasodilation with a fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes. Local type 1 hypersensitivity reactions They occur when the antigen exposure is confined to a particular site, such as the skin (following contact), the gastrointestinal tract (following ingestion), or the lung (following inhalation). 2  General Pathology, 15-18 / 12 / 2024 Immune system disorders Allergic rhinitis, atopic dermatitis, atopic asthma, and food allergies are examples of localized allergic reactions. Type II hypersensitivity reactions (Antibody-mediated hypersensitivity reactions) Antibody-mediated hypersensitivity reactions against target antigens on the surface of cells or other tissue components. Occur in previously sensitized individuals within hours after exposure to the antigens. The target antigens may be: 1. Endogenous antigens e.g., normal protein molecules intrinsic to cell membranes or in the extracellular matrix. Or 2. Adsorbed exogenous antigens e.g., a drug metabolite. Mechanisms of antibody-mediated hypersensitivity reactions 1. Antibody-mediated cell opsonization and phagocytosis Antibody-mediated cell opsonization and phagocytosis play an important role in some pathological situations e.g.: a. Certain types of drug allergies, in which the concerned drug attaches to plasma membrane proteins of RBCs and antibodies are produced against the drug-protein complex. b. Autoimmune hemolytic anemia in which affected individuals produce antibodies against their own RBCs. c. Transfusion reactions, in which the host body produce antibodies against cells (RBCs or platelets) from an incompatible donor. d. Hemolytic disease of the fetus and 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. 2. Antibody-mediated inflammation Antibody-mediated inflammation plays an important role in in tissue injury in some pathological disorders e.g.: a. Some forms of glomerulonephritis (antibody-mediated glomerulonephritis). b. Antibody-mediated vascular rejection in organ grafts. 3. Antibody mediated cellular dysfunction The antibodies are bound to surface receptors of specific body cells resulting in impairment or dysregulation of the function, e.g., Myasthenia gravis and Graves’ disease. 3  General Pathology, 15-18 / 12 / 2024 Immune system disorders Type III hypersensitivity reactions (Immune complex diseases) Take place when the antigen–antibody complexes (immune complexes) are formed in the circulation and deposit in blood vessels walls, leading to complement activation and acute inflammation. Occur in previously sensitized individuals within hours after exposure to the antigens. The antigens that form the immune complexes may be: 1. Exogenous, such as a foreign protein that is injected or produced by an infectious microbe. Or 2. Endogenous, if the individual produces antibody against self-antigens (autoimmunity). Most commonly, immune complex–mediated diseases tend to be systemic and characterized by preferential deposition of the immune complexes in: 1. Small blood vessels 2. Kidneys 3. Joints Examples of immune complex diseases: 1. Poststreptococcal glomerulonephritis. 2. Systemic lupus erythematosus (skin lesions, arthritis and nephritis). Type IV hypersensitivity reactions (T cell mediated hypersensitivity reactions) Involved in the pathogenesis of: 1. Several autoimmune disorders 2. Pathologic reactions to environmental chemicals and persistent microbial infections. Mechanisms of T Cell mediated hypersensitivity reactions 1. Cytokine-mediated inflammation in which the cytokines are produced mainly by CD4+ T cells. This reaction is also known as CD4+ T cell-mediated hypersensitivity reaction. 2. Direct cell cytotoxicity mediated by CD8+ T cells. This reaction is also referred to as CD8+ T cell-mediated hypersensitivity reaction. CD4+ T cell–mediated hypersensitivity reaction It takes place when CD4+ T cells (helper T cells) are activated by exposure to a protein antigen. Subsequent exposure to the same antigen causes these activated CD4+ T cells to secrete cytokines such as: 1. Interlukein-17 which recruit leukocytes, thus promoting inflammation. 2. Interferon gamma (INF-γ) which activates macrophages to produce substances that cause tissue damage and promote fibrosis. The CD4+ T cell–mediated hypersensitivity reaction is involved in the pathogenesis of several diseases, e.g.: 1. Psoriasis: Chronic autoimmune disease characterized by destructive skin lesions. 4  General Pathology, 15-18 / 12 / 2024 Immune system disorders 2. Multiple sclerosis: Chronic autoimmune disease that takes place due to nerve fibers demyelination in white matter of the brain and spinal cord. 3. Inflammatory bowel disease: A chronic disease characterized by an inappropriate activation of the intestinal mucosa due to complex interactions between intestinal microbiota and host immunity in genetically predisposed individuals. ❖ This disease is postulated to be of autoimmune origin and it includes 2 entities: a. Ulcerative colitis which is limited to the colon and rectum and its lesions extend only into the mucosa and submucosa. b. Crohn disease which is frequently transmural (its lesions extend from the mucosa to serosa) and it may involve any part of the GIT. 4. Delayed-type hypersensitivity (DTH): The prototypical example of T cell–mediated inflammatory reaction. It develops in response to antigens given to previously sensitized individuals. ❖ In comparison with type 1 immediate hypersensitivity, the DTH reaction is delayed for 24 to 48 hours. ❖ Prolonged DTH reactions against persistent microbes (e.g, M. tuberculosis) or other stimuli may result in a special pattern of reaction called granulomatous inflammation. ❖ The DTH is involved in the pathogenesis of: a. Drug allergy: DTH is responsible for many allergic drug reactions which are often manifested as skin rashes. b. Tuberculin reaction (Tuberculin test) which is used to screen populations for people who have had previous exposure to tuberculosis. It is produced by intradermal injection of a purified protein (tuberculin) derived from M. tuberculosis bacillus. c. Allergic contact dermatitis (ACD) which can be triggered by skin contact with a sensitizing environmental chemical agent such as nickel, chromium, cobalt, cosmetics & fragrances, and oxidative hair dye ingredients. CD8+ T cell-mediated hypersensitivity reaction Mediated by the CD8+ T cells (cytotoxic T cells “CTLs”) which are responsible for the tissue damage by recognizing and direct killing the antigen-bearing body cells. It takes place when CD8+ T cells are activated by exposure to a protein antigen. Subsequent exposure to the same antigen causes these activated CD8+ T cells to recognize and directly kill body cells that express that antigen. CD8+ T cell–mediated hypersensitivity reaction plays an important role in the pathogenesis of: 1. Type 1 diabetes 2. Graft rejection (organ or tissue-transplant rejection) 5  General Pathology, 15-18 / 12 / 2024 Immune system disorders 3. Viral infections: The killing of viral-infected cells leads to elimination of the infection, but in some cases, it is responsible for cell damage that accompanies the infection; e.g., viral hepatitis. Autoimmune diseases Autoimmune diseases or disorders are characterized by immune reactions against self- antigens. Self-tolerance Self-tolerance is the lack of immune responsiveness to own tissue antigens (self-antigens). Normal persons are self-tolerant. Failure of self-tolerance is the basis of autoimmune diseases. During their development (maturation) in the central (primary) lymphoid organs, the T and B lymphocytes acquired billions of different antigen receptors. ❖ During this huge process of lymphocytes maturation, it is possible that, some of the T and B lymphocytes generate receptors that can recognize self-antigens. Such lymphocytes are known as self-reactive lymphocytes. ❖ In normal conditions, the immune system try to eliminate or control the self-reactive lymphocytes by normal body pathways called immunologic-tolerance pathways. Main causes of failure of self-tolerance Failure of self-tolerance and development of autoimmune diseases results from a combination of: 1. Inheritance of susceptibility genes that may disrupt the immunologic-tolerance pathways. This is indicated by the fact that autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins. 2. Alteration of the self-antigens display by environmental factors such as infections and tissue damages. The altered display of self-antigens results in activation of the antigen presenting cells (APCs) and enhancing the activation of self-reactive lymphocytes. The altered display of self-antigens also may be caused by other environmental insults, e.g.: 1. Ultraviolet (UV) radiation causes cell death and may lead to the exposure of nuclear antigens resulting in pathologic immune responses. ❖ This mechanism (radiation-induced cell death and exposure of nuclear antigens) is the probable cause of expression of lupus flares upon exposure to sunlight in systemic lupus erythematosus patients. 2. Smoking is a risk factor for rheumatoid arthritis (RA), perhaps because it leads to chemical modification of self-antigens. 6  General Pathology, 15-18 / 12 / 2024 Immune system disorders Many of the autoimmune diseases are more common in women than in men. The underlying mechanisms are not well understood and may include the effects of hormones and other factors. Molecular mimicry Viruses and other microbes may share cross-reacting antigen epitopes with self-antigens; therefore, immune responses against these viruses or microbes also may attack self-antigens. This phenomenon (referred to as molecular mimicry) is the probable cause of a few diseases, the best example being rheumatic heart disease, in which an immune response against the streptococci cross-reacts with cardiac self-antigens. Epitope spreading Epitope spreading is a term referring to an immunogenic expose of self-antigen epitopes (that were previously hidden) to the T cells due to tissue injury that results from an autoimmune response. It is referred to as “epitope spreading,” because the immune response spreads to epitopes that were not recognized initially. Epitope spreading is one of the mechanisms that may contribute to the chronicity of autoimmune diseases. 7