Immunopathology PDF

Immunopathology Ariette Acevedo, O.D. BMS 2 Objectives Review immunology principles  Innate Immunity  Adaptive Immunity Discuss antibody importance and functions Discuss the immune mechanism of tissue injury  Type I-IV Discuss tests for immunodeficiency and autoimmune related disease Disorders of...

Immunopathology Ariette Acevedo, O.D. BMS 2 Objectives Review immunology principles  Innate Immunity  Adaptive Immunity Discuss antibody importance and functions Discuss the immune mechanism of tissue injury  Type I-IV Discuss tests for immunodeficiency and autoimmune related disease Disorders of the immune system  Immunodeficiency Syndromes  Congenital/Acquired  Autoimmune Disease  Acquired Transplant Rejection  Causes/Mechanisms Principles of Immunology Innate and Adaptive Immunity Complement System in Disease Immune System In order to maintain homeostasis in the body, there is a need for constant combat against harmful agents, bot internal and external.  Recognition and elimination or control of foreign microbes. Immunity is the ability to ward off damage or disease through our defense system.  Susceptibility is the absence of immunity. 2 main types of immunity:  Innate (non-specific) immunity  Adaptive (specific) immunity The efficacy of the immune system is determined by the ability to distinguish between foreign and dangerous invaders versus self-components. Innate (Non-Specific) Immunity First line of defense against pathogens is the skin and mucous membranes.  Physical and chemical barriers Defenses are present at birth and always are present Provide rapid response to antigens, but not specific It does not have memory, it cannot recall previous antigen encounter Adaptive (Specific) Immunity Presents once the antigen has been identified. Mounts a specific response to a specific microbe Slow to respond Has a memory component Cells of the Innate Immune System Monocytes Macrophages Dendritic Cells Natural Killer Cells (NK or NK T) Neutrophils Eosinophils Basophils Mast Cells Cells of the Adaptive Immune System T-Cells B-Lymphocytes Antibodies Can combine specifically with the epitope on the antigen.  The part of the antigen that the Ab recognizes.  It functions as a lock and key Belong to a group of proteins called globulins (immunoglobulins) Composed of a four peptide chain  2 identical Heavy (H) chains  2 identical Light (L) chains  Connected to each other by S-S Variable regions: Antigen-Binding Site  This changes depending on the antigen  Attaches to the antigen Constant regions: neatly the same in all antibodies of the same class  Distinguishing mechanism between the 5 different types of Ab  IgA, IgM, IgD, IgE, IgG Immunoglobulin A (IgA) 10-15% of the antibodies present in the body. Produced by glandular epithelium      Nasal mucosa Breast milk Gastrointestinal secretions Sweat Tears Provides ab to newborns Provides localized protection of mucous membrane against bacteria and viruses.  Levels decrease due to stress Immunoglobulin G (IgG) 75-80% of all antibodies Present in all body fluids Smallest and most common antibody Provides memory immunity Passive immunity to the fetus  Crosses the placenta Protects by enhancing phagocytosis, neutralizing toxins and triggering the complement system. Immunoglobulin M (IgM) 5-10% of all antibodies Present in blood and lymph Largest antibody Induces other immune system cells to destroy foreign substances  Activates complement system and creates agglutination and lysis of microbes. First antibody to respond in infections In blood plasma, he anti-A and anti-B Ab of the ABO group, which bind to A and B antigens during incompatible blood transfusions are IgM. Immunoglobulin D (IgD) Produces in small quantities  0.2% of all antibodies in blood Function is unknown but it is known to activate B-cells Present n the digestive tract and lining tissue of chest cavity Immunoglobulin E (IgE) Less than 0.1% of all antibodies. Located on mast cells and basophils. Present in the skin, lungs, mucous membranes. Involved in allergic and hypersensitivity reactions  Also provides protection against parasites  Responds in the presence of fungus, animal dander, and parasites Methods to Acquire Adaptive Immunity Naturally Acquired Active Immunity  Following exposure to a microbe Naturally Acquired Passive Immunity  Transfer of IgG across the placenta and IgA from breast-feeding Artificially Acquired Active Immunity  Antigens induced during vaccination, they are immunogenic but not pathogenic Artificially Acquired Passive Immunity  IV injections of immunoglobulins Hypersensitivity Reactions Type I-IV Hypersensitivity Hypersensitivity occurs when a foreign substances that is common in the environment and innocuous, trigger an immune response. This is commonly known as an allergic reaction. Can range from minor manifestations (atopic dermatitis, rhinitis) to severe manifestations (anaphylaxis). These hypersensitivities care divided into 4 presentations.  Type I-IV  Classified according to mechanism Type I-III: are antibody mediated Type IV: T-cell mediated Hypersensitivity Type I Anaphylactic type reaction Mechanism: IgE mediated release of antibodies against a soluble antigen. IgE binds to Mast Cells, causing activation which leads to histamine release and other inflammatory mediators. This causes:  An increase in vascular permeability which leads to edema  Constriction of smooth muscle leading to bronchoconstriction  Stimulation of mucus secretion Acute phase is evident within 5-30 minutes after exposure, and typically subsides after 60 min.  Presents with vasodilation, vascular leakage, smooth muscle spams Late phase presents in ~50% of individuals, 4-12 hours after initial exposure without additional stimulation  Intense tissue infiltration and destruction Hypersensitivity Type I Examples of Type I reactions:         Asthma Allergic rhinitis Urticaria Angioedema Allergic dermatitis Food allergies (peanuts, shellfish) Allergic conjunctivitis Anaphylaxis Anaphylaxis: medical emergency leading to acute, life threatening respiratory failure.  Most severe allergic reaction  Bronchospasm, laryngeal edema, cyanosis, hypotension and shock Hypersensitivity Type II IgG or IgM mediated cytotoxic-mediated response against cell surface and extracellular matrix proteins.  Reaction leads to cellular destruction It happens in response to cell surface modifications or matrix-associated antigens generating antigenic epitopes 3 mechanisms:  Antibody binding to cell surface receptor, altering cellular activity  Activation of the complement pathway  Antibody dependent cellular toxicity Most common causes include:  Medications (penicillin, thiazides, cephalosporins, and methyldopa)  Against organ functions (Grave’s Disease, Myasthenia Gravis)  Hemolytic disease of the newborn Type II: Cell Destruction w/o Inflammation Can occur in 3 main mechanisms:  Antibodies (IgG) bind to the target cell’s surface and to macrophages  Fcγ receptor  They can also bind the Ab to the target cell and activate the complement pathway  Ab can bind to the target cell, activate the complement pathway and activation of the membrane attack complex  Creates a channel to induce lysis Both mechanisms act as an opsonin (opsonization)  Targeting the cells for phagocytosis This type is seen:  Hemolytic anemia  Autoimmune thrombocytopenia  Erythroblastosis fetalis Type II: Inflammation Mediated by Complement Ab (IgG or IgM) can activate the complement pathway by binding to selfantigens resulting in he formation of complement C3a and C5a These act as chemotactic factors, recruiting and activating neutrophils  Neutrophils release enzymes and reactive oxygen species, causing lysis on target cell Type II: Cellular Dysfunction by Ab Autoantibodies bind to the receptors on target cells, causing dysfunction without causing inflammation or destruction. Hypersensitivity Type III Ag-Ab complex initiate an acute inflammatory reaction. Immune complexes are antigen-antibody aggregates  They can accumulate in multiple tissue locations (skin, vessels, joints, ect…)  Can be circulating or fixed (in situ) The accumulation of Ag-Ab aggregates leads to complement activation, leading to recruitment of inflammatory cells (monocytes/neutrophils) which release lysosomal enzymes and free radicals at site, causing tissue damage. Can present as Serum Sickness Type or Arthus Reaction Serum Sickness Caused by drugs containing proteins of other species (antivenom, vaccines, antitoxins and synthetic monoclonal antibodies). The protein acts as an Ag triggering an immune response medium/large complexes are removed from circulation from mononuclear cells, but small/intermediate size complexes are harder to remove and continue circulating.  They can filter out of circulation in organs where blood is transformed (urine/synovial fluid), thus they tend to affect the kidneys and joints. After deposition, an inflammatory reaction begins (~10 days after exposure) with non-specific symptoms.  Fever, urticaria, arthralgias, proteinuria, adenopathy. After deposition, activation of the complement (C3a and C5a) which recruit macrophages and neutrophils causing inflammatory damage to tissues. Arthus Reaction Localized inflammatory response, typically seen after vaccination. Typically presents at site of injection as swelling after 24 hours. Injected Ag create complexes Ag-Ab and activate the complement cascade, leading to vasculitis near the injection site.  Vasculitis: inflammation of small blood vessels Hypersensitivity Type IV Delayed reaction mediated by cellular response  T-cells T-cells mount an inflammatory reaction against endogenous or exogenous Ag. APC phagocytose the Ag and present it to the T-cells which then become sensitized and activates.  Release cytokines and chemokines, causing tissue damage This reactions are important in fighting pathogens such as mycobacteria and fungi and play a role in tumor immunity and transplant rejection.  Up to a certain extent they are normal Can cause transplant rejection, contact dermatitis (poison ivy), drug hypersensitivity, and TB test (Mantoux/PPD) Transplant Rejection Acute transplant rejection occurs due to preformed anti-donor Ab present in the recipients circulation. Within minutes to a few hours the reaction is activated leading to transplant rejections. Characterized by widespread acute arteritis, arteriolitis, thrombosis of vessels and necrosis.  Essentially the new graft never gets vascularized and undergoes ischemic necrosis. Summary Type I: https://youtu.be/2tmw9x2Ot_Q?si=jQ9JZAgBW-7E7j7w Type II: https://youtu.be/kLaUz58CBMc?si=GkTm_Xq9LOgluW81 Type III: https://youtu.be/0T_SAXyMs_c?si=7AeHoqBIaQmgsOL6 Type IV: https://youtu.be/QgES9AwWB8s?si=Sbbk-BnLzUaSQcgZ Test for Immunodeficiency and Autoimmune Related Disease C Reactive Protein (CRP) Erythrocyte Sedimentation Rate (ESR) Rheumatoid factor (RF) Antinuclear Antibody (ANA) Test Human Leukocyte Antigen (HLA-B27) Anti-nuclear cytoplasmic antibodies (ANCA) Antibodies for H. pylori Diseases of the Immune System Acquired: HIV/AIDS Congenital: DiGeorge Syndrome Wiskott-Aldrich Syndrome Deficiency of IgA Epidemiology: 2016: 36.7 million people worldwide S/S: Pathophysiology: Primary infection presents 2-4 weeks, with no—specific symptoms. Fever, fatigue, adenopathy, myalgia, arthralgia, sore throat… Chronic infection without AIDS Chronic infection with AIDS AIDS is defined as a CD4 cell count less than 200 cells/microL Severe/Advanced HIV/AIDS: 50cells/microL AIDS predisposes the patient to more frequent and severe opportunistic infections Cytomegalovirus (retinitis) Kaposi Sarcoma Rapid Tests (results within 1 hour) ELISA test Western Blot PCR tests DX: HIV infection is caused by an enveloped retrovirus that causes AIDS AIDS is late-stage HIV infection HIV attaches to CD4 cells and CCR5 receptors, binding with the cell membrane and entering the T-helper lymphocytes. Causes DNA changes to produce proteins HIV/AIDS Highly Active Antiretroviral Therapy (HAART) Prevention: Pre-Exposure Prophylaxis (PReP) TX: Epidemiology: S/S: Pathophysiology: 1:4000 Learning and behavior Most common problems immune defect Developmental delays Both sexes Speech/hearing problems affected equally Abnormal facies Congenital heart disease Underdeveloped parathyroid glands Decreased immunodeficiency More prone to infections Absent or hypoplastic thymus Genetic testing at birth DX: Autosomal dominant defect Genetic condition caused by a deletion on 22q11.2 Lack or decreased of T-Cells for cellular immunity DiGeorge Syndrome No cure or treatment TX: Epidemiology: Rare disease 1-10/million males S/S: Eczema Thrombocytopenia Immune deficiency Recurrent infections Prone to autoimmunity or inflammatory disease: Autoimmune hemolytic anemia, vasculitis, IBS Increased risk of lymphoma In the 1sr year of life Testing in males with eczema and thrombocytopenia Decreased IgM, in some cases increases IgA or IgE Genetic testing DX: Pathophysiology: X-linked, Autosomal recessive genetic disease Caused by mutations in the WAS gene Wiskott Aldrich Syndrome No treatment, managing symptoms. TX: Epidemiology: S/S: Most common of primary Immunodeficiency disorders Pathophysiology: Most affected individuals are asymptomatic Higher propensity for: Asthma, rheumatoid arthritis, Gluten intolerance and IBS Deficiency of IgA (IgA less of M, 10X more common in women  Childbearing age  Highest incidence in African Americans, with a younger presentation Mechanism: a breakdown in tolerance in genetically susceptible individuals, which leads to the activation of autoimmunity. Systemic Lupus Erythematosus S/S:        Fatigue, malaise, fever, anorexia and weight loss. Mucocutaneous manifestations: malar or butterfly rash Musculoskeletal involvement Cardiac involvement Pulmonary involvement Lupus Nephritis GI manifestations Ophthalmic involvement:  Keratoconjunctivitis sicca, retinal vasculitis, optic neuritis, uveitis, scleritis/episcleritis  Higher incidence of drug induced damage (Plaquenil/Steroids) Systemic Lupus Erythematosus Diagnosis:  (+) ANA Treatment:     According to presentation Plaquenil Corticosteroid (oral/topical) NSAIDS Sjogren’s Syndrome Systemic autoimmune disorder of unknown etiology presenting with severe dryness (Sicca) due to inflammation and damage to lacrimal and salivary glands 1/3 of patients also develop extra-glandular involvement of the joints, skin, lungs, GI, nervous system and/or kidneys. Frequently occurs in conjunction with other autoimmune conditions  RA/SLE  Secondary Sjogren’s Incidence 0.5-1.0% of the population  400,000-3.1 million adults  50% also have RA Typically affects F>M (9:1) Sjogren’s Syndrome Diagnosis:     Clinical diagnosis Confirmatory biopsy of salivary glands Lab: ANA, RF, SS-A and SSTear and salivary function tests Treatment  Management of dry eye  Lubricant drops  Punctal plugs  Cyclosporine drops  Serum tears Grave’s Disease Autoimmune disease that affect primarily the thyroid gland but can also affect eyes and skin. It is the most common cause of hyperthyroidism (60-80%) Higher incidence if positive family history 1.2% USA prevalence F>M, aged 20-50 y/o Mechanism:  Caused by thyroid stimulating immunoglobulin (TSI) synthesized by B-cells within the thyroid  TSI binds to thyroid stimulating hormone (TSH) receptor on the thyroid membrane to stimulate the production of TSH  TSH stimulated both thyroid hormone synthesis and thyroid gland growth  Hyperthyroidism and Thyromegaly Grave’s Disease S/S:        Heat intolerance Sweating Fatigue Weight loss Palpitations Nervousness/anxiety Goiter Can also present with Grave’s Orbitopathy/Thyroid Eye Disease (TED)  Caused by inflammation and cellular proliferation       Exophthalmos Eyelid retraction Periorbital edema Chemosis Injection Exposure keratitis Grave’s Disease Diagnosis:  TSH, Free T4, Free T3, Total T4, Total T3  Typically TSH is decreased, while FT4 and FT3 are elevated Treatment:  Antithyroid drugs  Radioactive iodine  Total or partial thyroidectomy Pernicious Anemia Rare autosomal disorder (less than 1%) Causes a decrease in vitamin B12 (cobalamin) absorption  Results in a B12 deficiency and subsequent megaloblastic anemia Affects people of all ages, more over 60 y/o Mechanism:  Intrinsic factor that facilitates B12 transport is inhibited and anti-IF antibody preventing intestinal absorption 25% of autoimmune gastritis have pernicious anemia Associated with a higher incidence:  DM1, autoimmune thyroid disease and vitiligo Vasculitis GCA Takayasu Arteritis Giant Cell (Temporal) Arteritis Systemic inflammatory vasculitis of medium and large arteries Typically a disease of the elder, very rarely before 50 y/o, mean age 75 y/o Mechanism:  Immune-mediated inflammatory changes in vessel wall  Risk factor: smoking 20/100,000, most common vasculitis  F>M (1:2) Diagnosis:  Temporal artery biopsy  Elevated ESR and CRP Giant Cell (Temporal) Arteritis S/S:       Constitutional symptoms: weight loss, malaise, fever Headache: new-onset or changing Scalp tenderness Jaw claudication Enlargement of the temporal artery, unilateral or bilateral Ophthalmic manifestations  15% of patients develop ocular presentations  Most common Anterior Ischemic Optic Neuropathy (AION)  Transient vision loss/Amaurosis fugax Treatment  Anti-inflammatories Takayasu Arteritis Aka: “pulseless disease” Systemic inflammatory condition that creates damage to large and medium arteries that leads to stenosis, occlusion or aneurysmal damage.     Aorta Renal Carotid Subclavian Mechanism:  Abnormality in cell-mediated immunity, but etiology is unknown. Rare disease: 1-2/million  F>M (9:1)  Young patients: 40-50 years of age  Rare in North America, mostly in Asian or Mexican descent Takayasu Arteritis Diagnosis:  By arterial imaging abnormalities  CTA/MRA S/S: non-specific  Fever, malaise, weight loss, anorexia  Visual symptoms:  Visual defects  Retinal hemorrhages  Total blindness