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Diseases of Immunity 2011 CL Davis General Pathology Paul W. Snyder, DVM, PhD Purdue University Hypersensitivity reactions • • • • Altered reactivity to an antigen that results in pathologic reactions upon the exposure of a sensitized host to that antigen. Four different types based on the mechanism (effector molecules) by which the immune reactions initiate the tissue injury: • Humoral immunity • Cell mediated immunity “Over reactive immune response” Immune reaction elicits an inflammatory response that is more harmful than the pathogen or antigen. Snyder 2010 2 Snyder 2010 3 Snyder 2010 4 Classification of hypersensitivity Hypersensitivity Reactants Antibodies Cells Reaction type I II III IV Major mediator IgE IgG IgG T cells Allergens Insoluble Soluble Soluble & Insoluble Antigens Snyder 2010 5 Type I hypersensitivity reactions • Immediate hypersensitivity, anaphylactic reaction or allergy. • Immunologic reaction that manifests itself by tissue reactions within minutes after exposure. • Cells involved: – Mast cell – Plasma cell – Eosinophil • Mediators involved: – Histamine – AA products – ECF – Proteases Snyder 2010 6 Type I hypersensitivity: Components • Antibody IgE: – Reagenic antibody – Extra heavy chain domain on constant portion – Low serum levels in the dog: • IgG 1000-2000 mg/dL • IgM 100-200 mg/dL • IgA 30-240 mg/dL • IgE 2-40 mg/dL – CH2 domain binds to mast cells via Fc receptor – Longer half-life when bound (weeks vs. days) – Genetically determined ability to form IgE Snyder 2010 7 Type I Hypersensitivity: Components • Mast cell: – Metachromatic granules – Connective tissue vs. mucosal mast cells – Localized release of mediators • Mechanism of mast cell degranulation: – Allergen cross-links receptor bound antibody – Changes in cyclic nucleotide levels • cAMP • cGMP – Influx of calcium – Methylation of membrane phospholipids Snyder 2010 8 Type I hypersensitivity: Pathogenesis • • • • • Sensitization of the host Production of antibody (IgE) Antibody fixes to the surface of mast cells Host is now sensitized Second exposure to the antigen results in cross linking of IgE on the mast cell surface • Activation of the mast cell – pre-formed mediators – newly synthesized mediators • Inflammatory reaction Snyder 2010 9 Snyder 2010 10 Snyder 2010 11 Type I hypersensitivity: Consequences • Conditions range from life-threatening (systemic anaphylaxis and asthma) to annoying localized reactions (dermatitis and rhinitis). • Mediators result in: – Increased vascular permeability – Smooth muscle contraction – Influx of inflammatory cells – Tissue damage • Reaction may be systemic or localized. Snyder 2010 12 IL-4 IL-5 IL-6 TNF Snyder 2010 13 Snyder 2010 14 Snyder 2010 15 Snyder 2010 16 Snyder 2010 17 Type I hypersensitivity: Components • Eosinophils: – Allergic and parasitic reactions – ECF and LTB4 are chemotactic for eosinophils – Major basic protein and lysosomal enzymes – Diamine oxidase and arylsulfatase (anti AA products) – Some anti-inflammatory effects but still largely proinflammatory overall. • Allergens: – Proteins, Plant pollens, Drugs, Foods, Insect venoms, Molds, Animal hair/dander Snyder 2010 18 Snyder 2010 19 Regulation of the Type 1 Response • TH1- decreases the response – IFN • TH2- increases the response – IL-3, mast cell production – IL-4, class switching to IgE – IL-5, eosinophil maturation and activation – IL-10, mast cell production • Soluble antigens – Fail to elicit a co-stimulatory signal, anergy Snyder 2010 20 Type I hypersensitivity: Specific disease syndromes • Target organ depends on the route of administration of the antigen. • Atopic dermatitis: – A familial tendency to develop a localized type I hypersensitivity reaction – Genetic predisposition to develop IgE antibodies and clinical allergy to environmental allergens – Involves the skin in dogs – Breeds predisposed (Terriers and Dalmations) – Clinically present with erythema, edema and papules – Secondary changes include hyperpigmentation and alopecia – Serum concentrations of IgE are variable Snyder 2010 21 Type I Hypersensitivity: Specific diseases • Acute systemic anaphylaxis: – Systemic type I hypersensitivity – Occurs with rapid administration of an antigen to a sensitized host • Food allergy – Skin or GI signs • Allergies to vaccines, drugs, parasites... • Laminitis • Milk allergy – Cattle allergic to casein Snyder 2010 22 Type II Hypersensitivity Cytotoxic reactions • Defined as the binding of an antibody to an antigen on the surface of a cell such that the cell is destroyed • Pathogenesis – Antibody activates the complement system (MAC) – Cell is opsonized and removed or destroyed by the RE system in the liver or spleen – Cell surface antigen elicits an antibody response > antibodies bind to the cell > the cell is either lysed or complement components attract phagocytic cells > damage to tissues from the release of proteolytic enzymes. Snyder 2010 23 Snyder 2010 24 Cytotoxic reactions: Specific disease syndromes • Anti-receptor antibodies • Antibody binds to a cell receptor and either activates or blocks the activation of the cell – Myasthenia gravis, anti-Ach receptor antibodies block – Graves disease –hyperthyroidism from anti-TSH receptor antibodies activate – Other endocrine organs – Most frequently involves IgG and IgM • Inflammatory reaction results in tissue damage Snyder 2010 25 Stimulating antibodies Blocking antibodies Snyder 2010 26 Cytotoxic reactions: Specific disease syndromes • Hematologic diseases • Cytotoxic reactions are most commonly seen in hematologic diseases due to cell surface antigens present on RBC’s, platelets, etc. • Immune mediated hemolytic anemia • Autoimmune hemolytic anemia • Blood groups-alloantibody induced – Complex system of antigens on the surface determine the blood group – Genetically controlled Snyder 2010 27 Cytotoxic reactions: Transfusion reactions • Incompatible blood transfusions where the recipient has natural antibodies or becomes sensitized to antigens on the surface of allogeneic RBC’s • First transfusion sensitizes the recipient and second results in an anamnestic response • Cross matching – Major- mixing of donor RBC’s with recipient serum – Minor – mixing of donors serum with recipient RBC’s – Antigen-antibody reactions can be temperature sensitive Snyder 2010 28 Snyder 2010 29 Cytotoxic reactions: Hemolytic Disease of the Newborn • Neonatal isoerythrolysis • Females sensitized to the blood group antigens of their young will produce antibodies which can be passed to the newborn in the colostrum and are absorbed • Heterophile antigens common to a number of organisms – M antigen – Forsman antigen Snyder 2010 30 Passive transfer of antibody Species Placenta type Primates hemochorial IgG transfer 100% Dogs, cats endotheliochorial 5-10% Pigs, Horses epitheliochorial 0% Ruminants syndesmochorial 0% Snyder 2010 31 Neonatal isoerythrolysis • • • • Anti-erythrocyte antibodies Aa and Qa blood types Testing foals RBC with colostrum • Rouleaux formation complicates Hemolysis test • Foals RBC, exogenous IgG, NRS (C’) Snyder 2010 32 Hemolytic disease of the newborn: Foal • Four conditions: – Mare inherits a unique blood group antigen – Mare must be sensitized – Mare must be boosted late gestation – Foal must ingest and absorb antibodies • Direct antiglobulin (Coombs) test – Foals RBC + mares serum • Treatment? Snyder 2010 33 Diseases with a Type II Pathogenesis • Pemphigus diseases • Intercellular junctions • • Bullous pemphigoid • • Epidermal cadherin, desmoglein 1 Collagen type XVII within hemidesmosomes Pernicious anemia • • Intrinsic factor of gastric parietal cells Decreased B12 absorption Snyder 2010 34 Cytotoxic reactions: Drug reactions • Many drugs non-specifically bind to the surface of RBC’s and if the patient is producing antibodies against the drug these antibodies will also bind to the RBC bound drug and activate complement • Some drugs are capable of altering the RBC surface antigens and the immune system recognizes them as foreign • Many drugs are haptens Snyder 2010 35 Cytotoxic Reactions: Infectious agents • Absorption of bacterial, viral, protozoal, etc. antigens to the surface of RBC may also result in new antigenic determinants and the initiation of an antibody response • In most instances the actual antigen is unknown Snyder 2010 36 Type II Hypersensitivity: Diagnosis • Immune mediated hemolytic anemias • Indirect Coombs test: patients serum and test RBC from the same species • Direct Coombs test: patients RBC and anti-IgG, anti-IgM and anti-C3 (Coombs reagent) + Coombs Reagent Snyder 2010 37 Type III Hypersensitivity: Immune Complex-mediated • “Innocent bystander” • Immune complexes are formed and either stick onto a cell or are deposited in that tissue. • Pathogenesis: immune complex formation > complexes become lodged or deposited in tissues > complement activation > anaphylatoxins, chemotactic factors > neutrophil infiltration and activation > release of enzymes > tissue damage • Cell or tissue injury is similar to that in a type II reaction even though the pathogenesis is different. Snyder 2010 38 Type III Hypersensitivity • Most often involves IgG and IgM • Antibody > antigen. The complexes are large and insoluble, and are normally removed from circulation by the MPS. • Antigen > antibody. The complexes remain small and soluble, and become trapped beneath endothelial cells along basement membranes. • In extreme antigen excess the complexes are too small to become lodged and the immunoglobulin is incapable of complement activation. Snyder 2010 39 Snyder 2010 40 Snyder 2010 41 Snyder 2010 42 Snyder 2010 43 Type III Hypersensitivity • Pathology: – Vascular lesions with a predominance of neutrophils – Site and amount of complex deposition determines the severity and significance – Most often deposited in filtering structures, therefore their accumulation is and anatomic and physiologic process with no immunologic basis • Blood vessels • Glomeruli • Skin • Joints • RBC and platelets Snyder 2010 44 Snyder 2010 45 Type III Hypersensitivity: Local reactions • Arthus reaction: parenteral administration of an antigen to an animal that has circulating antibody specific for the antigen. • Blue-eye: anterior uveitis leading to corneal edema and opacity. Canine type 1 adenovirus infections. • Hypersensitivity pneumonitis, alveolitis and vasculitis in animals sensitized to inhaled antigens. Micropolyspora faeni. • Staphylococcal hypersensitivity: Staphylococcus aureus. Snyder 2010 46 Snyder 2010 47 Snyder 2010 48 Type III Hypersensitivity : Generalized reactions • Serum sickness: heterologous antisera to provide antibody against a particular antigen. – Fever – Vasculitis – Arthritis – Glomerulonephritis • Clinical manifestations are dependent on: – Quantity of complexes – Size of complexes Snyder 2010 49 Type III Hypersensitivity: Generalized reactions • Virally-induced: repeated or persistent presence of moderate amounts of antigen accompanied by low level antibody production. • Bacterially-induced • Drug Reactions – Allergies to penicillin and sulfonamides Snyder 2010 50 Infectious Diseases Erysipelothrix rhusiopathae Mycobacterium johnei Streptococcus equi Staphlococcus aureus Borrelia burgdorferi Ehrlichiosis Canine adenovirus 1 Canine adenovirus 2 Feline leukemia Feline infectious peritonitis Aleutian disease Hog cholera African swine fever Bovine virus diarrhea Equine viral arteritis Equine infectious anemia Visceral leishmaniasis Dirofilaria immitis Arthritis Enteritis Purpura Dermatitis Glomerulonephritis Glomerulonephritis Uveitis, glomerulonephritis Glomerulonephritis Glomerulonephritis Peritonitis, glomerulonephritis Glomerulonephritis, arteritis, anemia Glomerulonephritis Glomerulonephritis Glomerulonephritis Arteritis Anemia, glomerulonephritis Glomerulonephritis Glomerulonephritis Snyder 2010 51 Snyder 2010 52 Type III Hypersensitivity Autoimmune Diseases • Systemic lupus erythematosus – autoantibodies, anti-DNA • Rheumatoid arthritis – IgM anti-IgG (rheumatoid factor) Snyder 2010 53 Type III Hypersensitivity Diagnosis • Indirect immunofluorescence with anti-IgG, anti-IgM and anti -C3. Immune complex Blood vessel Snyder 2010 54 Snyder 2010 55 Type IV Hypersensitivity: Cell-mediated or delayed hypersensitivity • Results from sensitization of T lymphocytes. • Resulting immune response is mediated by either direct cytotoxicity or by the release of cytokines which activate macrophages. • Immunologically specific. • Mononuclear inflammatory cells. • Transferable with lymphoid cells and not serum. • Dependent on T lymphocytes. Snyder 2010 56 Snyder 2010 57 Snyder 2010 58 Snyder 2010 59 Type IV Hypersensitivity • Pathogenesis: binding of antigen to sensitized T lymphocytes > cytokine synthesis (attract, activate, immobilize) > lymphocyte proliferation > generation of cytotoxic T lymphocytes > infiltration of macrophages. • 24-48 hours to develop. • TH1 cells. • Cytokines: – IL-2 – IFN – macrophage migration-inhibition factor (MIF) – TNF Snyder 2010 60 Snyder 2010 61 Type IV Hypersensitivity Classical example • Tuberculin reaction. • Tuberculin refers to extracts of M. tuberculosis, M. bovis or M. avium. • Intradermally administered. • Purified protein derivative (PPD). • Positive reaction. Snyder 2010 62 Type IV Hypersensitivity • • Allergic contact dermatitis • Langerhans cells process antigen and present to naïve T cells in lymph nodes (sensitization). • Horses, dogs and rarely cats • Numerous causes: plants, plastics, insecticides, flea collars, etc. • Haptens Demodecosis - Demodex canis Snyder 2010 63 Snyder 2010 64 Type IV Hypersensitivity Lesions • Delayed type hypersensitivity vs cell mediataed immunity – Beneficial = immunity – Harmful = hypersensitivity • Granulomatous inflammation – Epitheliod macrophages, multinucleated giant cells Snyder 2010 65 Pathogens and Contact Antigens Associated With a Type IV Pathogenesis • Bacteria • • Viruses • • • Dimorphic yeasts Haptens • • LCM Fungi • • Mycobacteria, Listeria, Yersinia Oils of insecticides, plasitics, metals, etc Allograft MHC molecules Neoplastic cell antigens Snyder 2010 66 Granulomatous inflammation Snyder 2010 67 Snyder 2010 68 Snyder 2010 69