Diseases of Immunity 2011 CL Davis General Pathology. Paul W. Snyder, DVM, PhD Purdue University

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1 Diseases of Immunity 2011 CL Davis General Pathology Paul W. Snyder, DVM, PhD Purdue University

2 Immunodeficiency Diseases Primary Congenital, inherited defects Secondary Acquired alterations Clinically important to differentiate Diverse group of diseases Hematopoietic stem cells Lymphocytes Phagocytic cells Complement proteins Snyder

3 Immunodeficiency Diseases Further classified as to which arm of the immune response that is affected Specific immunity T cells B cells Non-specific immunity Neutrophils Macrophages Complement proteins Snyder

4 Infections in Immunodeficiencies Pathogen T cell defect B cell defect Granulocyte defect Bacteria Sepsis Staph, Strep, Staph, Pseudomonas Complement defect Pyogenic bacterial infections Viruses Cytomegalovius, chronic respiratory & GI infections Enteroviral encephalitis Fungi & parasites Candida, Pneumocystis Intestinal giardiasis, Aspergillosis Candida, Norcardia, Aspergillus Special features Aggressive disease, adverse reactions to MLV Chronic recurrent infections, sepsis, meningitis Neutrophilia Snyder

5 Primary Immunodeficiency Specific immune responses Severe combined immunodeficiency Agammaglobulinemia Common variable immunodeficiency Selective IgA deficiency Selective IgM deficiency Transient hypogammaglobulinemia Snyder

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7 Human SCID Snyder

8 Immunodeficiency Diseases of Horses SCID AR in Arabian breed Severe lymphopenia Agammaglobulinemia Defect in DNA-dependent protein kinase Heterozygotes risk for sarcoids Agammaglobuminemia Selective IgM deficiency Common variable immunodeficiency Snyder

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10 Equine SCID Mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) on chromosome 9 Snyder

11 Immunodeficiency Diseases of Dogs SCID Bassett hounds & Cardigan Welsh Corgis Common chain deficiency (IL-2, 4, 7, 9 and 15 receptors) Jack Russell Terriers DNA-dependent protein kinase defect Lymphopenia CD4:CD8 = 15:1 vs 2:1 normal Hypogammaglobulinemic Normal IgM levels Snyder

12 Immunodeficiency Diseases of Dogs IgA deficiency German shepherd, Shar-Pei, Irish setter, Beagles IgM deficiency T cell deficiency Weimaraner dogs Snyder

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14 Canine SCID Snyder

15 Immunodeficiency Diseases of Mice Nude mice (nu/nu) Thymic hypoplasia Developmental arrest of thymus GD12 SCID mice CB-17 strain DNA-dependent protein kinase defect leaky phenotype Snyder

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17 Complement Deficiencies Classical pathway deficiencies Associated with SLE-like disease Impaired immune complex clearance Canine C3 deficiency Homozygotes no C3 Heterozygotes 50% of normal levels Porcine Factor H deficiency Inactivates C3b of alternative pathway Membranoproliferative glomerulonephritis C1 Inhibitor deficiency Angioneurotic edema DAF or CD59 deficiency RBC lack protective mechanism and are susceptible to C - mediated lysis hemoglobinuria Snyder

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20 Chediak-Higashi Syndrome Aleutian mink, persian cats, white tigers, cattle, beige mice, killer whales and humans LYST gene defect Lysosomal membrane fusion Abnormal granules Neutrophil, platelet, T cell and NK cell defects Neutrophil Snyder

21 Leukocyte Adhesion Deficiency 2 -integrin defect (CD18) Increased numbers of circulating neutrophils Canine (CLAD) Irish Setters Bovine (BLAD) Holstein cattle Snyder

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23 Extravasation of leukocytes Snyder

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25 Secondary Immunodeficiency Failure of passive transfer Viral infections Canine distemper virus Canine parvovirus FeLV Feline panleukopenia virus Equine herpes 1 BVD FIV and BIV Snyder

26 % of total lymphocytes Effect of FIV on CD4 and CD8 T cells in cats control 4-10 mo mo. CD4 CD8 J. AIDS, 4:219, 1991 Snyder

27 Secondary Immunodeficiency Drugs Cytotoxic Metabolic disorders Diabetes Hyperadrenalcorticism Uremia Pregnancy Snyder

28 Secondary Immunodeficiency Nutritional disorders Zinc deficiency Iron deficiency Vitamin E deficiency Bacterial infections Mycobacterium paratuberculosis Snyder

29 Secondary Immunodeficiency Parasites Eperythrozoonsis Trypanosomiasis Demodex canis Ehrlichia spp. Toxins Mycotoxins Bracken fern toxicosis Snyder

30 Secondary Immunodeficiency Endocrine disorders GH deficiency Estrogen toxicity Radiation Neoplasia Snyder

31 Amyloidosis A broad spectrum of clinical and pathological conditions that all have in common the deposition of amyloid material A pathologic proteinaceous substance of different chemical entities with an identical conformational property of forming -pleated sheets of nonbranching fibrils Congophilic Green birefringent material Potassium permanganate sensitive = AA Snyder

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35 Chemical Nature of Amyloid 95% fibrillar proteins, 5% P component, etc 15 biochemically distinct forms Three most common are Amyloid light chain (AL) Amyloid associated (AA) A Amyloid light chain Complete light chain (λ κ) NH 2 terminus Immunglobulin secreting cells Snyder

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37 Chemical Nature of Amyloid Amyloid associated Proteolytic fragment of SAA SAA is an acute phase protein Systemic inflammation A Proteolytic fragment of APP Associated with cerebral amyloid angiopathy of Alzheimer s disease Other biochemically distinct forms Snyder

38 Pathogenesis of Amyloid Snyder

39 Classification of Amyloid Primary Amyloidosis AL type Plasma cell tumors Light chain only = Bence Jones protein Reactive Systemic Amyloidosis Aka Secondary Amyloidosis Chronic inflammation or non-immunocyte dyscrasias or idiopathic Snyder

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42 Classification of Amyloid Familial Amyloidosis Siamese and Abyssinian cats & Shar-Pei dogs Abyssinian cat glomerular Siamese cat liver Shar-Pei dog medullary interstitium AA proteins Amyloid of Aging A in brain, heart, and GI of dogs Snyder

43 Classification of Amyloid Endocrine Amyloid Pancreatic islets Cats, macaques, baboons Islet amyloid polypeptide (IAPP) synthesized by cells of the pancreatic islets Diabetes mellitus Localized Amyloid Calcifying epithelial odontogenic tumors Transmissible spongiform encephalopathies Amyloid plaques in brain Snyder

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