Diseases of Immunity 2009 CL Davis General Pathology Paul W. Snyder, DVM, PhD Purdue University 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 2 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 3 1
Infections in Immunodeficiencies Pathogen Bacteria T cell defect Sepsis B cell defect Staph, Strep, Granulocyte defect Staph, Pseudomonas Complement defect Pyogenic bacterial infections Viruses Fungi & parasites Special features Cytomegalovius, chronic respiratory & GI infections Candida, Pneumocystis Aggressive disease, adverse reactions to MLV Enteroviral encephalitis Intestinal giardiasis, Aspergillosis Chronic recurrent infections, sepsis, meningitis Candida, Norcardia, Aspergillus Neutrophilia 4 Primary Immunodeficiency Specific immune responses Severe combined immunodeficiency Agammaglobulinemia Common variable immunodeficiency Selective IgA deficiency Selective IgM deficiency Transient hypogammaglobulinemia 5 6 2
Human SCID 7 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 8 9 3
Equine SCID 10 Immunodeficiency Diseases of Dogs SCID Bassett hounds & Cardigan Welsh Corgis Common γ chain deficiency (IL-2, 4, 7, 9 and 15 receptors) Jack Russell Terriers DNA-dependent protein kinase defect Lymphopenia CD4:CD8 = 15:1 vs 1:2 normal Hypogammaglobulinemic Normal IgM levels 11 Immunodeficiency Diseases of Dogs IgA deficiency German shepherd, Shar-Pei, Irish setter, Beagles IgM deficiency T cell deficiency Weimaraner dogs 12 4
13 Canine SCID 14 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 15 5
16 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 17 18 6
19 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 20 Leukocyte Adhesion Deficiency β 2 -integrin defect (CD18) Increased numbers of circulating neutrophils Canine (CLAD) Irish Setters Bovine (BLAD) Holstein cattle 21 7
22 Extravasation of leukocytes 23 24 8
Secondary Immunodeficiency Failure of passive transfer Viral infections Canine distemper virus Canine parvovirus FeLV Feline panleukopenia virus Equine herpes 1 BVD FIV and BIV 25 Effect of FIV on CD4 and CD8 T cells in cats % of total lymphocytes 45 40 35 30 25 20 15 10 5 0 control 4-10 mo. 25-40 mo. CD4 CD8 J. AIDS, 4:219, 1991 26 Secondary Immunodeficiency Drugs Cytotoxic Metabolic disorders Diabetes Hyperadrenalcorticism Uremia Pregnancy 27 9
Secondary Immunodeficiency Nutritional disorders Zinc deficiency Iron deficiency Vitamin E deficiency Bacterial infections Mycobacterium paratuberculosis 28 Secondary Immunodeficiency Parasites Eperythrozoonsis Trypanosomiasis Demodex canis Ehrlichia spp. Toxins Mycotoxins Bracken fern toxicosis 29 Secondary Immunodeficiency Endocrine disorders GH deficiency Estrogen toxicity Radiation Neoplasia 30 10
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 β-pleated sheets of non-branching fibrils Congophilic Green birefringent material Potassium permanganate sensitive = AA 31 32 33 11
34 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) Aβ Amyloid light chain Complete light chain (λ > κ) NH 2 terminus Immunglobulin secreting cells 35 36 12
Chemical Nature of Amyloid Amyloid associated Proteolytic fragment of SAA SAA is an acute phase protein Systemic inflammation Aβ Proteolytic fragment of APP Associated with cerebral amyloid angiopathy of Alzheimer s disease Other biochemically distinct forms 37 Pathogenesis of Amyloid 38 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 39 13
40 41 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 Aβ in brain, heart, and GI of dogs 42 14
Classification of Amyloid Endocrine Amyloid Pancreatic islets Cats, macaques, baboons Islet amyloid polypeptide (IAPP) synthesized by βcells of the pancreatic islets Diabetes mellitus Localized Amyloid Calcifying epithelial odontogenic tumors Transmissible spongiform encephalopathies Amyloid plaques in brain 43 44 15