Diseases of Immunity 2017 CL Davis General Pathology Paul W. Snyder, DVM, PhD Experimental Pathology Laboratories, Inc.
Autoimmunity Reflects a loss of immunologic tolerance Mechanisms Auto-antibodies Immune complex deposition Sensitization of effector T cells Immunoregulatory abnormality most likely centered on T helper cell and/or Treg cell Snyder 2017 2
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Tolerance Active physiologic process Failure to respond to a specific antigen Factors involved: Immunologic status Young > old Dose of antigen Large > small Insoluble > soluble Antigen persistence is required Snyder 2017 4
Tolerance T cells B cells Induction period short long Duration long short Dose of antigen small large Importance: Low tolerogenic concentrations may only induce tolerance in T cells Self antigens: low vs high concentrations Snyder 2017 5
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Etiology of Autoimmunity Multifactorial Genetic Environment Self-reactive antibodies and T cells can be identified in normal individuals MHC associations Lymphocyte infiltrate Snyder 2017 7
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Autoimmune Diseases: Organ Specific Diseases Direct cellular damage: Thyroiditis, pancreatitis, meningitis IMHA, ITP IDDM Polymyositis Recurrent uveitis Stimulating antibodies: Grave s disease Blocking antibodies Myasthenia gravis Snyder 2017 13
Autoimmune Diseases: Systemic Diseases Systemic lupus erythematosus Anti-DNA Anti-nuclear proteins in dog (eg. histones) ANA test TLR7 & TLR9 cross-react with normal constituents Failure of apoptosis? Rheumatoid arthritis IgM anti-igg Rheumatoid factor Erosive polyarthritis Multiple sclerosis Myelin sheath proteins Snyder 2017 14
Systemic Lupus Erythematosus Chronic multi-system disease Collies and Shetland sheep dogs, horses, and cats Type III Clinical signs: Major Polyarthritis Dermatitis Anemia Thrombocytopenia Glomerulonephritis Leukopenia Vasculitis Minor Fever CNS signs Pleuritis Pericarditis Polymyositis Snyder 2017 15
Systemic Lupus Erythematosus Diagnosis requires two major or one major and two minor Serological evidence: Antinuclear antibody test LE preparation Bone marrow with phagocytosed nulcei ANA test Histopathology IFA on skin or kidney Snyder 2017 16
Role of CD4+ Cells, Association with the MHC, and Certain TCR In experimental models you can transfer the disease by transferring CD4+ T cells Treatment with anti-cd4 antibodies suppresses the disease HLA alleles associated risks TCR variable region genes in autoimmune T cell clones Snyder 2017 17
Type II Type III Type IV Proposed mechanisms T helper cells direct: CD 4+ responses CD 8+ responses High affinity antibody responses T cell tolerance provides B cell tolerance Snyder 2017 18
Defective Fas or FasL Mouse models Fail to remove auto reactive cells Defective AIRE AIRE is responsible for expression of self-antigens in the thymus Defective CTLA-4 CTLA-4 is an inhibitory receptor for T cells IL-2 or IL-2R defects Inflammatory bowel disease, anti-dna, anemia Snyder 2017 19
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Tumor Immunology Host Responses Reactive components Inflammation Healing and regeneration Immune Responses Tumor specific antigens ADCC NK cells C8+ Cytotoxic T cells TNF-α (cachexin) Snyder 2017 23
Immunosuppressive Mechanisms and Pro-tumorgenic Phenotypes Myeloid Derived Suppresor Cells (MDSCs) Heterogeneous population of cells Monocytic Polymorphonuclear Enhance tumor cell survival and promote metastasis Strong angiogenic functions Promote tissue remodeling Local and systemic Snyder 2017 24
Immunosuppressive Mechanisms and Pro-tumorgenic Phenotypes Tregs Peripheral tolerance Immune check points for T effector cells and T reg cells Cytotoxic T cell associated protein 4 (CTLA-4) Glucocorticoid-induced TNFR-related protein (GITR) CD25 FoxP3 Snyder 2017 25
Immunosuppressive Mechanisms and Pro-tumorgenic Phenotypes Extracellular vesicles Intercellular communication Normal and transformed cells Exosomes, microvesicles, ectosomes, apoptotic bodies, large oncosomes, etc Tumor promoting role T cell apoptosis Monocyte MDSC differentiation Tumor Acidity Inhibits T cell activation and function Pro-inflammatory stromal cells Snyder 2017 26
Immunosuppressive Cycle Snyder 2017 27