Veterinary Immunology Type III Hypersensitivity Dr. Chi-Young Wang

Two major forms of reactions dependent on the amount and site of deposition of immune complexes Two major forms of reactions dependent on the amount and site of deposition of immune complexes Local reactions: immune complexes form within tissue Local reactions: immune complexes form within tissue Large quantities of immune complexes within the bloodstream Large quantities of immune complexes within the bloodstream

which are deposited in glomeruli in the kidney (glomerulonephritis), bound to blood cells (anemia, leukopenia, and deposited in blood walls) or joints (vasculitis or arthritis) which are deposited in glomeruli in the kidney (glomerulonephritis), bound to blood cells (anemia, leukopenia, and deposited in blood walls) or joints (vasculitis or arthritis)

Local Type III Hypersensitivity Arthus reaction: antigen is injected subcutaneously into animals that already have precipitating antibodies Arthus reaction: antigen is injected subcutaneously into animals that already have precipitating antibodies Red, edematous swelling, local hemorrhage, thrombosis, and local tissue destruction (if severe) Red, edematous swelling, local hemorrhage, thrombosis, and local tissue destruction (if severe)

Local Type III Hypersensitivity Histology: neutrophils adhere to vascular endothelium (6-8 hours at peak), mononuclear cells appear at 24 hours or later, depending on the amount of antigen injected Histology: neutrophils adhere to vascular endothelium (6-8 hours at peak), mononuclear cells appear at 24 hours or later, depending on the amount of antigen injected Antigen diffuses into the vessel walls and encounters antibodies Antigen diffuses into the vessel walls and encounters antibodies

Local Type III Hypersensitivity and complement and complement Mast cells and neutrophils were activated by the immune complexes Mast cells and neutrophils were activated by the immune complexes

Local Type III Hypersensitivity Immune complexes can be removed after binding with Fcγ RIIa on sentinel cells Immune complexes can be removed after binding with Fcγ RIIa on sentinel cells Nitric oxide, leukotrienes, prostaglandins, cytokines, and chemokines released by macrophages bound with immune complexes Nitric oxide, leukotrienes, prostaglandins, cytokines, and chemokines released by macrophages bound with immune complexes

Local Type III Hypersensitivity Neutrophil chemotactic factors and proteases which activates kinins, lipid mediators, and complement by mast cells Neutrophil chemotactic factors and proteases which activates kinins, lipid mediators, and complement by mast cells

Local Type III Hypersensitivity The immune complexes activate complex to generate the chemotactic peptide C5a which attracts neutrophils The immune complexes activate complex to generate the chemotactic peptide C5a which attracts neutrophils Neutrophils emigrate from the blood vessels and eliminates complexes by phagocytosis Neutrophils emigrate from the blood vessels and eliminates complexes by phagocytosis Neutrophils degranulate proteases and oxidants (OCl - ) Neutrophils degranulate proteases and oxidants (OCl - )

Local Type III Hypersensitivity

A reverse Arthus reaction-if antibodies are administrated intradermally to an animal with a high level of circulating antigen A reverse Arthus reaction-if antibodies are administrated intradermally to an animal with a high level of circulating antigen Blue eye: infected or vaccinated with canine adenovirus type I; an anterior uveitis leading to edema and opacity; the cornea is infiltrated Blue eye: infected or vaccinated with canine adenovirus type I; an anterior uveitis leading to edema and opacity; the cornea is infiltrated

by neutrophils and virus-antibody complexes (develops about 1-3 weeks) by neutrophils and virus-antibody complexes (develops about 1-3 weeks)

Generalized Type III Hypersensitivity Reaction Serum sickness: a generalized vasculitis with erythema, edema, and urticaria of the skin, neutropenia, lympho node enlargement, joint swelling, and proteinuria Serum sickness: a generalized vasculitis with erythema, edema, and urticaria of the skin, neutropenia, lympho node enlargement, joint swelling, and proteinuria Administration of intravenous dose of antigen Administration of intravenous dose of antigen

Generalized Type III Hypersensitivity Reaction Acute if a single, large injection of an antigen or chronic, if caused by multiple small injections; glomerulonephritis and arteritis Acute if a single, large injection of an antigen or chronic, if caused by multiple small injections; glomerulonephritis and arteritis

Glomerulonephritis: complexes are deposited in the glomeruli leading to basement membrane thickening and proliferation of glomerular cells Glomerulonephritis: complexes are deposited in the glomeruli leading to basement membrane thickening and proliferation of glomerular cells MPGN (membranoproliferative glomerulonephritis): epithelial cells, endothelial cells, and mesangial cells MPGN (membranoproliferative glomerulonephritis): epithelial cells, endothelial cells, and mesangial cells

MPGN lesions are classified into three major types based on their histopathology MPGN lesions are classified into three major types based on their histopathology

Type I Membranoproliferative Glomerulonephritis Type I MPGN: immune complexes deposited in glomerular vessels Type I MPGN: immune complexes deposited in glomerular vessels Usually trapped on the endothelial side, which stimulates endothelial cell swelling and proliferation Usually trapped on the endothelial side, which stimulates endothelial cell swelling and proliferation Animals are given small doses of an antigen for a long time Animals are given small doses of an antigen for a long time

Type I Membranoproliferative Glomerulonephritis TGF-β production which stimulate nearby cells to yield fibronectin, collagen, and proteoglycans TGF-β production which stimulate nearby cells to yield fibronectin, collagen, and proteoglycans Wire loop lesions: a thickening of the basement membrane Wire loop lesions: a thickening of the basement membrane Alternatively, complex may be Alternatively, complex may be

Type I Membranoproliferative Glomerulonephritis deposited in the mesangial region (a smooth muscle cells) which proliferate and release IL-6 and TGF-β…eventually produce extracellular matrix deposited in the mesangial region (a smooth muscle cells) which proliferate and release IL-6 and TGF-β…eventually produce extracellular matrix Lumpy aggregates of immune complexes deposited in capillary Lumpy aggregates of immune complexes deposited in capillary

Type I Membranoproliferative Glomerulonephritis walls on the epithelial side of the glomerular basement membrane walls on the epithelial side of the glomerular basement membrane

Type II Membranoproliferative Glomerulonephritis There is endothelial and mesangial proliferation as well as the presence of homogenous, dense deposits within the glomerular basement membrane rather than its surface There is endothelial and mesangial proliferation as well as the presence of homogenous, dense deposits within the glomerular basement membrane rather than its surface The deposits contain C3 not immunoglobulin The deposits contain C3 not immunoglobulin

Type III Membranoproliferative Glomerulonephritis Type III contains the presence of immune complexes on both the endothelial and epithelial sides of the basement membrane Type III contains the presence of immune complexes on both the endothelial and epithelial sides of the basement membrane Very small immune complexes penetrate the basement membrane Very small immune complexes penetrate the basement membrane Epithelial cell swelling and proliferation- epithelial crescents Epithelial cell swelling and proliferation- epithelial crescents

Type III Membranoproliferative Glomerulonephritis Type III contains the presence of immune complexes on both the endothelial and epithelial sides of the basement membrane Type III contains the presence of immune complexes on both the endothelial and epithelial sides of the basement membrane Very small immune complexes penetrate the basement membrane Very small immune complexes penetrate the basement membrane Epithelial cell swelling and proliferation- epithelial crescents Epithelial cell swelling and proliferation- epithelial crescents

Clinical Features of MPGN Equine anemia virus, ICH, African swine fever, Lyme disease, FLV, pyometra, distemper encephalitis, and ehrlichiosis- proteinuria: Type I MPGN with proteinuria Equine anemia virus, ICH, African swine fever, Lyme disease, FLV, pyometra, distemper encephalitis, and ehrlichiosis- proteinuria: Type I MPGN with proteinuria Glomeruli lesions by neutrophils, mesangial cells, macrophages, and platelets Glomeruli lesions by neutrophils, mesangial cells, macrophages, and platelets

Clinical Features of MPGN Plasma proteins (albumin) in the urine, edematous and ascitic animals Plasma proteins (albumin) in the urine, edematous and ascitic animals Low RGF, retention of urea and creatinine, azotemia, and hypercholesterolemia Low RGF, retention of urea and creatinine, azotemia, and hypercholesterolemia Nephrotic syndrome-anorexia, weight loss, vomiting, polyuria, polydipsia, and azotemia Nephrotic syndrome-anorexia, weight loss, vomiting, polyuria, polydipsia, and azotemia

Polyarthritis Immune complexes found in the blood and synovial fluid of animals with rheumatoid arthritis and osteoarthritis-local trauma (not clear) Immune complexes found in the blood and synovial fluid of animals with rheumatoid arthritis and osteoarthritis-local trauma (not clear)

Dirofilariasis The heartworm Dirofilaria imitis develops glomerular lesions and proteinuria The heartworm Dirofilaria imitis develops glomerular lesions and proteinuria Thickening of the glomerular basement membrane with minimal endothelial or mesangial proliferation Thickening of the glomerular basement membrane with minimal endothelial or mesangial proliferation IgG1-containing deposits found on IgG1-containing deposits found on

Dirofilariasis the epithelial side of the basement membrane (type III MPGN) and it has been suggested that immune complexes formed by antibodies to heartworm antigens provoke these lesions the epithelial side of the basement membrane (type III MPGN) and it has been suggested that immune complexes formed by antibodies to heartworm antigens provoke these lesions