Immunologic mechanisms of renal di seases Chen weilin, Ph.d o6 Institute of Immunology ZJU Email:cWl@zju.edu.cn
Immunologic mechanisms of renal diseases Chen weilin，PH.D Institute of Immunology, ZJU Email：cwl@zju.edu.cn
Antigens The cause of immunologically mediated renal disease is antigenic triggering of an immune reaction The list of associated antigens is extensive and continually expanding. These antigens are categorized as renal or non-renal and as self or foreign The causative antigen is often unknown
• The cause of immunologically mediated renal disease is antigenic triggering of an immune reaction. • The list of associated antigens is extensive and continually expanding. These antigens are categorized as renal or non-renal and as self or foreign . • The causative antigen is often unknown. Antigens
ANTIGENS ASSOCIATED WITH IMMUNOLOGICALLY MEDIATED RENAL DISEASE Renal Self (endogenous) Glomerular basement membrane (particularly type Iv collagen) Tubular basement membrane Foreign (exogenous) Transplantation antigens (HLA) Nonrenal Self (endogenous) Nucleic acids PMN cVtoplasmic antigens Tumor antigens Cryoglobulins Foreign (exogenous) Bacteria (eg. B-hermolytic strepto coccus) iruses (eg, HIV) Allergens (eg bee sting, pollen. vaccines Drugs (eg. methicillin)
ANTIGENS ASSOCIATED WITH IMMUNOLOGICALLY MEDIATED RENAL DISEASE
Antigens To cause immunologically mediated renal disease, an antigen must localize to the kidney and trigger a local immune inflammatory response. Renal antigens are inherently localized, being constituent proteins of the kidney Non-renal antigens require a mechanism for depositing in the kidney
Antigens • To cause immunologically mediated renal disease, an antigen must localize to the kidney and trigger a local immune inflammatory response. • Renal antigens are inherently localized, being constituent proteins of the kidney. • Non-renal antigens require a mechanism for depositing in the kidney
Immunologic mechanisms of renal diseases Type ll hypersensitivity (Cytotoxic Antibody-mediated Type Ill hypersensitivity (Immune Complex-mediated Cell-mediated immunity (CD4+ CD8+ T) Abnormal Immune regulation(Ts) Immune hereditary factors (HLA)
Immunologic mechanisms of renal diseases • Type II hypersensitivity (Cytotoxic Antibody-mediated ) • Type III hypersensitivity (Immune Complex-mediated ) • Cell-mediated immunity (CD4+ ,CD8+ T) • Abnormal Immune regulation(Ts) • Immune hereditary factors(HLA)
Type ll hypersensitivity A Complement- and Fc receptor-mediated inflammation Complemen Ags on the surface of target cells body >IgG, IgM (B Opsonization and phagocytosis 1. damage the target cell 1 activation of complement Phagocyte 2)opsonization FcR C3bR mplement 3)ADCC activator 2. target cell dysfunction Antibody against Antibody stimulat ntibody inhibits binding receptor without hor of neurotransmitter to receptor ElsevierAbbas&LichtmanBasicImmunology,updated2e-www.studentconsult.com
Type II hypersensitivity Ags on the surface of target cells ↓ body→IgG, IgM ↓ 1. damage the target cell 1) activation of complement 2) opsonization FcR C3bR 3) ADCC 2. target cell dysfunction
Cytotoxic Antibody-mediated Renal Disease Prototype: Anti-GBM disease Goodpasture's disease) Renal damage is caused by linear deposition of antibody specific for type iv collagen of the gBm. The antibody attaches to its antigen and activates the complement Cytotoxic antibody localizes along the GBm in a linear pattern with c
Cytotoxic Antibody-mediated Renal Disease • Prototype: Anti-GBM disease (Goodpasture's disease) • Renal damage is caused by linear deposition of antibody specific for type IV collagen of the GBM. The antibody attaches to its antigen and activates the complement. • Cytotoxic antibody localizes along the GBM in a linear pattern with C
Anti-GBM Antibody -Mediated Nep hritis(Good pasture Syndrome) Rare Etiology -Unknown Type II HSR Include Pulmonary Haemorrhage Rapid Progressive Glomerulonephritis (with Oliguric Renal Failure) within Weeks→ Moths Clinical Haematuria, Proteinuria(Gross, Microscopic N 24h Creatinine Clearance 个 Blood urea 个 Serum creatinine Hallmark Autoantibodies to Type M Collagen (Present in Capillary BM of Kidney, Lung) (Antiglomerular Basement Membrane Antibodies (Detected in Immunoassays)(Early in Course Linear Deposition of Immu noglobulin G, C3 Treatment Pulse Methylprednisolone Cydophospha mid Plasma Exchange
Nephropathia s associated with aNCA (ANCA -Anti-Neutrophil Cytoplasmic Antibody Renal Involvement (common in Vasculitis) PAN (Polyarteritis Nodosa) Wegener Granulomatous Arteries outside glomerulus Arterieswithin the Glomerulus affected atfected Lesions Focal, Segmental Distribution wth Fibrinoid Necrosis, Crescent Formation Presence of anca Strong correlation between Presence of ANCA, Glomerular Involvement in Vasculitis(but precise mechanism not understood Treatment Early Phase Rapid Progressive GN Glucocorticoids Pulse Methylprednisolone Prednisolone, Cyclopho sphamide Plasmapheresis (value not proven Renal Vasculitis ANCA Test Positivity (%) P-ANCA C-ANCA PAN 10-20 10-20 Microsco pic Polyangitis 5080 10-20 Wegener Granulomatosis 10-20 8090 Necrotizing, Cresce ntic GN 5080 1020
Type Ill hypersensitivity Type Ill Hypersensitivity Ag >body ]IgG, IgM, IgA Mast cell FavRIlE immune complexes(IC) soluble Ic o recruitment fluid serum proteins ICs are deposited from the circulation into vascular basement membranes ① ②√FcR PMN activation of complement plat. and basophils C3a, C5a >mast cell release of vasoactive amines √ basophils ③ Neutrophils vasodilation lysosomal edema enzymes >damage the tissue
Type III hypersensitivity Ag→body→IgG, IgM, IgA ↓ immune complexes (IC) ↓ soluble IC ↓ ICs are deposited from the circulation into vascular basement membranes ①↓ ② ↓FcR activation of complement plat. and basophils ↓ C3a, C5a →mast cell → release of vasoactive amines ↓ basophils ③ Neutrophils vasodilation ↓ lysosomal edema enzymes→damage the tissue