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The immunogenetic mechanism of renal injury
George P Lai
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Basic component of renal immune response
• Humoral response– Anti-GBM disease– Immune complex disease
• The cellular response– T cells and macrophages– Particularly in crescent formation and
tubulointerstitial disease
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Adaptive immunity
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To Establish Relationship
• A present when B occur (TNF elevated when GN occur)
• B improved when A removed (TNF knock out model)
• A transfer will make B occur (Transfer model, transgenic model)
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Animal Models
• NTN model (Nephrotoxic nephritis)-Crescentic GN– Rat: WKY (macrophage dependent)– Mouse: C57BL/6 (T cell/Th1 dependent)– Rabbit
• EAG model (Experimental autoimmune glomerulonephritis)
• Thy 1.1 model (mesangial proliferative GN)• Heymann’s nephritis—MGN• Puromycin induced nephrosis--MCD
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Main players in GN
• Macrophage
• T cells
• B cells
• Neutrophil
• Endothelial cells
• Mesangial cells
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The results come from
• The initiating events
• The genetic background
• The immune responses (mechanisms)– Humoral immunity– Cellular immunity
• The glomerular responses
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Initiating Events
• Infectious antigen: streptococcus, virus (HBV, HCV, HIV)– Circulating immune complex – Autoimmune response
• Non-infectious antigen– Drug, toxin
• Modified by genetic background– Suspectibility (DRB1 in goodpasture’s disease; DR3 in MGN; 1-
antitrypsin deficiency in Wegener’s granulomatosis)– Severity– Response to therapy– Outcome
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Humoral mechanisms of renal injury
• Predominantly IgG (Except in IgA nephropathy)– Trapping of circulating immune complex
• Subendothelial, mesangial areas
– In situ formation of immune complex• Fixed glomerular antigen(anti-basement membrane
antibody)
• Planted antigen (PSGN, Lupus, Goodpasture, MGN)
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Immunoglobulin
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Immunoglobulin classes
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Injury induced by antibody alone
• Complement independent• Anti-nephrin antibody
– A slip-pore diaphragm antigen
– Offering insight into glomerular permeability barrier
• Nephrotoxic nephritis– Cathepsins B and Cathepsins L
– Cysteine proteinases inhibitor such as E-64, Ep 475 reduced proteinuria
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Goodpasture’s syndrome
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Injury mediated by C5b-9
• C5b-9 deposition in – subepithelial area induce proteinuria
• Activate epithelial cell---overproduction of oxidant, proteases, growth factors such as PDGF
– Subendothelial and mesangial area• Adhesion molecule• Proinflammatory cytokines such as IL-1• Growth factors (TGF-1)
• C3 NeF-autoantibody nephritic factor 3– Autoantibody that stabilize the alternative pathway C3
convertases---membranoproliferative GN type II
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C5a
• C5a a chemotaxic factor for neutrophil• Adhesion molecule upregulated in endothelial cell
and neutrophil Selectin, ICAM-1, VCAM-1• Evidences of neutrophil in glomerular disease
– PMN can injure glomeruli and degrade GBM in vitro– PMN are present in glomerular disease– PMN depletion reduces glomerular injury in
experimental models such as nephrotoxic nephritis– PMN repletion reconstitutes injury in PMN-depleted
rats with nephritis
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Neutrophil
• Evidences of neutrophil in glomerular disease– PMN can injure glomeruli and degrade GBM in vitro
– PMN are present in glomerular disease
– PMN depletion reduces glomerular injury in experimental models such as nephrotoxic nephritis
– PMN repletion reconstitutes injury in PMN-depleted rats with nephritis
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Neutrophil induced glomerular injury
• Neutrophil induced disease by– Release Oxidants: OH, O2
-, H2O2
– Proteases: lysozyme, defensins – Lipid mediators: thromboxane A2, Leukotriene
B4, – Cytokines: IL-1 TNF, IL-6– Reactive nitrogen species: NO, peroxynitrite
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Platelets
• Evidences of platelet involvement– Platelet activation in MGN, Lupus, MPGN,
FSGN, DM nephropathy– Elevated platelet secretory products: -
thromboglobulin, PF4– Renal localization of platelets:
mesangiocapillary glomerulonephritis, FSGN, Lupus nephritis
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Platelets induced renal injury
-granule : PDGF, TGF-, HGF, EGF
• Lysosomal enzymes– Proeinases: cathepsin, collagenase, neutral protease, acid
hydrolases
• Lipid and eicosanoids– Phospholipase A2– Prostaglandin E2– Thromboxane A2– Leukotrienes
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Cellular immunity
• T cell and macrophages• T cell activation and antigen presentation
– Antigen presenting cells: dendritic cells, B cells and macrophage
– MHC class I—CD8; MHC class II—CD 4– Costimulatory signals (Signal II)
• B7.1, B7.2—CD28; LFA-1---ICAM family; CD40—CD40L
– Immunological synapse
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Macrophage and T cell
T cell Macrophage
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T cell receptors
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Immunologic synapse
Affinity constants and Roles of Co-receptors in TCR binding.
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T helper and cytotoxic cells
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Cellular immunity
• T cells are important in transplantation biology and crescentic glomerulonephritis
• T cell effector functions– Cytotoxic T cell: perforin, FasL– Naïve T cell---Activated Th0 cell
• (IL12) Activated Th1 cells: IL-2, IFN- TNF-• (IL-4) Activated Th2 cells: IL-4 IL-5, IL-10, IL-11,
humoral immunity
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Macrophage
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Cellular immunity
• Macrophages– Multiple roles in glomerulonephritis
• Antigen presenting cells
• Effector cells (activation and proliferation in glomeruli)
• Profibrotic activity: Tissue factor, procoagulant factors(fibrin)
• Tissue repairing:phagocytosis, removing apoptotic cells, secreting HGF, VEGF
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Mediators macrophages secrete
• Reactive oxygen species• Nitric oxide• Metaloproteinases• Complements• Procoagulant activity• Thromboxane/eicosanoids• IL-1, IL-4, IL-10, IL-12• TNF-• MIF• PDGF, TGF-, Fibronectin, FGF-2• PAF
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Glomerular response to immune injury
• Four factors are important– Site of immune event happen
• Subendothelium—attract severe inflammation and decrease GFR such as PSGN and Type IV lupus nephritis
• Mesangium– mesangial proliferation and matrix deposition such as IgA nephropathy
• Subepithelium—few systemic reactions; injury occurred through C5-9 deposition and local release of mediators
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Glomerular response to immune injury
• The mechanism of deposition– In situ immune complex formation is more damaging
than pass trapping circulating immune complex
• The property of deposited antibody– IgG>IgA>IgM
• The quantity of IgG deposition beyond mesangium> within mesangium
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Glomerular intrinsic cells
• Mesangial cells, Endothelial cells, epithelial cells• Mesangial cells:
– Best studied among the three
– Proliferate in response to injury such as IgA nephropathy, Lupus nephritis
– Release proinflammatory mediator• Oxidants and proteases
• Cytokines: MCP-1, growth factor(PDGF), prostaglandins, leukotrienes, endothelin, nitric oxide
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Glomerular intrinsic cells
• Glomerular epithelial cells– Important in pathogenesis of minimal change
disease, focal sclerosing GN, MGN, HIV related GN
– Release mediators such as hydrogen peroxide and matrix components
– Don’t proliferate in response to mitogen
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Glomerular intrinsic cells
• Endothelial cells– Lease studied– Important in Hemolytic uremic syndrome,
Thrombotic thrombocytopenic purpura, HCV related renal disease, cryoglobulinemia, lupus nephritis
– Adhesion molecule, angiogenesis, production of pro & anti-coagulant molecules
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Cellular mediator of interstitial disease
• Tubularinterstitial injury is the common pathway to end stage renal disease
• Involved T cell, dendritic cell and macrophage, fibroblast• Tubular interstitial nephritis without glomerulonephritis
may due to – expression of latent protein from virus-herpex or lentivirus– Lose immune tolerance– Tubular reclamation– Secretion of chemokine and cytokine
• Tubulointerstitial nephritis after glomerulonephritis– Heavy proteinuria, activate complement, chemokine, cytokine
during tubular reclamation
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Humoral mediator of interstitial nephritis
• Source: adjacent somatic cell(epithelial cell, dendritic cell)
• Mediators: prostaglandin, leukotriene nitric oxide endothelin, complement, protease, oxidants
• Persistence is important (1-2 weeks)• Fibrogenesis—TGF-, angiotensinII, PDGF,
plasminogen activator inhibitor 1, fibroblast specific protein 1.