– hemodynamic and physical forces that cause intraglomerular HTN and abnormal stress and strain on the vascular wall
Immune mechanisms
Humoral: mediated by B cells and Ab’s derived from them
Cellular: directed by T cells
Immune mechanisms of glomerular injury
In situ immune complex disease: antibody bound to the antigen localized within a specific tissue
Circulating immune complex disease: soluble circulating Ag-Ab complexes become passively trapped within the glomerulus, subsequently resulting in renal injury through complement activation, leukocyte infiltration, and glomerular cell proliferation.
Normal Immune Response
Endogenous antigen by any cell – MHC class 1
Þ co-stimulatory + CD8+ T-cellÞ CTL Þ lysis of cell
Extracellular antigen presented by APC – MHC class 2
Þ CD4+ Tcell + co-stimulatory moleculesÞ cytokines Þ Ag-specific activated B cell Þ clonal expansion with Ab production Þ Macrophage production
Antibody deposition
Þ complement, etc. Þ attenuation of glomerular or tubular basement membranes accompanying fibrosis
Antibody sensitized T cellls
Þ epithelial injury Þ Attenuation of glomerular or tubular basement membranes accompanying fibrosis
Autoimmunity
Loss of tolerance to a protein or peptide which initiates the immune response
Þ Renal Disease
Immunologic tolerance is a physiologic state that prevents an immune response against self antigens
Mechanisms of tolerance:
Clonal deletion – T cells and B cells are lost via negative selection by binding to autologous antigen.
Clonal anergy – Functional inactivation of T cells occurs when APC, presenting self-antigen, lacks co-stimulatory signals.
T cell peripheral suppression – cellular (suppressor Tcells) and humoral molecules (anti-inflammatory cytokines) can suppress autoreactive lymphocytes.
Loss of Self-tolerance can occur by:
Peripheral tolerance may be overcome.
Antigen-independent stimuli may activate self-reactive lymphocytes not depleted during development.
Antibodies or activated T-cells produced in a normal immune response may recognize (cross-react) both normal or modified self proteins.
Loss of self tolerance may also occur when a neoantigen, that is sequestered during development, becomes exposed by tissue damage. (Goodpasture’s disease)
Loss of suppressor T-cell function or excessive T-cell help may create an imbalance and a loss of immunologic tolerance.
Humoral Immunity and Renal Disease
Antibody deposits in kidney structures (glomerulus – visualized by immunofluorescence)
In situ immune complex deposition – implanted or endogenous protein recognized as non-self, antibody adheres
Antigens can be "native" – intrinsic glomerular protein constituents or "planted" – not intrinsic to the glomerulus.
"Native" Antigens
Goodpasture’s Ag
Þ antibody formed against epiithelium of basement membrane
Contained in mammalian lung and kidney basement membrane
Induces Goodpasture’s disease or anti-GBM nephritis in humans. Clinical picture is rapidly progressive glomerulonephritis. Kidney biopsy shows crescentic glomerulonephritis.
Þ Ý in parietal epithelial cells
Goodpasture’s Ag is two discontinuous epitopes hidden within hexamers in the non-collagenous domain of the
a 3 chain of type IV collagen.
Lierner: demonstrated that Abs eluted from nephritic kidneys of patients. with Goodpasture’s syndrome caused fulminant GN, proteinuria, renal failure and pulmonary hemmorhage in monkeys.
Heymann’s Nephritis
Þ antibody formed against epithelial cells on the podocyte
Generated by Abs against a kidney antigen (Fx1A) contained in brush border of proximal tubule
Fx1A has been identified as gp330 or megalin, a member of the LDL receptor superfamily. May bind and clear proteases.
Can cause idiopathic nephrotic syndrome
Complement MAC (C5b-C9) system can be activated by antibodies
Þ proteinuria (takes days - Ab has to go through more structures to get to the podocyte); in Anti -GBM Þ proteinuria takes hours, since immune complex is right on the basement membrane.
"Planted" antigens (DNA, IgA, drugs, lecitins) are not intrinsic to the glomerulus, may bind specifically or be trapped in the glomerulus due to charge, size, molecular or carbohydrate characteristics. Can be endogenous or exogenous.
Circulating immune complex disease
Soluble circulating immune complexes become trapped within the glomerulus
Size and charge characteristics determine sit of deposition. Circulating immune complexes lodge in the subendothelial space, rarely progressing further into the basement membrane, to generate a subendothelial deposit or paramesangial deposit.
Once formed, deposited human complexes can be modified and rearrange in situ as a result of changing Ag:Ab ratios. Excess Ag can dissolve already formed deposits by modifying the deposit.
Classic experimental models for glomerular injury induced by circulating immune complexes are acute and chronic serum sickness. Ag-Ab complexes can be endogenous (DNA, thyroglobulin, thyroid antigens) or exogenous (streptococci, hepatitis B and C).
Cell Mediated Immunity and Renal Disease
A number of studies using animal models of glomerulonephritis strongly implicate T-cell mediated, immune mechanisms, which are independent of antibody deposition in kidney injury.
Transfer of sensitized T cells from animals with experimental GN can initiated glomerular injury in normal recipient in absence of immune complex deposition.
In a rat model of nephrotoxic serum nephritis, depletion of CD8+ T-cells prior to the administration of nephrotoxic serum completely prevented anti-GBM disease (proteinuria) despite equivalent antibody deposition in the glomeruli of the CD8+ T-cell depleted animals and the control animals.
Sensitized T cells appear to mediate injury in a mouse model of anti-tubular basement membrane disease in bursectomized chickens given anti-GBM antibody.
Secondary mediators: Besides T cells, other inflammatory leukocytes (neutrophils, macrophages, and platelets) can localize in the glomerulus to promote immune injury. Release of cytokines, proteases, and/or oxidants from these cells can damage the GBM resulting in detachement of the epithelial cells foot processes from the filtration barrier with subsequent protein leakage. Primary injury
Þ secondary mediators Þ kidney disease.
Complement pathway activation may promote immune-mediated renal injury in one of two ways: either by recruitment of inflammatory cells to the site of immune injury, or by generation of the C5b-9 membrane attack complex (MAC).
The alternative pathway of complement activation has been specifically implicated in the pathogenesis of membranoproliferative glomerulonephritis (MPGN) and IgA nephropathy.
Necrotizing and crescentic glomerulonephritis, also known as pauci-immune glomerulonephritis, lack any evidence of glomerular antibody deposition. The immunopathogenesis of this disease remains unclear, but approximately 90% of patients. have anti-neutrophil cytoplasmic antibodies (ANCA) in their serum.
Cell-mediated pathways of immune pathways of immune injury appear to be the primary mechanisms of tubulointerstitial nephritis.