Deposition of circulating immune complexes In situ binding of antibodies with or without immune complex formation Subepithelial (at outer surface of glomerular basement membranes) Subendothelial (at inner surface of glomerular basement membranes) Antibody against antigen on podocytes Anti-glomerular basement membrane antibody Subepithelial immune complex formation (membranous nephropathy) Anti-glomerular basement membrane glomerulonephritis (no immune complexes formed) Granular immunofluorescence Linear immunofluorescence Mesangial
Fig. 14.3 Antibody-mediatedglomerularinjury.Injurycanresulteitherfromthedepositionofcirculatingimmunecomplexesorfromantibody-bindingtoglomerularcomponentsfollowedbyformationofcomplexesinsitu.Depositionofcirculatingimmunecomplexesgivesagranularimmunofluorescencepattern.Anti-glomerularbasementmembrane(anti-GBM)antibodyglomerulonephritisischaracterizedbyalinearimmunofluorescencepattern;thereisnoimmunedepositformationinthisdisease.
antigen is unknown, as in most cases of membranoproliferative GN.
Once antigen-antibody complexes are deposited or formed in the glomeruli, they produce injury by activating complement and recruiting leukocytes. Binding of immune complexes to Fc receptors on leukocytes also may contribute to activation of the cells and injury. Morphologically, affected glomeruli exhibit leukocytic infiltrates and variable proliferation of mesangial and parietal epithelial cells. Electron microscopy reveals electron-dense immune deposits in one or more of three locations: between the endothelial cells and the GBM (subendothelial deposits), between the outer surface of the GBM and the podocytes (subepithelial deposits), or in the mesangium. The localization of antigen, antibody, or immune complexes determines the glomerular injury response. Studies in experimental models have shown that complexes deposited in the endothelium or subendothelium elicit an inflammatory reaction in the glomerulus with infiltration of leukocytes and exuberant proliferation of glomerular resident cells. By contrast, antibodies directed to the subepithelial region of glomerular capillaries are often noninflammatory, as seen in primary membranous nephropathy (discussed later). The presence of immunoglobulins and complement in these deposits can be demonstrated by immunofluorescence microscopy. The pattern of immune complex deposition by immunofluorescence microscopy is granular, given the rather picturesque description of “lumpy-bumpy” by pathologists (
Fig. 14.4A
Once deposited in the kidney, immune complexes may eventually be cleared by degradation or phagocytosis, mostly by infiltrating leukocytes and mesangial cells. The inflammatory reaction may then subside if the exposure to the inciting antigen is short-lived and limited, as in most cases of poststreptococcal or acute infection–related GN. However, if exposure to antigen is sustained, repeated cycles of immune complex formation, deposition, and injury occur, leading to chronic GN. In some cases, the source of chronic antigenic exposure is clear, such as in hepatitis B virus infection and self nuclear antigens in systemic lupus erythematosus, but more often the antigen is unknown. Although immune complex deposition is a common mechanism of injury, circulating complexes are almost never identified in human disease, likely because of technical limitations.