Deposition of antibodies specific for fixed (intrinsic) or planted (from outside) antigens in the glomerulus is another major pathway of glomerular injury. Antigens expressed by podocytes have been implicated in membranous nephropathy. Antibodies also may react in situ with previously “planted” nonglomerular antigens, which deposit and become concentrated in the kidney through interaction with various glomerular components. Planted antigens include nucleosomal complexes, mainly derived from breakdown of apoptotic cells, in patients with systemic lupus erythematosus; bacterial products, such as endostreptosin, a protein expressed by group A streptococci; and large aggregated proteins (e.g., aggregated immunoglobulin G [IgG]), which tend to deposit in the mesangium. Locally formed immune complexes may also grow in size through additional interactions with circulating free antibodies and antigens. Most of these planted antigens, as with circulating immune complexes deposited on the GBM, show a granular pattern of deposition by immunofluorescence microscopy.
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Fig. 14.4 Twopatternsofdepositionofimmunecomplexesasseenbyimmunofluorescencemicroscopy.(A)Granular,characteristicofcirculatingandinsituimmunecomplexdeposition.(B)Linear,characteristicofclassicanti-glomerularbasementmembrane(anti-GBM)antibodyglomerulonephritis.(A, Courtesy of Dr. J.Kowalewska,Department of Pathology,University of Washington,Seattle,Washington.)
Antibody-mediated GN results from the glomerular deposition of autoantibodies directed against protein components of the GBM. The best-characterized disease in this group is anti-GBM antibody–mediated crescentic GN (see
Fig. 14.3 ), also known as Goodpasture disease. In this type of injury, antibodies are directed against fixed antigens in the GBM, creating a linear pattern of staining when visualized with immunofluorescence microscopy (
Fig. 14.4B ). This pattern is useful in the diagnosis of glomerular disease. A known antigen that is the target of anti-GBM antibodies is the α3 chain of the type IV collagen of the GBM. Sometimes the anti-GBM antibodies cross-react with basement membranes of lung alveoli, resulting in simultaneous lung and kidney lesions (Goodpasture syndrome, Chapter 13).
The primary cause of these diseases is unregulated activation of the alternative complement pathway, which may be triggered by acquired autoantibodies against complement components or inherited abnormalities of complement regulatory proteins. Ensuing complement-mediated injury may result in renal and systemic disease. Two forms of GN (dense deposit disease and C3 GN) and one form of a systemic disease with significant renal manifestations (complement-mediated thrombotic microangiopathy [TMA] or atypical hemolytic uremic syndrome) belong to this category. Although complement-mediated thrombotic microangiopathy is a systemic condition, renal manifestation represents the major morbidity of the disease.
Mediators of Immune Injury