Circulating immune complexes in renal injury.

Abstract

T HE IMMUNOLOGIC basis of most forms of glomerulonephritis (GN) is well established. Immune-mediated glomerulonephritis in humans was initially defined by the pattern of glomerular immune deposits observed by immunofluorescence microscopy. Linear immunoglobulin (1g)G deposits along the glomerular basement membrane (GBM) were thought to be and have since been proven to be the result of antibodies binding directly to intrinsic renal antigens. In contrast, granular immune deposits were thought to result from passive trapping of circulating immune complexes (CIC). Following considerable controversy, it is now well established that granular immune deposits can arise from several mechanisms. In some cases, like anti-GBM disease, antibodies bind directly to intrinsic renal antigens; however, when the antigen is discontinuously distributed in the glomerulus, granular rather than linear deposits result. This is one form of in situ immune complex (IC) formation. Alternatively, granular immune deposits can be composed primarily of nonrenal antigens and their antibodies and reflect the formation of antigen-antibody (immune) complexes in the circulation and their localization within renal structures. The dynamics of formation of these complexes in the circulation, their trapping, rearrangement, and further accretion within the glomerulus, and the immunochemical characteristics that determine their ability to initiate renal injury are the focus of this article. The considerable progress that has been made in the previous 40 years in our understanding of immunecomplex mediated glomerulonephritis (ICGN) has been extensively reviewed previously and the reader is referred to those reviews for additional background. ‘-I2 The pathogenic potential of nonrenal circulating antigens is dependent on unique biochemical characteristics of the antigen as well as the nature of the immune response elicited by the antigen. Glomerular properties such as the high rate of blood flow, transcapillary hydraulic pressure gradient, fixed-negative charges within the capillary wall, and the unique set of extracellular matrix and cell surface proteins all contribute to the potential for macromolecular interactions that facilitate glomerular IC accumulation. The efficiency of the mononuclear phagocyte system for clearance of CIC is critically important, because glomerular IC accumulation increases when phagocyte function is impaired or overwhelmed.3~‘3~‘4 The dynamic equilibrium that exists between IC formation, clearance, and tissue accumulation is further illustrated in Fig 1 and discussed below. Despite our considerable knowledge, many questions remain unanswered. Early studies2*‘4-16 focused on quantitation of CIC as correlates of disease activity. These studies found the presence of CIC in the absence of disease manifestations and suggested that only subsets of IC were pathogenic. It was initially thought that CIC analysis would lead to antigen identification in human ICGN and thereby elucidate the etiologic agent and lead to an obvious approach to prevention and treatment. Early studies of serum sickness in the rabbit shed light on why our original hopes have not been fulfilled. Rabbits given identical antigen with identical dosage schedules develop a wide variety of histological forms and variable severity of ICGN. This indicated the critical importance of the individual animal’s immune response to the ultimate development of renal disease. Most current attempts to understand the pathogenic mechanisms responsible for ICGN are focused on basic concepts of regulation of the immune response and the unique biochemical characteristics of IC and their constituents that convey the capacity to deposit in the kidney (nephrotropic) and initiate injury (nephritogenic). In light of this, the antigen features that dictate antibody specificity, regulation of antibody synthesis, and the structure,