Primary IgA nephropathy is the most common of the primary glomerulonephritides worldwide, with a significant number of patients progressing to end-stage renal disease. Other disorders, such as Henoch-Schoenlein purpura and dermatitis herpetiformis, share the characteristic immunopathology of this disease, i.e., mesangial deposition of IgA as the most prevalent immunoglobulin isotype; together all of these disorders are called the IgA nephropathies (IgA NP). The pathogenesis of IgA NP is unknown. However, because most patients with IgA NP have elevated levels of circulating immune complexes (CIC) containing IgA (often co- complexed with IgG), and because the C3 component of complement is usually found codeposited with IgA in the kidney, many investigators have speculated that the IgA NP are immune complex- mediated diseases. Characterization of the CIC would be expected to provide insight into pathogenetic mechanisms of IgA NP. Thus it is the objective of the proposed investigation to describe fully the CIC of patients with this disease, with specific respect to the immunoglobulin molecules contained within the complex matrices. Therefore, we will perform spectrotypic analyses of IgA and IgG proteins (in serum, saliva, CIC, lymphoid cells, and mesangial deposits) of IgA NP as well as determine the presence of disease- specific idiotypic markers of these immunoglobulins. We will also search for crossreactive idiotypes on IgA rheumatoid factors as well as study the possibility that autologous IgG anti-idiotypic antibodies specific for IgA rheumatoid factors contribute to the formation of the CIC. Further, we will ascertain the potential contribution to the antibodies specific for Fab of autologous IgA. All of these studies will be performed on longitudinal samples obtained from a large population of patients, many of whom have familial disease. Other studies will characterize both immunoglobulin heavy chain and light chain restrictions previously reported in IgA NP: we will determine IgG subclasses in serum and CIC and in IgG codeposited in mesangia with IgA; further, putative lambda chain restriction will be studied with respect to definition of variable region subgroups. Finally, we will study the potential functional significance of the CIC by examining the effects on B and T cells in vitro. The proposed experiments are designed to define the clonal origins of CIC-bound immunoglobulins in IgA NP and ultimately elucidate the pathogenesis of these disease.
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