GENETIC ANOMALIES OF C4,CR1 & FCGR IN JUVENILE IGA-N

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This work will test the hypotheses that: 1) Abnormalities in complement and/or FcR mechanisms for processing and clearing circulating. immune complexes (lC) are often present in lgA nephritis (lgA-N) and, 2) The extent of these abnormalities can determine whether the patient will experience juvenile or adult-onset lgA-N. The concept that abnormalities in lC processing and clearance can contribute to the development of lgA-N is based in part on the well described association of lgA-N with deficiencies of complement components and regulators that result in impaired C3b generation. Impaired C3b generation is thought to predispose to lC disease because of abnormal lC processing and clearance. Thus, deficient or dysfunctional proteins involved in lC processing or clearing, could play a role in the pathogenesis of lgA-N. Previous studies have not critically tested this hypothesis. The concept that abnormalities in lC processing and Clearance can predispose to juvenile-onset lgA-N is speculative. However, as discussed herein, it is likely that the induction of lgA-N requires the concurrence of various combinations of abnormalities including abnormal production of lgA, production of abnormal lgA, and abnormal lC processing and clearance. We suggest that, the greater the number of such abnormalities, the earlier might be the age of onset of lgA- N. To search for abnormalities in lC processing and clearance, we will analyze both genomic DNA and cDNA of key proteins of the lC processing an clearance mechanism. The goal is to determine whether there are allelic differences or differences in the primary structure (amino acid sequence) of key proteins involved in lC processing and clearance that can distinguish lgA-N patients from normals, or adult-onset lgA-N from juvenile-onset lgA-N. Such differences would define risk factors for lgA-N. The mechanism of that risk would then need to be determined. The power of the present approach is that defining alleles, or proteins at the amino acid level, can reveal critical differences between proteins that can not be revealed by analyses of the intact proteins. The key components of the lC processing and clearing mechanisms chosen for study are the fourth component of complement (C4), complement receptor Type 1 (CR1) that is expressed on erythrocytes (E), and FcgammaRII. These components were chosen because of evidence from previous studies that deficient amounts of these proteins can be associated with lgA-N (C4 and E-CR1) or, in the case of FcgammaRII, that certain isoforms are strongly associated with IC- mediated glomerulonephritis of SLE. FcgammaRII is relevant because in lgA- N, circulating lC and glomerular lC deposits often contain IgG. Previous studies assessing lC clearance in lgA-N used preformed lC probes infused intravenously. These lC probes are probably not suitable surrogates for pathogenic circulating lC, as discussed herein. Thus, such studies cannot be regarded as a critical test of the role of lC processing and clearance in lgA-N. We have large cohorts to study: 35 juvenile-onset (age < 16 years), and 105 adult-onset (median age 37 years) lgA-N patients. Controls will be 35 unaffected siblings of lgA-N patients, and 35 unrelated normals. In summary, the present study will provide a genetic characterization of key components of the lC processing and clearing mechanisms in lgA-N compared to normals. More importantly the present study represents a novel and more definitive approach to the search for abnormalities in lC Processing and clearance in IgaA-N. and whether such abnormalities might be determinants of juvenile onset IgA-N.