Nodular Glomerulosclerosis with Deposition of Monoclonal Immunoglobulin Heavy Chains Lacking CH1

Abstract. The objective of this study was to further characterize the clinical and immunopathologic features of heavy chain deposition disease (HCDD), a recently described entity. Four patients were diagnosed as having HCDD on a kidney biopsy. All presented with nodular glomerulosclerosis with deposition of γ1 heavy chains lacking C H 1 epitopes, but without light chains. Two different patterns were observed in the serum. First, patients 1 and 2 had a circulating monoclonal IgGλ containing a short γ1 heavy chain lacking C H 1 epitopes, with an apparent molecular weight of 40 kD consistent with a complete C H 1 deletion. Biosynthetic experiments also showed that the deleted heavy chain was produced in excess compared with light chains, and was secreted in vitro together with half Ig molecules, although these abnormal components were not detected by Western blot analysis of whole serum. Second, patients 3 and 4 had a circulating monoclonal IgG1λ with an apparently normal, nondeleted heavy chain subunit, but serum fractionation followed by immunoblotting revealed an isolated monoclonal γ1 chain lacking C H 1 epitopes. These data strongly suggest that renal deposition of a C H 1-deleted heavy chain circulating in low amounts in the serum as a free unassembled subunit is a major feature of HCDD. The C H 1 deletion is most likely responsible for the premature secretion in blood of the heavy chain by a clone of plasma cells.