A patient presented with heavy-chain deposition disease (HCDD), exhibiting severe erosive polyarthropathy caused by synovial deposits of abnormal monoclonal, heavily deleted free gamma3 heavy chains lacking the V(H) and C(H)1 domains. The absence of V(H) was surprising, since it is considered important for pathogenic tissue deposition. This study was undertaken to analyze the genetic structure of the heavy chain, the protein product synthesized in vitro, and that deposited in the synovium in comparison with the serum and urinary proteins.
Hybridomas were made by fusion of blood and bone marrow mononuclear cells with mouse myeloma cells. Cloned B cell hybridomas secreting gamma3 were selected and analyzed by polymerase chain reaction. Purified hybridoma Ig was sequenced by Edman degradation. Antiserum raised to a peptide corresponding to residues 2-15 of the truncated V(H) was used in Western blots of synovial tissue.
The hybridomas secreted free gamma3 chains consisting of a V(H)4 gene truncated 21 nucleotides into the first complementarity-determining region and then reading straight into the hinge region. The amino acid sequence confirmed the presence of residues 1-32 of the V(H)4 gene. Immunoblotting of synovial tissue showed the presence of Ig with truncated V(H).
The gamma3 heavy chain had a deletion of V(H) from codon 33 and of the entire C(H)1. In vivo, the 32 V(H) amino acids were proteolytically degraded. In the joint, however, the 32 residues of V(H) remained intact, consistent with a pathogenic role of V(H) for tissue deposition. To our knowledge, this is the first reported case of gammaHCDD causing an erosive, polyarticular arthropathy as the dominating clinical feature.