Articular, monoclonal gamma3 heavy-chain deposition disease: characterization of a partially deleted heavy-chain gene and its protein product synthesized in vivo and in vitro.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Thompson
Keith M
KM
Rikshospitalet University Hospital, Oslo, Norway.
Sletten
Knut
K
Brandtzaeg
Per
P
Källberg
Eva
E
Wien
Tale Norbye
TN
Husby
Gunnar
G
D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D015153:Blotting, Western; D001854:Bone Marrow Cells; D002999:Clone Cells; D005260:Female; D017353:Gene Deletion; D006362:Heavy Chain Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006825:Hybridomas; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D007142:Immunoglobulin gamma-Chains / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008875:Middle Aged; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000302:isolation & purification; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D012333:RNA, Messenger