Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals.
Immunoglobulin secretion by plasma cells infiltrating synovial membranes is a prominent feature of RA. Previous analyses of a cDNA library generated from synovium of RA patient BC revealed immunoglobulin kappa light chain transcripts with extensive somatic mutation, frequent N region addition, and unexpected variation in the lengths of CDR3 regions which form the center of the antigen binding site. To determine if these characteristics are present in other individuals, we performed reverse transcription-polymerase chain reaction amplification and sequenced > or = 10 V kappa-containing amplicons from nine tissue samples: synovia of three individuals with long-standing RA (including patient BC), PBLs of two of these individuals, and PBLs or splenocytes of four normal individuals. Increased levels of somatic mutation in PBLs appeared to correlate with increased age, which may reflect accumulation of circulating memory cells and/or decreased bone marrow production of naive B lymphocytes. Two of three RA synovial samples and both RA PBL samples exhibited increased proportions of clones with unusual CDR3 lengths. Enrichment for these antibody binding sites could be due to abnormal regulation of the emerging repertoire or to selection for B lymphocytes bearing antibodies of unusual specificity, and may play a role in the pathogenesis of RA.
Bridges
S L
SL
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham 35294-3300, USA.
Lee
S K
SK
Johnson
M L
ML
Lavelle
J C
JC
Fowler
P G
PG
Koopman
W J
WJ
Schroeder
H W
HW
D000328:Adult; D000367:Age Factors; D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D001666:Binding Sites, Antibody / Q000235:genetics*; D003062:Codon / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013583:Synovial Membrane / Q000276:immunology
D003062:Codon; D018076:DNA, Complementary; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains