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| GENETIC-ANALYSIS OF SELF-ASSOCIATING IMMUNOGLOBULIN-G RHEUMATOID FACTORS FROM 2 RHEUMATOID SYNOVIA IMPLICATES AN ANTIGEN-DRIVEN RESPONSE |
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| Author(s): OLEE TW, LU EW, HUANG DF, SOTOGIL RW, DEFTOS M, KOZIN F, CARSON DA, CHEN PP |
| Source: JOURNAL OF EXPERIMENTAL MEDICINE Volume: 175 Issue: 3 Pages: 831-842 Published: MAR 1 1992 |
| Times Cited: 102 References: 80 |
| Abstract: Although much has been learned about the molecular basis of immunoglobulin M (IgM) rheumatoid factors (RFs) in healthy individuals and in patients with mixed cryoglobulinemia and rheumatoid arthritis, little is known about the genetic origins of the potentially pathogenic IgG RFs in the inflamed rheumatoid synovia of patients. Recently, we generated from unmanipulated synovium B cells several hybridomas that secreted self-associating IgG RFs. To delineate the genetic origins of such potentially pathogenic RFs, we adapted the anchored polymerase chain reaction to rapidly clone and characterize the expressed Ig V genes for the L1 and the D1 IgG RFs. Then, we identified the germline counterparts of the expressed L1 IgG RF V genes. The results showed that the L1 heavy chain was encoded by a Vh gene that is expressed preferentially during early ontogenic development, and that is probably located within 240 kb upstream of the Jh locus. The overlap between this RF Vh gene and the restricted fetal antibody repertoire is reminiscent of the natural antibody-associated Vh genes, and suggests that at least part of the "potential pathogenic" IgG RFs in rheumatoid synovium may derive from the "physiological" natural antibody repertoire in a normal immune system. Indeed, the corresponding germline Vh gene for L1 encodes the heavy chain of an IgM RF found in a 19-wk-old fetal spleen. Furthermore, the comparisons of the expressed RF V genes and their germline counterparts reveal that the L1 heavy and light chain variable regions had, respectively, 16 and 7 somatic mutations, which resulted in eight and four amino acid changes. Strikingly, all eight mutations in the complementarity determining regions of the V gene-encoded regions were replacement changes, while only 6 of 11 mutations in the framework regions caused amino acid changes. Combined with L1's high binding affinity toward the Fc fragment, these results suggest strongly that the L1 IgG RF must have been driven by the Fc antigen. |
| Document Type: Article |
| Language: English |
| Reprint Address: OLEE, TW (reprint author), UNIV CALIF SAN DIEGO, DEPT MED, 0663, LA JOLLA, CA 92093 USA |
Addresses:
1. UNIV CALIF SAN DIEGO, SAM & ROSE STEIN INST RES AGING, LA JOLLA, CA 92093 USA
2. UNIV CALIF SAN DIEGO, DEPT PATHOL, LA JOLLA, CA 92093 USA
3. Scripps Res Inst, RES INST, DEPT MOLEC & EXPTL MED, LA JOLLA, CA 92037 USA |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 |
| Subject Category: Immunology; Medicine, Research & Experimental |
| IDS Number: HF640 |
| ISSN: 0022-1007 |
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