Rheumatoid Arthritis: Rochas C

Rochas C, Hillion S, Youinou P, Jamin C, Devauchelle-Pensec V. · Laboratory of Immunology, Brest University Medical School Hospital, BP 824, F 29609 Brest, France. · Autoimmun Rev. · Pubmed #18035327 No free full text.

Abstract: Rheumatoid arthritis (RA) induces major changes in synovial tissue (ST) and cartilage and bone destruction. Still, its pathogenesis is poorly understood. Accumulating evidence points to an important role for B lymphocytes. Rheumatoid-ST is characterized by activation of the synoviocytes and infiltrated by various inflammatory cells such as B and T lymphocytes. The infiltrate is diffuse or organized as germinal centers (GCs). These accommodate the immune response and favor self-tolerance breakdown. Receptor revision in B cells results from re-expression of the recombination activating genes (RAGs) which reinitiate immunoglobulin gene recombination, and modify the B-cell antigen receptor accordingly. In rheumatoid ST, secondary VDJ rearrangements occur and RAG proteins are detected. The mechanism that triggers and controls this revision remains elusive. We favor the hypothesis that such an uncontrolled process leads to autoimmunity.

Bosello S, Pers JO, Rochas C, Devauchelle V, De Santis M, Daridon C, Saraux A, Ferraccioli GF, Youinou P. · Laboratory of Immunology, Medical School, Brest, France. · Int J Immunopathol Pharmacol. · Pubmed #17346422 No free full text.

Abstract: Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.

Rochas C, Hillion S, Saraux A, Mageed RA, Youinou P, Jamin C, Devauchelle V. · Université Européenne de Bretagne, Université de Brest, IFR 148 ScInBioS, and Laboratory of Immunology, Centre Hospitalier Universitaire, Brest Hôpital Morvan and Cavale Blanche, Brest, France. · Arthritis Rheum. · Pubmed #19404965 No free full text.

Abstract: OBJECTIVE: B cells that accumulate in the synovial tissue of rheumatoid arthritis (RA) patients revise their receptors due to coordinate expression of recombination-activating gene 1 (RAG-1) and RAG-2 genes. The aim of this study was to determine the mechanisms that control this re-expression. METHODS: B cells from healthy control subjects were cocultured with fibroblast-like synoviocytes (FLS) from patients with RA and osteoarthritis (OA). Re-expression of RAG messenger RNA (mRNA) and proteins was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and indirect immunofluorescence. Activity of RAG enzymes was evaluated by flow cytometry to measure variations in immunoglobulin kappa and lambda light chain expression and by ligation-mediated-PCR to assess specific DNA breaks. Blocking antibodies, short hairpin RNA, and recombinant cytokine were used to identify the molecules involved in RAG re-expression. RESULTS: RA FLS, but not OA FLS, induced B cells to re-express RAG mRNA and proteins. Enzymes were functional, since the kappa-to-lambda ratios decreased and specific DNA breaks were detectable after coculture with RA FLS. Transmembrane BAFF provided the first signal of RAG re-expression, since its down-regulation in RA FLS prevented RAG gene transcription in B cells. The failure of transmembrane BAFF from OA FLS to induce RAG suggests that a second signal was provided by RA FLS. Interleukin-6 (IL-6) is a candidate, since blockade of its receptors precluded transcription of RAG genes by RA FLS. Unless supplemented with IL-6, OA FLS were unable to induce RAG gene expression in normal B cells. CONCLUSION: Two independent signals are required for the induction of RAG gene expression in B cells that infiltrate the synovium of patients with RA.