Rheumatoid Arthritis: Le Berre R

Youinou P, Devauchelle V, Hutin P, Le Berre R, Saraux A, Pers JO. · Department of Immunopathology, Brest University Medical School, Brest, France. · Clin Rev Allergy Immunol. · Pubmed #17992590 No free full text.

Abstract: Although the relative contributions of T cells and B cells in Sjögren's syndrome (SS) are far from being settled, recent studies have suggested a crucial role for B cells in its pathophysiology. Early investigations have focused on the ability of B cells to produce autoantibodies, and new studies have enlarged the range of their functions. For example, beyond the paradigm that T lymphocytes maintain strict control over B cells, the latter cells are now acknowledged to solicit their own help from the former cells and release a flurry of cytokines. Further, some of these B cells act as antigen-presenting cells. Increased levels of the B cell activating factor (BAFF) found in SS may be responsible for high numbers of circulating Bm2/Bm2' cells and associated functional abnormalities of B cells, such as a BAFF-induced increased expression of CD19, which decreases the required strength generated by antigen binding for transmitting its signal. This review reports compelling evidence that B cells are involved in the pathophysiology of SS. As this brings novel prospects for the treatment of the disease, it is no surprise that B cell ablative treatment has proven to be relatively efficacious in SS.

Pers JO, Devauchelle V, Daridon C, Bendaoud B, Le Berre R, Bordron A, Hutin P, Renaudineau Y, Dueymes M, Loisel S, Berthou C, Saraux A, Youinou P. · Brest University Medical School, Brest, France. · Arthritis Rheum. · Pubmed #17469105 links to  free full text

Abstract: OBJECTIVE: Treatment with rituximab depletes B cells from the peripheral blood (PB) and salivary glands (SGs) of patients with primary Sjögren's syndrome (SS). The purpose of this study was to track the repopulation of B cell subsets in PB as well as their subsequent homing into SGs in patients with primary SS treated with rituximab. METHODS: A series of 4-color flow cytometry experiments delineated B cell subsets in 15 patients with primary SS. All were tested on days 8 and 15 of treatment. Nine of the patients were followed up monthly for 10 months, and the remaining 6 patients were followed up monthly for 24 months. Enzyme-linked immunosorbent assays were developed to measure serum levels of BAFF and rituximab. SGs were biopsied at the start of the study and 4 months after treatment in 15 patients, 12 months after treatment in 3 patients, and 24 months after treatment in 2 patients. RESULTS: Baseline serum levels of BAFF correlated inversely (r = -0.92, P < 5 x 10(-4)) with the duration of B cell depletion: the higher the BAFF levels, the shorter the duration of B cell depletion. Four B cell subsets repopulated the PB: plasmablasts (CD19+, CD5-,IgD-,CD38++), transitional type 1 (T1) B cells (CD19+,CD5+,IgD+,CD38++), mature Bm2 cells (CD19+,CD5+/-,IgD+,CD38+/-), and memory B cells (CD19+,CD5-,IgD-,CD38-). Increased numbers of Bm2 cells and decreased memory B cells reappeared with time. Sequential SG biopsies revealed that B cells were absent in these glands for 12 months: they were detected 24 months after rituximab treatment. Memory and T1 B cells were the first B cells identified locally. CONCLUSION: The timing of B cell repopulation is modulated by BAFF and is followed by reconstitution of the preexisting abnormalities.

Daridon C, Devauchelle V, Hutin P, Le Berre R, Martins-Carvalho C, Bendaoud B, Dueymes M, Saraux A, Youinou P, Pers JO. · Laboratory of Immunology, Brest University Medical School Hospital, Brest, France. · Arthritis Rheum. · Pubmed #17393395 links to  free full text

Abstract: OBJECTIVE: To identify the cells that produce BAFF in the salivary glands of patients with primary Sjögren's syndrome (SS), and to analyze BAFF receptor expression by local T and B lymphocytes. METHODS: We used 3 methods to identify the source of BAFF: in situ hybridization of the transcripts for BAFF combined with staining of membrane markers, regular and real-time reverse transcription-polymerase chain reaction (RT-PCR) of cultured epithelial cells, and RT-PCR of sorted single-cell T and B lymphocytes eluted from salivary glands. Cells expressing TACI, BCMA, and B lymphocyte stimulator receptor 3 (BR-3) were disclosed by combining each specific staining of the receptors with each specific staining of the cells. The function of BAFF generated by epithelial cells on B lymphocytes was determined in short-term cocultures. RESULTS: Transcripts for BAFF were seen in epithelial cells and infiltrating T lymphocytes and, for the first time, were detected in local B cells. It is interesting that BR-3 was present on these B cells but not on T cells. In contrast, TACI and, to a lesser degree, BCMA were observed on transitional B lymphocytes, whereas T lymphocytes were devoid of receptors for BAFF. Furthermore, this cytokine was shown to be functional, in that epithelial cell-bound BAFF extended the survival of normal B cells, but cell-free BAFF released in the supernatants did not. CONCLUSION: These experiments establish that in primary SS, BAFF is produced not only by epithelial cells and T cells but also by B cells. The expression of receptors for BAFF would thus allow these receptors to participate in an autocrine pattern of self-stimulation.

D'Arbonneau F, Ansart S, Le Berre R, Dueymes M, Youinou P, Pennec YL. · Laboratory of Immunology, Brest University Medical School Hospital, F-29609 Brest Cedex, France. · Arthritis Rheum. · Pubmed #14673967 links to  free full text

Abstract: OBJECTIVE: To evaluate the prevalence of thyroid dysfunction and related autoantibodies in patients with primary Sjögren's syndrome (pSS), and to determine whether these abnormalities develop over time. METHODS: pSS patients (n = 137) and controls (n = 120) were investigated for thyroid dysfunction and for the presence of anti-thyroid peroxidase antibody (anti-TPO) and antithyroglobulin antibody (ATG). Followup time for patients was 1-16 years, and 72 of the 120 controls were reevaluated 3 years after initial evaluation. RESULTS: Thyroid disease was more frequent in the pSS patients than in the controls (30% versus 4%; P < 10(-4)), as were anti-TPO and ATG (11% versus 3%; P < 0.02, and 3% versus 1%, not significant). Ten of 107 euthyroid pSS patients dropped out of the study, and thyroid dysfunction became apparent at followup in 12 of the remaining 97. Most of the patients with thyroid-related autoantibodies at entry developed autoimmune thyroid disease thereafter. CONCLUSION: Thyroid dysfunction is frequent in pSS patients, and those prone to develop thyroid disorders are identified by thyroid-related autoantibodies, or by rheumatoid factor and anti-Ro/SSA activity.