Rheumatoid Arthritis: Renaudineau Y

Renaudineau Y, Jamin C, Saraux A, Youinou P. · Brest University Medical School, Brest, France. · Autoimmunity. · Pubmed #15804700 No free full text.

Abstract: Rheumatoid factors (RF), which are antibodies (Ab) with specificity directed against gamma (?) globulins, are the commonest auto-Ab ever described in man. Some of them are referred to as agglutinating RF, others designated non-agglutinating RF. Not only do these characterize rheumatoid arthritis (RA), but they are also encountered in a variety of disease conditions, as well as a proportion of healthy controls. Although non-specific for RA, the measurement of agglutinating IgM-RF remains the most useful serological test for the diagnosis of this disease. Demonstration of abnormal amount of serum RF by any method for which the result has been positive in less than 5% of normal subjects has indeed become one of the seven revised criteria, listed by the American College of Rheumatology (Arnett, FC, Edworthy, SM, Bloch, DA, McShane, DJ, Fries, JF, Cooper, NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum, 1988: 31: 315-24), for the classification of RA. Over the course of years, the relative importance of genetic (Carson, DA, Chen, PP, Kipps, TJ, Radoux, V, Jirik, FR, Goldfien, RD, et al. Idiotypic and genetic studies of human rheumatoid factors. Arthritis Rheum, 1987: 30: 1321-1325) and environmental (Nemazee, DA, Sato, VL. Enhancing antibody, a novel component of the immune response. Proc Natl Acad Sci USA, 1982: 79: 3828-3832) factors in the production of such intriguing auto-Ab has been delineated.

Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roué IQ, Cochener B, Youinou P, Saraux A. · Hôpital de la Cavale Blanche, CHU Brest, France. · Arthritis Rheum. · Pubmed #17330280 links to  free full text

Abstract: OBJECTIVE: There is evidence to support a dominant role for B cells in the pathophysiology of primary Sjögren's syndrome (SS). Therefore, we evaluated the safety and efficacy of anti-CD20 monoclonal antibody. METHODS: Sixteen patients who met the new American-European Consensus Group criteria for primary SS and scored >50 on at least 2 of 4 visual analog scales (VAS; 100 mm) evaluating global disease, pain, fatigue, and global dryness received infusions of low-dose rituximab (375 mg/m(2)) at weeks 0 and 1 without steroid premedication. RESULTS: Slow rituximab infusions (100 mg/hour) were well tolerated, with only 1 patient experiencing serum sickness-like disease. There was a dramatic reduction in B cells of the blood and salivary gland (SG). At week 12, VAS scores with respect to fatigue and dryness (P < 0.05), tender point count (P < 0.035), and quality of life as evaluated by the Short Form 36 questionnaire (SF-36; P < 0.001) were significantly improved. At week 36, significant improvements were noted in the 4 VAS scores (P < 0.05), tender joint count (P = 0.017), tender point count (P = 0.027), and SF-36 (P < 0.03). Pulmonary manifestations were ameliorated in 1 patient. Patients with improvements on at least 3 of the 4 VAS scores at any visit (n = 11) had a shorter disease duration than the other patients (n = 5; mean +/- SD duration 3.8 +/- 5.4 versus 30.1 +/- 29.5 years; P = 0.02). CONCLUSION: Low-dose rituximab infusions were well tolerated without the benefit of steroids. Infusions induced a rapid depletion of B cells in the blood and SG and could improve primary SS. Controlled studies are needed.

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.

Croquefer S, Renaudineau Y, Jousse S, Gueguen P, Ansart S, Saraux A, Youinou P. · Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609 Brest, France. · Ann N Y Acad Sci. · Pubmed #16014531 No free full text.

Abstract: In murine systemic lupus erythematosus (SLE) models, nephritogenic anti-dsDNA IgG has been shown to cross-react with a kidney antigen, alpha-actinin, and to be critical in renal pathogenesis. In humans, studies of anti-alpha-actinin antibodies (Abs) are scarce, and these antibodies remain to be evaluated. We have thus far tested sera from patients with SLE (n = 103), rheumatoid arthritis (RA, n = 93), and primary Sjögren syndrome (pSS, n = 34), and from healthy subjects (n = 160), for the presence of anti-alpha-actinin and anti-DNA Abs. The latter were tested using several methods [IIF on Crithidia luciliae (Crit) and ELISA using dsDNA]. Anti-alpha-actinin Abs were confirmed by Western blot. Sera from 23 of 103 SLE patients, 3 of 93 RA patients, 1 of 33 pSS patients, and 1 of 160 controls scored positive for anti-alpha-actinin Abs. In SLE, the positivity was significantly associated with anti-dsDNA reactivity (22 of 23): 19 of 23 sera were alpha-actinin-positive/dsDNA-positive and 13 were alpha-actinin-positive/Crit-positive. Few cases were alpha-actinin-positive/dsDNA-negative: 1 SLE, 3 RA, and 1 control. Furthermore, anti-alpha-actinin Abs have been detected at high level before or at the early stage of lupus nephritis when compared with active and inactive SLE without kidney manifestations.

Bordron A, Révélen R, D'Arbonneau F, Dueymes M, Renaudineau Y, Jamin C, Youinou P. · Laboratory of Immunology, Institut de Synergie des Sciences et de la Santé, Brest University Medical School, Brest, France. · Clin Exp Immunol. · Pubmed #11472414 links to  free full text

Abstract: While it has been claimed that some anti-endothelial cell antibodies (AECA) activate EC, there is also evidence that others trigger apoptosis. To address the issue of whether activation is a prerequisite for AECA-mediated apoptosis of EC, 23 AECA-positive sera were evaluated for their ability to induce activation and/or apoptosis. Activation was defined as an over-expression of E-selectin and intercellular adhesion molecule 1. Optical microscopy, annexin V binding, hypoploid cell enumeration, and determination of poly (ADP-ribose) polymerase cleavage-related products were used to assess apoptosis. Four functional profiles were defined: 10 sera promoted activation and apoptosis (act+/apo+), one was act+/apo-, six act-/apo+, and the remaining six act-/apo-. The reduced membrane expression of thrombomodulin was associated with apoptosis, rather than activation. Caspase-3 was implicated in the two models of apoptosis, the ratios of several survival proteins to Bax decreased, regardless of the ability of apo+ AECA to activate the cells, while radical oxygen species did not appear to be involved. Furthermore, it occurred that macrophages engulfed EC treated with apoptosis-promoting AECA, but not those incubated with AECA that did not induce apoptosis. Hence, AECA represent an extremely heterogeneous family of autoantibodies, not only because of the variety of their target antigens, but also the subsequent diversity of their effects.

Durand V, Pers JO, Renaudineau Y, Saraux A, Youinou P, Jamin C. · Laboratory of Immunology, Institut de Synergie des Sciences et de la Santé, Brest University Medical School, France. · J Leukoc Biol. · Pubmed #11272273 links to  free full text

Abstract: Anti-Fc gamma receptor IIIb (Fc gammaRIIIb) human autoantibodies (Ab) have been classified previously into three groups, based on the results of an indirect immunofluorescence (IIF) test and an enzyme-linked immunosorbent assay (ELISA): IIF+/ELISA+ (group A), IIF+/ELISA- (group B), and IIF-/ELISA+ (group C) sera. In this study, differential effects between IIF+ autoAb, recognizing cell-bound Fc gammaR, and those ELISA+, recognizing only cell-free Fc gammaR, were studied on polymorphonuclear neutrophils (PMN). Neither group A nor B autoAb was cytotoxic, although both prolonged the survival of PMN by delaying spontaneous apoptosis. By the same extent, the PMN-binding antisera stimulated the appearance of a CD11b(dim) population, following a 12-h incubation. This event was associated with a lowered expression of beta2 integrin molecules, resulting in altered PMN function. Treatment with groups A and B autoAb reduced adhesiveness and respiratory burst. This impairment of the responses was more pronounced when the cells originated from donors NA1+ NA1+ rather than donors NA2+ NA2+. From our observations, the influences of anti-Fc gammaRIIIb autoAb on PMN survival, as well as function and subsequent dysregulation of the inflammatory response, have proven somewhat dependent on their target antigens, as determined by IIF coupled with ELISA and Fc gammaRIIIb polymorphism.