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Extrafollicular CD19lowCXCR5−CD11c− double negative 3 (DN3) B cells are significantly associated with disease activity in females with systemic lupus erythematosus
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International audience. Objective. B cells play a major role in the development and maintenance of systemic lupuserythematosus (SLE). Double negative (DN) B cells defined by the lack of surface expressionof IgD and CD27 have attracted recent interest for their sensitivity to Toll-like receptor 7(TLR7) ligands and their potential role in the production of autoantibodies. Here we aimed atinvestigating the possible association of DN B cells and their subsets with SLE diseaseactivity specifically in female patients, in which TLR7 gene has been reported to escape Xchromosome inactivation.Methods. Peripheral blood mononuclear cells were purified from woman participating to theclinically well-characterized Swiss SLE Cohort Study (SSCS). PBMC from age-matchedhealthy females were used as controls. PBMC were stained for cell surface markers,intracellular Tbet and analyzed by multicolor cytofluorimetry. Single nucleotide TLR7polymorphisms were assessed by polymerase chain reaction.Results. The median SLE disease activity index of the 86 females was 2, IQR [0-6], all but 8were under chronic SLE treatment. B cells co-expressing CD11c and Tbet were increased,the mean fluorescence intensity (MFI) of CD19 was considerably reduced and we observed alarge increase in CD11c+CXCR5- and CD11c-CXCR5- concomitantly with a reduction ofCD11c-CXCR5+ B cells in SLE compared to 40 healthy donors (HD). When focusing on theDN B cell subset, we found a reduction of DN1 (CD11c-CXCR5+) and an increase of DN2(CD11c+CXCR5-) and most impressively of DN3 (CD11c-CXCR5-) cells. The DN subset,particularly DN3, showed the lowest level of CD19 expression. Both DN1 and DN3percentages as well as the CD19 MFI of DN cells were associated with SLE disease activity.The use of glucocorticoids, immunosuppressants, and antimalarials impacted differentially onthe frequencies of DN B cell subsets. CD19 MFI in B cells and the percentage of DN3 werethe strongest biomarkers of disease activity. The TLR7 snp3853839 G allele was associatedwith increased percentages of B cells and CD19+CD11c-CXCR5+ and decreasedCD19+CD11c-CXCR5-.Conclusions. DN3 B cells are strongly associated with SLE clinical activity pointing to theirpotential involvement in disease pathogenesis, and CD19 expression level performsaccurately as disease activity biomarker.
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