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Summary Systemic lupus erythematosus (SLE) and Transitional B cellsB cell development in the bone marrow occurs continuously throughout life. The diverse antigen-binding repertoire of B cell surface immunoglobulin is generated as B cells develop by a process of gene rearrangement that produces both wanted and unwanted specificities. In mice, there are two known major check-points that filter out autoreactive and to some extent polyspecific B cells from the newly generated cells, thus ensuring that they make a minimal contribution to the mature recirculating B cell population. The first check-point for specificity, in humans as in mice, occurs in the bone marrow, where selection of B cells is achieved mainly by eliminating autoreactive B cells. B cells that react with selfantigens present in the bone marrow will be removed by mechanisms that include anergy [1,2] clonal deletion [3,4] and receptor-editing [5], particularly editing of the immunoglobulin (Ig) light chain. Receptor editing replaces one gene rearrangement with another in immature B cells, often on the same allele. There is evidence of light chain editing in human cells as well as animal models; in human cells, the most V proximal IGKJ segment is more common in the unproductive than the productive rearrangements [6,7]. Positive selection and B cell survival requires the anti-apoptotic cytokine BLyS (B lymphocyte stimulator, also known as BAFF or TNFSF13B) [8]. Moreover, current data suggest that tonic signals via B cell receptors (BCRs) are critical for immature B cells to suppress Rag expression and maintain specific developmental stages [9]. Only a small percentage of transitional B cells manage to pass through the first tolerance check and will then enter the periphery in mice and humans. The second check-point for selection seems to be the spleen and the bone marrow in mice where transitional B cells need to receive survival signals before they differentiate into mature naive B cells [10,11]. The sites and mechanisms involved in human transitional B cell selection are less clearly understood.

Our study illustrated increased cTFHs with decreased antigen-experienced Tregs in GPA patients on conventional therapies, but in B cell-depleted patients the levels of cTFHs and Tregs were similar to healthy controls. The negative correlation between cTFHs and Tregs implies the balance between T cell subsets and its B cell dependence impact on disease activity in GPA.