Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells

Abstract

The autoimmune disease systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens such as chromatin, DNA, and RNA. This focused autoreactivity is thought to arise from the ability of DNA or RNA specific B cells to receive dual signals from the BCR and TLR9 or TLR7, respectively. The Tec kinase Btk is necessary for the production of anti-DNA antibodies in several murine models of SLE. To assess the role of Btk in the fate of DNA reactive B cells, we generated Btk−/− mice carrying the 56R anti-DNA Ig transgene on the C57BL/6 background. dsDNA specific B cells were present in 56R.Btk−/− mice, although they were not preferentially localized to the marginal zone. These cells were able to proliferate in response to large CpG DNA containing fragments that require BCR-induced internalization to access TLR9. However, anti-DNA antibodies were not observed in the serum of 56R.Btk−/− mice. A transgene expressing a low level of Btk in B cells (Btk lo ) restored anti-DNA IgM in these mice. This correlated with partial rescue of proliferative response to BCR engagement and TLR9-induced IL-10 secretion in Btk lo B cells. anti-DNA IgG was not observed in 56R.Btk lo mice, however. This was likely due, at least in part, to a role for Btk in controlling the expression of T-bet and AID in cells stimulated with CpG DNA. Thus, Btk is required for the initial loss of tolerance to DNA and the subsequent production of pathogenic autoantibodies once tolerance is breached.

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

“…Finally, we showed that all 3 TKIs suppress Btk activity in memory B-cell subsets, known to be critical to B-cell memory development and class switching. 48 Our study was not designed to address the underlying reasons for differential responses to pneumococcal vaccine in CML patients on TKI. A possible explanation could be variations in serum TKI levels due to interindividual differences in drug metabolism 49 or adherence that may in turn impact the in vivo B-cell response to the vaccine.…”

The role of tyrosine kinases in systemic lupus erythematosus and their potential as therapeutic targets

“…Re-introduction of Btk expression at low levels (Btk lo ) in the B6.56R mice restored anti-DNA IgM but not anti-DNA IgG. Overexpression of Btk had no effect on anti-dsDNA IgG levels in B6.56R mice [15]. …”

Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man

“…Myeloid cells, B cells [149][150][151][152][153] CD303 (BDCA-2) Plasmacytoid dendritic cells [154] Epo: Erythropoietin; GPVI: Collagen receptor glycoprotein VI; R: Receptor; TLR: Toll like receptor; TRAIL: TNF-related apoptosis-inducing ligand.…”