Lrba participates in the differentiation of IgA plus B lymphocytes through TGFβR signaling

Introduction Lrba is a cytoplasmic protein involved in vesicular trafficking. Lrba-deficient (Lrba-/-) mice exhibit substantially higher levels of IgA in both serum and feces than wild-type (WT) mice. Transforming growth factor beta 1 (TGF beta 1) and its receptors (TGF beta R I and II) is essential for differentiating IgA+ B cells. Furthermore, increased IgA production suggests a potential connection between Lrba and the TGF beta R signaling pathway in IgA production. However, the specific function of Lrba in B cell biology remains unknown.Aim Given the increased IgA levels in Lrba-/- mice, the goal in this work was to explore the lymph organs where the switch to IgA occurs, and if TGF beta R function is affected.Methods Non-immunized Lrba-/- mice were compared with Lrba+/+ mice. IgA levels in the serum and feces, as well as during peripheral B cell development, were determined. IgA+ B cells and plasma cells were assessed in the small intestine and secondary lymphoid organs, such as the spleen, mesenteric lymph nodes, and Peyer's patches. The TGF beta R signaling pathway was evaluated by determining the expression of TGF beta R on B cells. Additionally, SMAD2 phosphorylation was measured under basal conditions and in response to recombinant TGF beta. Finally, confocal microscopy was performed to investigate a possible interaction between Lrba and TGF beta R in B cells.Results Lrba-/- mice exhibited significantly higher levels of circulating IgA, IgA+ B, and plasma cells than in peripheral lymphoid organs those in WT mice. TGF beta R expression on the membrane of B cells was similar in both Lrba-/- and Lrba+/+ mice. However, intracellular TGF beta R expression was reduced in Lrba-/- mice. SMAD2 phosphorylation showed increased levels under basal conditions; stimulation with recombinant TGF beta elicited a poorer response than in that in Lrba+/+ B cells. Finally, we found that Lrba colocalizes with TGF beta R in B cells.Conclusion Lrba is essential in controlling TGF beta R signaling, subsequently regulating SMAD2 phosphorylation on B cells. This mechanism may explain the increased differentiation of IgA+ B cells and production of IgA-producing plasma cells.