■Lrba是参与囊泡运输的细胞质蛋白。Lrba缺陷型(Lrba-/-)小鼠在血清和粪便中表现出比野生型(WT)小鼠显著更高水平的IgA。转化生长因子β1(TGFβ1)及其受体(TGFβR1和II)对于IgAB细胞的分化至关重要。此外,IgA产生增加提示Lrba和TGFβR信号通路在IgA产生中存在潜在的联系.然而,Lrba在B细胞生物学中的具体功能仍然未知。
■鉴于Lrba-/-小鼠的IgA水平升高,这项工作的目标是探索发生IgA转换的淋巴器官,以及TGFβR功能是否受到影响。
■将未免疫的Lrba-/-小鼠与Lrba+/+小鼠进行比较。血清和粪便中的IgA水平,以及在外周B细胞发育过程中,决心。在小肠和次级淋巴器官中评估IgA+B细胞和浆细胞,比如脾脏,肠系膜淋巴结,和Peyer的补丁。通过测定TGFβR在B细胞上的表达来评价TGFβR信号通路。此外,在基础条件下并响应于重组TGFβ测量SMAD2磷酸化。最后,进行共聚焦显微镜检查以研究B细胞中Lrba和TGFβR之间可能的相互作用。
■Lrba-/-小鼠表现出明显更高水平的循环IgA,IgA+B,和浆细胞比WT小鼠的外周淋巴器官中的浆细胞。在Lrba-/-和Lrba+/+小鼠中,B细胞膜上的TGFβR表达相似。然而,Lrba-/-小鼠细胞内TGFβR表达降低。SMAD2磷酸化在基础条件下显示出升高的水平;与Lrba/B细胞相比,用重组TGFβ刺激引起的反应较差。最后,我们发现Lrba与TGFβR在B细胞中共同定位。
■Lrba在控制TGFβR信号传导中至关重要,随后调节SMAD2在B细胞上的磷酸化。这种机制可以解释IgAB细胞的分化增加和产生IgA的浆细胞的产生。
UNASSIGNED: 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 β1 (TGFβ1) and its receptors (TGFβR I and II) is essential for differentiating IgA+ B cells. Furthermore, increased IgA production suggests a potential connection between Lrba and the TGFβR signaling pathway in IgA production. However, the specific function of Lrba in B cell biology remains unknown.
UNASSIGNED: 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 TGFβR function is affected.
UNASSIGNED: 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 TGFβR signaling pathway was evaluated by determining the expression of TGFβR on B cells. Additionally, SMAD2 phosphorylation was measured under basal conditions and in response to recombinant TGFβ. Finally, confocal microscopy was performed to investigate a possible interaction between Lrba and TGFβR in B cells.
UNASSIGNED: Lrba-/- mice exhibited significantly higher levels of circulating IgA, IgA+ B, and plasma cells than in peripheral lymphoid organs those in WT mice. TGFβR expression on the membrane of B cells was similar in both Lrba-/- and Lrba+/+ mice. However, intracellular TGFβR expression was reduced in Lrba-/- mice. SMAD2 phosphorylation showed increased levels under basal conditions; stimulation with recombinant TGFβ elicited a poorer response than in that in Lrba+/+ B cells. Finally, we found that Lrba colocalizes with TGFβR in B cells.
UNASSIGNED: Lrba is essential in controlling TGFβR 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.