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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Lrba is a cytoplasmic protein involved in vesicular trafficking. <jats:italic>Lrba<\/jats:italic>-deficient (<jats:italic>Lrba-\/-<\/jats:italic>) mice exhibit substantially higher levels of IgA in both serum and feces than wild-type (WT) mice. Transforming growth factor \u03b21 (TGF\u03b21) and its receptors (TGF\u03b2R I and II) is essential for differentiating IgA+ B cells. Furthermore, increased IgA production suggests a potential connection between Lrba and the TGF\u03b2R signaling pathway in IgA production. However, the specific function of Lrba in B cell biology remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>Given the increased IgA levels in <jats:italic>Lrba<\/jats:italic>-\/- mice, the goal in this work was to explore the lymph organs where the switch to IgA occurs, and if TGF\u03b2R function is affected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Non-immunized <jats:italic>Lrba-\/-<\/jats:italic> mice were compared with <jats:italic>Lrba+\/+<\/jats:italic> 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\u2019s patches. The TGF\u03b2R signaling pathway was evaluated by determining the expression of TGF\u03b2R on B cells. Additionally, SMAD2 phosphorylation was measured under basal conditions and in response to recombinant TGF\u03b2. Finally, confocal microscopy was performed to investigate a possible interaction between Lrba and TGF\u03b2R in B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Lrba-\/-<\/jats:italic> mice exhibited significantly higher levels of circulating IgA, IgA+ B, and plasma cells than in peripheral lymphoid organs those in WT mice. TGF\u03b2R expression on the membrane of B cells was similar in both <jats:italic>Lrba-\/-<\/jats:italic> and <jats:italic>Lrba+\/+<\/jats:italic> mice. However, intracellular TGF\u03b2R expression was reduced in <jats:italic>Lrba-\/-<\/jats:italic> mice. SMAD2 phosphorylation showed increased levels under basal conditions; stimulation with recombinant TGF\u03b2 elicited a poorer response than in that in <jats:italic>Lrba+\/+<\/jats:italic> B cells. Finally, we found that Lrba colocalizes with TGF\u03b2R in B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Lrba is essential in controlling TGF\u03b2R 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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1386260","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T04:42:05Z","timestamp":1718944925000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Lrba participates in the differentiation of IgA+ B lymphocytes through TGF\u03b2R signaling"],"prefix":"10.3389","volume":"15","author":[{"given":"Jos\u00e9 Mizael","family":"Flores-Hermenegildo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe de Jes\u00fas","family":"Hern\u00e1ndez-C\u00e1zares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"P\u00e9rez-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor","family":"Romero-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Rodr\u00edguez-Alba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Licona-Limon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred W.","family":"Kilimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leopoldo","family":"Santos-Argumedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"L\u00f3pez-Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12069","article-title":"The BEACH is hot: a LYST of emerging roles for BEACH-domain containing proteins in human disease","volume":"14","author":"Cullinane","year":"2013","journal-title":"Traffic"},{"key":"B2","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/j.ajhg.2012.04.015","article-title":"Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity","volume":"90","author":"Lopez-Herrera","year":"2012","journal-title":"Am J Hum Genet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.09.025","article-title":"The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency","volume":"137","author":"G\u00e1mez-D\u00edaz","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.7.4586","article-title":"Identification of a novel lipopolysaccharide-inducible gene with key features of both A kinase anchor proteins and chs1\/beige proteins","volume":"166","author":"Wang","year":"2001","journal-title":"J Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1663","article-title":"AUTOIMMUNE DISEASE. 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