{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:29:36Z","timestamp":1790206176653,"version":"4.1.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T00:00:00Z","timestamp":1475280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Myasthenia gravis (MG) is a chronic humoral immunity\u2013mediated autoimmune disorder of the neuromuscular junction characterized by muscle weakness. Follicular helper T (Tfh) cells may be the key Th cell subset that promotes MG development, as their major function is helping B cell activation and Ab production. Aberrance of thymus-derived Tfh cells might be implicated in autoimmune diseases including MG; just how circulating Tfh cells, especially those from patients with a normal thymus, contribute to MG pathogenesis remains to be uncovered. In this article, we characterize a population of circulating CD4+CXCR5+PD-1+ Tfh cells in ocular and generalized MG patients without thymic abnormalities and demonstrate that the circulating Tfh cells are significantly enriched in generalized MG patients but not in ocular MG patients compared with healthy subjects, whereas a proportion of follicular regulatory T cells decreased in MG patients. In addition, the frequency of plasma cells and B cells was higher and the serum levels of IL-6\/IL-21 were also elevated in these MG patients. The activated Tfh1 and Tfh17 in Tfh cells are the major source for IL-21 production in MG patients. A strong correlation between Tfh cells and the plasma cell frequency and anti\u2013acetylcholine receptor Ab titers was evident in generalized MG patients. In particular, we found that Tfh cells derived from MG patients promoted B cells to produce Abs in an IL-21 signaling\u2013dependent manner. Collectively, our results suggest that circulating Tfh cells may act on autoreactive B cells and thus contribute to the development of MG in patients without thymic abnormalities.<\/jats:p>","DOI":"10.4049\/jimmunol.1500725","type":"journal-article","created":{"date-parts":[[2016,8,20]],"date-time":"2016-08-20T02:59:14Z","timestamp":1471661954000},"page":"2610-2617","source":"Crossref","is-referenced-by-count":86,"title":["Augmentation of Circulating Follicular Helper T Cells and Their Impact on Autoreactive B Cells in Myasthenia Gravis"],"prefix":"10.1093","volume":"197","author":[{"given":"Cun-Jin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]},{"name":"Department of Neurology, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center , Phoenix, AZ 85013"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Sheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqiang","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital , Tianjin 300052,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center , Phoenix, AZ 85013"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-7860","authenticated-orcid":false,"given":"Kristofer","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center , Phoenix, AZ 85013"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shafeeq","family":"Ladha","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute, St. Joseph\u2019s Hospital and Medical Center , Phoenix, AZ 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Clin. Invest."},{"key":"2025030617515620400_r2","first-page":"874680","article-title":"Myasthenia gravis: a review","volume":"2012","author":"Jayam Trouth","year":"2012","journal-title":"Autoimmune Dis."},{"key":"2025030617515620400_r3","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1136\/jnnp.73.6.766","article-title":"Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome","volume":"73","author":"Wirtz","year":"2002","journal-title":"J. Neurol. Neurosurg. 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