Abstract
In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the MIF pathway controls B‐cell development and the induction of EAE. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients. B cells were identified as the main immune subset in blood expressing MIF. Blocking of MIF and CD74 signaling in B cells triggered CXCR4 expression, and vice versa, with separate effects on their proinflammatory activity, proliferation, and sensitivity to Fas‐mediated apoptosis. This study reveals a new reciprocal negative regulation loop between CD74 and CXCR4 in human B cells. The disturbance of this loop during MS onset provides further insights into how pathogenic B cells survive peripheral tolerance checkpoints to mediate disease activity in MS.
Highlights
MS is a chronic autoimmune disease of the CNS, in which infiltrating proinflammatory immune cells mediate local pathology [1]
To determine whether the B cell-intrinsic MIF pathway is differentially regulated in early MS, we assessed the expression levels of MIF receptors CXCR4 and CD74 on blood B cells of relapsingremitting MS (RRMS) patients and healthy controls (HC)
The ratio of CXCR4 and CD74 expression levels on B cells was even further enhanced in RRMS (2.1-fold, p = 0.004; Fig. 1F; Supporting Information Fig. 1C and D), suggesting that both MIF receptors are dysregulated on a per-patient basis
Summary
MS is a chronic autoimmune disease of the CNS, in which infiltrating proinflammatory immune cells mediate local pathology [1]. The strong effects of anti-CD20 monoclonal antibody therapy in MS patients demonstrate a key role for peripheral B cells during the pathogenesis [2]. Immature B cells survive peripheral tolerance checkpoints in MS [3], but underlying mechanisms are poorly understood. An important factor associated with chronic inflammation and cell survival is MIF [4]. In the animal model of MS, i.e. EAE, MIF levels are increased in the CNS [5]. Anti-MIF treatment prevents disease onset and improves the course of the disease by decreasing the expression of VCAM-1, which impairs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
