1. The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis
- Author
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Liza Rijvers, Maeva Stéphant, Annet F Wierenga-Wolf, Jamie van Langelaar, Marvin M van Luijn, Marie-José Melief, Roos M van der Vuurst de Vries, Rogier Q. Hintzen, Anneke Geurts-Moespot, Fred C.G.J. Sweep, Jeanet M Hogervorst, Immunology, and Neurology
- Subjects
Male ,0301 basic medicine ,CD74 ,Apoptosis ,CXCR4 ,0302 clinical medicine ,Autoimmune disease ,Immunology and Allergy ,B‐cell biology ,B-Lymphocytes ,Research Article|Clinical ,Peripheral tolerance ,Middle Aged ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,Up-Regulation ,Cell biology ,Intramolecular Oxidoreductases ,Immunodeficiencies and autoimmunity ,Female ,medicine.symptom ,Research Article ,Signal Transduction ,Adult ,Receptors, CXCR4 ,Multiple Sclerosis ,Cell Survival ,Immunology ,Down-Regulation ,chemical and pharmacologic phenomena ,Inflammation ,Biology ,Proinflammatory cytokine ,Clinical ,Young Adult ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Immune system ,Downregulation and upregulation ,otorhinolaryngologic diseases ,medicine ,Humans ,Macrophage Migration-Inhibitory Factors ,Aged ,Cell Proliferation ,Histocompatibility Antigens Class II ,MIF receptors CXCR4/CD74 ,MS ,Antigens, Differentiation, B-Lymphocyte ,Clinically isolated syndrome ,030104 developmental biology ,Macrophage migration inhibitory factor ,030215 immunology - 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.
- Published
- 2018
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