Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 6, Pages 2737-2741Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI68775
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Funding
- NIH-NIAID [AI061093, AI071087, AI082713, AI095848]
- Sigrid Juselius Foundation
- Finnish Medical Foundation
- Saastamoinen Foundation
- German Research Foundation (DFG) [MO 2160/2-1]
- Rubicon, Netherlands Organisation for Scientific Research
- Nancy Davis Foundation for Multiple Sclerosis
- National MS Society Collaborative Research Center Award [CA1061-A-18]
- NIH [AI045757, AI046130, AI070352, AI039671]
- Jacob Javits Merit Award from the National Institute of Neurological Disorders and Stroke [NS2427]
- Nancy Taylor Foundation for Chronic Diseases, Inc.
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Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. B cells have recently emerged as major contributors to disease pathogenesis, but the mechanisms responsible for the loss of B cell tolerance in patients with MS are largely unknown. In healthy individuals, developing autoreactive B cells are removed from the repertoire at 2 tolerance checkpoints during early B cell development. Both of these central and peripheral B cell tolerance checkpoints are defective in patients with rheumatoid arthritis (RA) and type 1 diabetes (T1D). Here, we found that only the peripheral, but not the central, B cell tolerance checkpoint is defective in patients with MS. We show that this specific defect is accompanied by increased activation and homeostatic proliferation of mature naive B cells. Interestingly, all of these MS features parallel defects observed in FOXP3-deficient IPEX patients, who harbor nonfunctional Tregs. We demonstrate that in contrast to patients with RA or T1D, bone marrow central B cell selection in MS appears normal in most patients. In contrast, patients with MS suffer from a specific peripheral B cell tolerance defect that is potentially attributable to impaired Treg function and that leads to the accumulation of autoreactive B cell clones in their blood.
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