Understanding and measuring human B-cell tolerance and its breakdown in autoimmune disease

• Type of Material: Article
• Authors: Kevin S. Cashman, Emory University; Scott Jenks, Emory University; Matthew Woodruff, Emory University; Deepak Tomar, Emory University; Christopher Tipton, Emory University; Christopher Scharer, Emory University; Frances Eun-Hyung Lee, Emory University; Jeremy Boss, Emory University; Ignacio Sanz, Emory University
• Language: English
• Date: 2019-11-22
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
• Final Published Version (URL): http://dx.doi.org/10.1111/imr.12820
• Title of Journal or Parent Work: IMMUNOLOGICAL REVIEWS
• Volume: 292
• Issue: 1
• Start Page: 76
• End Page: 89
• Grant/Funding Information: Funding support was provided by the National Institutes of Health (Sanz: U19-AI110483 Autoimmunity Center of Excellence, R37-AI049660; Lee: P01-AI078907, R01-AI121252, and U19-AI109962.; Sanz/Lee: P01-AI125180; Woodruff: T32-DK007656) and the United States-Israel Binational Science Foundation (Sanz: BSF-2013432)
• Keywords: human; APOPTOTIC CELLS; MONOCLONAL-ANTIBODIES; POSITIVE SELECTION; tolerance; epigenetics; PERIPHERAL-BLOOD; T FOLLICULAR HELPER; Immunology; autoreactivity; B-cell; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GERMINAL-CENTERS; SOMATIC HYPERMUTATION; RECEPTOR REPERTOIRE; Science & Technology; Life Sciences & Biomedicine; checkpoint; repertoire; SELF-REACTIVITY

Abstract

The maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B-cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess. Functional autoreactive, flow cytometric, and single-cell cloning assays have proven to be critical in deciphering breaks in B-cell tolerance within autoimmunity; however, newer approaches to assess human B-cell tolerance may prove to be vital in the further exploration of underlying tolerance defects. In this review, we supply a comprehensive overview of human immune tolerance checkpoints with associated mechanisms of enforcement, and highlight current and future methodologies which are likely to benefit future studies into the mechanisms that become defective in human autoimmune conditions.