REVIEW The role of B lymphocytes in the progression from autoimmunity to autoimmune disease Gabriela Franco Salinas a , b , Faouzi Braza c , d , Sophie Brouard c , Paul-Peter Tak a , e , Dominique Baeten a , b , ⁎ a Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands b Experimental Immunology, Academic Medical Center/University of Amsterdam, The Netherlands c Institut National de la Sante et de la Recherche Medicale INSERM U643, and Institut de Transplantation Urologie Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France d Université de Nantes, Nantes, France e Glaxo Smith Kline, Stevenage, UK Received 15 August 2012; accepted with revision 15 October 2012 Available online 22 October 2012 KEYWORDS B lymphocytes; Antigen presentation; Epitope spreading; Somatic hypermutation; Class switch; Regulatory B cells Abstract Autoimmunity, defined as the presence of autoreactive T and/or B lymphocytes in the periphery, is a frequent and probably even physiological condition. It is mainly caused by the fact that the central tolerance mechanisms, which are responsible for counter-selection of autoreactive lymphocytes, are not perfect and thus a limited number of these autoreactive cells can mature and enter the periphery. Nonetheless, autoreactive cells do not lead automatically to autoimmune disease as evidenced by a multitude of experimental and human data sets. Interestingly, the progression from autoimmunity to autoimmune disease is not only determined by the degree of central tolerance leakage and thus the amount of autoreactive lymphocytes in the periphery, but also by peripheral mechanism of activation and control of the autoreactive cells. In this review, we discuss the contribution of peripheral B lymphocytes in this process, ranging from activation of T cells and epitope spreading to control of the autoimmune process by regulatory mechanisms. We also discuss the parallels with the role of B cells in the induction and control of alloimmunity in the context of organ transplantation, as more precise knowledge of the pathogenic antigens and time of initiation of the immune response in allo- versus auto-immunity allows better dissection of the exact role of B cells. Since peripheral mechanisms may be easier to modulate than central tolerance, a more thorough understanding of the role of peripheral B cells in the progression from autoimmunity ⁎ Corresponding author at: Clinical Immunology and Rheumatology, F4-105, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: d.l.baeten@amc.uva.nl (D. Baeten). 1521-6616/$ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clim.2012.10.005 available at www.sciencedirect.com Clinical Immunology www.elsevier.com/locate/yclim Clinical Immunology (2013) 146, 34–45