Article

A novel subset of memory B cells is enriched in autoreactivity and correlates with adverse outcomes in SLE

Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Clinical Immunology (Impact Factor: 3.99). 03/2008; 126(2):189-201. DOI: 10.1016/j.clim.2007.10.004
Source: PubMed

ABSTRACT We previously reported that some systemic lupus erythematosus (SLE) patients have a population of circulating memory B cells with >2-fold higher levels of CD19. We show here that the presence of CD19(hi) B cells correlates with long-term adverse outcomes. These B cells do not appear anergic, as they exhibit high basal levels of phosphorylated Syk and ERK1/2, signal transduce in response to BCR crosslinking, and can become plasma cells (PCs) in vitro. Autoreactive anti-Smith (Sm) B cells are enriched in this population and the degree of enrichment correlates with the log of the serum anti-Sm titer, arguing that they undergo clonal expansion before PC differentiation. PC differentiation may occur at sites of inflammation, as CD19(hi) B cells have elevated CXCR3 levels and chemotax in response to its ligand CXCL9. Thus, CD19(hi) B cells are precursors to anti-self PCs, and identify an SLE patient subset likely to experience poor clinical outcomes.

Download full-text

Full-text

Available from: Mary Anne Dooley, Mar 17, 2014
0 Followers
 · 
146 Views
  • Source
    • "In healthy individuals, CXCR3 expression on B cells is limited to a fraction of naive and memory B cells, and its expression is induced by IFN- (Jones et al., 2000; Muehlinghaus et al., 2005). However, in certain diseases, such as active SLE, a subset of CD19 high B cells enriched in autospecific Ig receptors expresses CXCR3 (Nicholas et al., 2008). Thus, excessive IP-10 and its signaling to CXCR3 on activated B cells might favor persistence of autoreactive PCs, suggesting that targeting JEM Vol. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In tonsils, CD138(+) plasma cells (PCs) are surrounded by CD163(+) resident macrophages (Ms). We show here that human Ms (isolated from tonsils or generated from monocytes in vitro) drive activated B cells to differentiate into CD138(+)CD38(++) PCs through secreted CXCL10/IP-10 and VCAM-1 contact. IP-10 production by Ms is induced by B cell-derived IL-6 and depends on STAT3 phosphorylation. Furthermore, IP-10 amplifies the production of IL-6 by B cells, which sustains the STAT3 signals that lead to PC differentiation. IP-10-deficient mice challenged with NP-Ficoll show a decreased frequency of NP-specific PCs and lower titers of antibodies. Thus, our results reveal a novel dialog between Ms and B cells, in which IP-10 acts as a PC differentiation factor.
    Journal of Experimental Medicine 09/2012; 209(10):1813-23. DOI:10.1084/jem.20112142 · 13.91 Impact Factor
  • Source
    • "CD19(hi) B cells have elevated CXCR3 levels and chemotax in response to its ligand CXCL9. Thus, CD19(hi) B cells are precursors to anti-self PCs, and identify an SLE patient subset likely to experience poor clinical outcomes (Nicholas, 2008). CD19(hi)CD21(lo/neg) B cells of uncertain origin are expanded also in common variable immunodeficiency patients with autoimmune features (Warnatz et al, 2002). "
    Systemic Lupus Erythematosus, 03/2012; , ISBN: 978-953-51-0266-3
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: B cells are critical players in the orchestration of properly regulated immune responses, providing protection against infectious agents without inflicting autoinflammatory damage. A balanced B cell compartment is also essential to create protective immunity in response to vaccines. This difficult compromise is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to powerfully modulate other components of the innate and adaptive immune system. For the most part, however, the necessary division of labor among different B cell populations is poorly understood. B cell dysfunction has been implicated in multiple autoimmune conditions. The physiological importance and complexity of B cell functions has been brought to the fore in recent years by the success of rituximab-based B cell depletion therapy (BCDT) in multiple autoimmune diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS) which are conventionally viewed as T-cell mediated conditions. Given the widespread utilization of BCDT in malignant and autoimmune diseases and the key role of B cells in both protective immunity and pathogenic autoimmunity, a better understanding of B cell functions is of the essence and a focus of the research in our division. We are investigating these issues through a variety of approaches, including the study of the phenotype and function of human B cell populations in health, their perturbation in autoimmune disease states, the effects of targeted biologic therapies, and the study of relevant murine models.
    Immunologic Research 12/2009; 45(2):144-158. DOI:10.1007/s12026-009-8096-7 · 3.53 Impact Factor
Show more