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: 3.67). 03/2008; 126(2):189-201. DOI: 10.1016/j.clim.2007.10.004
Source: PubMed


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.

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Available from: Mary Anne Dooley, Mar 17, 2014
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    • "B cells from lupus patients are known to be hyperresponsive to stimulation through the BCR as evidenced by increased LYN and ERK1/2 phosphorylation [19], [31]. However, it was initially unclear if the same differences would be observed in EBV transformed B cell lines from lupus patients compared to B cell lines derived from unaffected controls. "
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    ABSTRACT: Recent application of gene expression profiling to the immune system has shown a great potential for characterization of complex regulatory processes. It is becoming increasingly important to characterize functional systems through multigene interactions to provide valuable insights into differences between healthy controls and autoimmune patients. Here we apply an original systematic approach to the analysis of changes in regulatory gene interconnections between in Epstein-Barr virus transformed hyperresponsive B cells from SLE patients and normal control B cells. Both traditional analysis of differential gene expression and analysis of the dynamics of gene expression variations were performed in combination to establish model networks of functional gene expression. This Pathway Dysregulation Analysis identified known transcription factors and transcriptional regulators activated uniquely in stimulated B cells from SLE patients.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "The MAPK pathway was also highlighted in network analysis. Nicholas et al. [44] demonstrated that CD19hi B cells had increased basal levels of phosphorylated Syk and ERK1,2. Similarly, B prosurvival signaling required sustained activation of Akt and ERK kinases which were associated with elevated anti-apoptotic proteins Mcl-1, Bcl-xL and XIAP [45]. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "Additional studies have characterized a population of CD19high-expressing B cells in patients with SLE and ANCA-associated vasculitis, representing up to 10% of the B cells in most patients and up to 30% in individual cases [79,88,89]. CD19high B cells showed markedly higher CD19 expression than B cells from healthy controls, while the remaining CD19low B cells recapitulated the reduced CD19 expression [79] as also documented by other studies [73,80,81]. "
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    ABSTRACT: Anti-CD20 therapy using rituximab directly targeting B cells has been approved for treatment of non-Hodgkin lymphoma, rheumatoid arthritis and anti-neutrophil cytoplasmic antibody-associated vasculitides and has led to reappreciation of B-lineage cells for anti-rheumatic treatment strategies. Moreover, blocking B-cell activating factor with belimumab, a drug that is licensed for treatment of active, seropositive systemic lupus erythematosus (SLE), represents an alternative, indirect anti-B-cell approach interfering with proper B-cell development. While these approaches apparently have no substantial impact on antibody-secreting plasma cells, challenges to improve the treatment of difficult-to-treat patients with SLE remain. In this context, anti-CD19 antibodies have the promise to directly target autoantibody-secreting plasmablasts and plasma cells as well as early B-cell differentiation stages not covered by anti-CD20 therapy. Currently known distinct expression profiles of CD19 by human plasma cell subsets, experiences with anti-CD19 therapies in malignant conditions as well as the rationale of targeting autoreactive plasma cells in patients with SLE are discussed in this review.
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