Plasma cells in systemic lupus erythematosus: The long and short of it all

Abstract

Plasma cells can be classified as long-or short-lived. The lifespan of a plasma cell largely depends on whether it arises from a germinal center or an extrafollicular locus and most importantly whether it can find a survival niche in the spleen or BM. In systemic lupus erythematosus (SLE) patients, long-lived plasma cells are believed to be responsible for the production of anti-RNA and anti-cardiolipin antibodies, whereas short-lived plasma cells, which are more susceptible to anti-proliferation therapies, are the main producers of anti-DNA antibodies. A previous study showed that transient overexpression of interferon-a (IFN-a), a cytokine that plays a pathogenic role in SLE, accelerates disease onset in lupusprone NZB/W mice. In this issue of the European Journal of Immunology, the same group report that IFN-a induces large numbers of short-lived plasma cells, accompanied by high titers of anti-dsDNA antibodies in NZB/W, but not BALB/c, mice. Our commentary discusses this interesting observation in the context of the previous data regarding plasma cell differentiation and conveys our view about the clinical implications with respect to therapies that target plasma cells in SLE patients.Keywords: Interferon-a . Plasma cells . Systemic lupus erythematosus See accompanying article by Mathian et al.Type I IFNs are believed to play a significant role in systemic lupus erythematosus (SLE) pathogenesis. IFN-a facilitates the maturation of myeloid DC that contribute to T-cell activation and follicular T-helper cell differentiation [1], and that produce the B-cell survival factor B-cell activating factor (BAFF) [2]. IFN-a also directly stimulates CD4 T cells to enhance antigen-specific B-cell activation, increases TLR7 expression in B cells, and promotes T-independent B-cell proliferation and differentiation into early plasmablasts [3]. In several lupus-prone mouse strains, type I IFNs accelerate the break in B-cell tolerance to nucleic acids that occurs spontaneously in these mice with age [4][5][6]. Nucleic acid-containing immune complexes, in turn, can activate intracellular TLRs, resulting in further release of type I IFNs and pro-inflammatory cytokines [7].Consistent with the known biologic functions of IFN-a, Mathian et al. [8] show in this issue of the European Journal of Immunology that NZB/W mice treated with a small dose of IFN-aexpressing adenovirus develop increased serum levels of BAFF, IL-6, and TNFa, and high titers of anti-dsDNA antibodies. In contrast, nonautoimmune BALB/c mice maintain tolerance to self-antigens despite IFN-a-induced upregulation of inflammatory mediators. This indicates that a genetic predisposition is required for IFN-a to initiate autoimmunity and may explain the reason why only few patients develop SLE during type I IFN therapy [3].The findings reported by Mathian et al. [8] complement the recent studies by our group, showing that IgG2a autoantibodies in IFN-a-induced NZB/W mice were derived from germinal centers, whereas IgG3 autoantibodies were derived predominantly from extra...

Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

“…In addition, it was reported that expanded PCs, which were generated through GCs in both the peripheral and bone marrow in SLE patients, 45,46 are responsible for the production of an array of autoantibodies against soluble and cellular constituents that are most commonly nuclear antigens. 47 Consistent with previous reports, the expression of CCND3 is significantly higher in GC B cells than in non-GC B cells, 7,8 and the expression of miR-15b in IMQ-treated GC B cells is significantly lower than IMQ-treated and wild-type non-GC B cells. The different expression levels and functions of CCND3 in different B-cell subsets indicated that CCND3 plays different roles in different stages and contexts, and that even the same type of cells may express different level of genes under different circumstances.…”

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

“…The anti-BAFF Ab belimumab reduces anti-dsDNA, anti-Smith, anticardiolipin, and anti-ribosomal P autoantibodies, normalizes C3/C4 complement levels, and decreases the amount of naive and activated B cells and PCs, but it does not deplete memory B cells (57). As such, the fraction of anti-dsDNA Abs secreted by short-lived PCs (SLPCs) (58), whose numbers correlate with flares (12), is targeted by belimumab whereas the Ab titers against pneumococci, tetanus, and influenza representing LLPCs are not reduced (59). This underscores the necessity to block both compensating BCMA ligands, that is, APRIL and BAFF, to deplete LLPCs (8,60).…”

Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE

“…Both mechanisms are central to the pathogenesis of SLE. Plasma cells produce much of the autoantigen specific antinuclear antibodies (ANAs) that are responsible for several pathological manifestations associated with SLE (e.g., glomerulonephritis, cardiomyopathies, dermatitis) [21]. Activation of the NF-κB cascade leads to several proinflammatory cytokine cascades that perpetuates the proliferation and differentiation of autoantigen specific T and B cells and drives the initial innate immune response that potentiates lupus-like symptoms in the early in disease [22].…”