The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology. In the present study, we analyzed the life span of (auto)antibody-secreting cells in the spleens of NZB × NZW F1 (NZB/W) mice, a murine model of systemic lupus erythematosus. The number of splenic ASCs increased in mice aged 1–5 mo and became stable thereafter. Less than 60% of the splenic (auto)antibody-secreting cells were short-lived plasmablasts, whereas 40% were nondividing, long-lived plasma cells with a half-life of >6 mo. In NZB/W mice and D42 Ig heavy chain knock-in mice, a fraction of DNA-specific plasma cells were also long-lived. Although antiproliferative immunosuppressive therapy depleted short-lived plasmablasts, long-lived plasma cells survived and continued to produce (auto)antibodies. Thus, long-lived, autoreactive plasma cells are a relevant target for researchers aiming to develop curative therapies for autoimmune diseases.

IntroductionAntibodies secreted by terminal differentiated B cells are important in immune defense, 1 but also can contribute to the pathogenesis of autoimmune diseases. 2 On stimulation by antigen and CD40 signaling by T cells, naive B cells can form germinal centers yielding memory B cells expressing antibodies of higher affinities. 3 On a second contact with antigen, memory B cells can differentiate into proliferating antibody-secreting plasmablasts found in the extrafollicular areas of secondary lymphoid tissues. 4 These cells further differentiate into mature nondividing plasma cells either remaining within the tissues of their origin or accumulating in mucosa-associated tissues, bone marrow, and sites of inflammation. 5,6 Plasma-cell homing to different tissues is a crucial regulator of the strength and duration of humoral immune responses. Maintained antibody responses are associated with plasma-cell homing to the bone marrow. 7 Under pathologic conditions, longterm survival of plasma cells is also supported in chronically inflamed tissues. 8,9 The local production of antibodies by plasma cells resident at such sites is likely to be important in clearing pathogens. In individuals suffering from systemic inflammatory autoimmune diseases, disturbed plasma-cell localization is associated with the production of autoantibody titers refractory to conventional therapy. 10 During differentiation into plasma cells, B cells change their chemokine receptor expression profile. 5,6,11 Expression of C-C chemokine receptor type 9 (CCR9) and CCR10 allows homing of immunoglobulin A (IgA) plasma cells to mucosal tissues. 12,13 IgG ϩ plasma-cell precursors formed in a secondary immune response against systemic antigenic challenge migrate toward ligands for C-X-C motif chemokine receptor 3 (CXCR3) and CXCR4, likely allowing them to migrate to inflamed tissue and bone marrow, respectively. 14,15 Additionally, both chemokine receptors and their cognate ligands likely also play a role for the localization of activated B cells, plasmablasts, and plasma cells within secondary lymphoid tissues. Plasma cells surrounding the germinal centers are colocalized with CXCL12, the ligand for CXCR4. 16,17 In the draining lymph nodes, CXCL9 is produced by a subset of high endothelial venules (HEVs) surrounding the B-cell follicles. 18 Here, we show that in vivo, CXCR3 is expressed only on a fraction of human memory B cells, preferentially those expressing IgG1. Once induced, the expression of this chemokine receptor is maintained during plasma-cell differentiation. Thus, the information whether this chemokine receptor is used during an immune response seems to be part of the B-cell memory. On CXCR3 Ϫ B cells, interferon ␥ (IFN-␥), but not interleukin 4 (IL-4), IL-1␤, IL-6, IFN-␣, IFN-␤, or tumor necrosis factor ␣ (TNF-␣), induces the expression of this receptor. For that, IFN-␥ must be present before day 3 following activation of the B cells. In vivo, during this period, activated B cells are located within the follicular areas, colocalized ...