Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE.

AM14 rheumatoid factor (RF) B cells in the MRL/lpr mice are activated by dual BCR and TLR7/9 ligation and differentiate into plasmablasts via an extrafollicular (EF) route. It was not known whether this mechanism of activation of RF B cells applied to other lupus-prone mouse models. We investigated the mechanisms by which RF B cells break tolerance in the NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) strain in comparison to C57BL/6 (B6) controls, each expressing the AM14 HC transgene (tg) in the presence or absence of the IgG2aa autoAg. The TC, but not B6, genetic background promotes the differentiation of RF B cells into Ab-forming cells (AFCs) in the presence of the autoAg. Activated RF B cells preferentially differentiated into plasmablasts in EF zones. Contrary to the MRL/lpr strain, TC RF B cells were also located within germinal centers (GC), but only the formation of EF foci was positively correlated with the production of RF AFCs. Immunization of young TC.AM14 HC tg mice with IgG2aa anti-chromatin immune complexes (IC) activated RF B cells in a BCR and TLR9-dependent manner. However, these IC immunizations did not result in the production of RF AFCs. These results show that RF B cells break tolerance with the same general mechanisms in the TC and the MRL/lpr lupus-prone genetic backgrounds, namely the dual activation of the BCR and TLR9 pathways. There are also distinct differences, such as the presence of RF B cells in GCs and the requirement of chronic IgG2aa anti-chromatin ICs for full differentiation of RF AFCs.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. This review summarizes first the results obtained in the mouse that have revealed how B cell tolerance is breached in SLE. We then review the B cell subsets, in addition to the autoAb producing cells, which contribute to SLE pathogenesis, focusing on marginal zone B cells, B-1 cells and regulatory B cells. Finally, we review the interactions between B cells and other immune cells that have been implicated in SLE, such as dendritic cells, macrophages, neutrophils and T cells.

The breakdown in tolerance of autoreactive B cells in the lupus-prone NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) mice results in the secretion of autoantibodies. TC dendritic cells (DCs) enhance B cell proliferation and antibody secretion in a cytokine-dependent manner. However, the specific cytokine milieu by which TC DCs activate B cells was not known. In this study, we compared TC and C57BL/6 (B6) control for the distribution of DC subsets and for their production of cytokines affecting B cell responses. We show that TC DCs enhanced B cell proliferation through the production of IL-6 and IFN-γ, while antibody secretion was only dependent on IL-6. Pre-disease TC mice showed an expanded PDCA1+ cells prior to disease onset that was localized to the marginal zone and further expanded with age. The presence of PDCA1+ cells in the marginal zone correlated with a Type I Interferon (IFN) signature in marginal zone B cells, and this response was higher in TC than B6 mice. In vivo administration of anti-chromatin immune complexes upregulated IL-6 and IFN-γ production by splenic DCs from TC but not B6 mice. The production of BAFF and APRIL was decreased upon TC DC stimulation both in vitro and in vivo, indicating that these B cell survival factors do not play a role in B cell modulation by TC DCs. Finally, TC B cells were defective at downregulating IL-6 expression in response to anti-inflammatory apoptotic cell exposure. Overall, these results show that the TC autoimmune genetic background induces the production of B cell-modulating inflammatory cytokines by DCs, which are regulated by the microenvironment as well as the interplay between DC.

The lupus-prone NZM2410 mice present an expanded B1a cell population that we have mapped to the Sle2c1 lupus susceptibility locus. The expression of Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18Ink4c and located within Sle2c1, is significantly lower in B6.Sle2c1 B cells than in B6 B cells. To test the hypothesis that the B1a cell expansion in B6.Sle2c1 mice was due to a defective p18 expression, we analyzed the B1a cell phenotypes of p18-deficient C57BL/6 mice. We found a dose-dependent negative correlation between the number of B1a cells and p18 expression in B cells, with p18-deficient mice showing an early expansion of the peritoneal B1a cell pool. p18-deficiency enhanced the homeostatic expansion of B1a cells but not of splenic conventional B cells, and the elevated number of B6.Sle2c1 B1a cells was normalized by cyclin D2 deficiency. This data demonstrated that p18 is a key regulator of the size of the B1a cell pool. B6.p18-/- mice produced significant amounts of anti-DNA IgM and IgG, indicating that p18-deficiency contributes to humoral autoimmunity. Finally, we have shown that Sle2c1 increases lpr-associated lymphadenopathy and T cell-mediated pathology. B6.p18-/-.lpr mice showed a greater lymphadenopathy than B6.Sle2c1.lpr mice, but their renal pathology was intermediate between that of B6.lpr and B6.Sle2c1.lpr mice. This indicated that p18-deficiency synergizes, at least partially, with lpr-mediated pathology. Taken together, these results show that Cdkn2c contributes to lupus susceptibility by regulating the size of the B1a cell compartment and hence their contribution to autoimmunity.