Dendritic Cells in Lupus Are Not Required for Activation of T and B Cells but Promote Their Expansion, Resulting in Tissue Damage

Abstract

Summary Dendritic cells (DCs) initiate and control the adaptive immune response against infections. However, their contributions to the anti-self adaptive immune response in autoimmune disorders like systemic lupus erythematosus are uncertain. By constitutively deleting DCs in MRL.Faslpr mice we show that they have complex roles in murine lupus. The net effect of DC deletion was to ameliorate disease. DCs were crucial for the expansion and differentiation of T cells but, surprisingly, not required for their initial activation. Correspondingly, kidney interstitial infiltrates developed in the absence of DCs, but failed to progress. DC deletion concomitantly decreased inflammatory and regulatory T cell numbers. Unexpectedly, plasmablast numbers and autoantibody concentrations depended on DCs, in contrast to total serum immunoglobulin concentrations, suggesting an effect of DCs on extrafollicular humoral responses. These findings reveal that DCs operate in unanticipated ways in murine lupus and validate them as a potential therapeutic target in autoimmunity.

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

“…Map3k7 DC mice contained a greatly reduced number of nT reg cells in the periphery under steady state. These results differ from the earlier reports excluding a role for DCs to regulate nT reg cells (20,21), but are consistent with more recent studies implicating a requirement for DCs to maintain the nT reg population (17,27,65). Interestingly, despite defective iT reg generation and nT reg homeostasis, T cells in Map3k7 DC mice exhibited no signs of prominent activation.…”

Re-thinking the functions of IgA+plasma cells

“…50 However, mice that constitutively lack DC display slightly increased levels of IgA compared to controls, indicating that other cell types besides DC are essential sources of iNOS and TNFa. 137 Our recent observations demonstrate that intrinsic iNOS expression by B cells is required for IgA C PC homeostasis. 1 Although our data do not eliminate the possibility that complete deletion of iNOS in all other stromal and haematopoietic cell types would have an impact on IgA production, our results show that the expression of iNOS in Blineage cells is essential for the homeostatic production of IgA within the small intestine.…”

Activated Protein C Attenuates Systemic Lupus Erythematosus and Lupus Nephritis in MRL-Fas(lpr) Mice

“…The proliferation of autoreactive B cells in lupus depends on autoantigen-presentation and costimulatory signals from dendritic cells (23,24). Therefore, it is of note that recombinant activated protein C suppressed the activation of spleen dendritic cells, which is an important determinant of SLE disease activity (23,24,37). The activation of dendritic cells also contributes to systemic inflammation; hence, we attribute the activated protein C-mediated suppression of plasma cytokine levels to its capacity to suppress dendritic cells.…”

“…Activated protein C significantly reduced all of these elements of humoral autoimmunity as well as subsequent glomerular IgG deposits, indicating that protection from severe lupus nephritis is due to a systemic suppression of immune complex disease. The proliferation of autoreactive B cells in lupus depends on autoantigen-presentation and costimulatory signals from dendritic cells (23,24). Therefore, it is of note that recombinant activated protein C suppressed the activation of spleen dendritic cells, which is an important determinant of SLE disease activity (23,24,37).…”

“…The activation of activated protein Cs is a major stimulus for B cell proliferation and autoantibody production in SLE (23,24). Therefore, we analyzed the activation of spleen dendritic cells by flow cytometry in MRL-Fas(lpr) mice of both treatment groups.…”