Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune, multi-systemic disease that potentially affects any organ in the body. Clinical efficacy of B cell-targeting therapy underscores a crucial role of the antibody (Ab)-independent functions of B cells in the pathogenesis of SLE. Among such functions, cytokine production by B cells has recently gained much attention. The type 2 interferon IFN-γ is a key cytokine involved in SLE and produced by a variety of immune cells, however it remains somewhat elusive whether human B cells have potential to produce this cytokine. Here, we have sought to identify IFN-γ-producing B cells in humans and investigate their role in the pathogenesis of SLE.

Methods: B cell subsets from peripheral blood (PB) from healthy controls (HC) and patients with SLE were enriched by cell sorting, stimulated with CD4⁺ T cell-related cytokines and subjected to the analysis of IFN-γ expression at both mRNA and protein levels. To check whether IFN-γ-producing B cells can be induced by CD4⁺ T cells, we co-cultured B cells with CD4⁺ T cell subsets. To determine the functional impacts of IFN-γ-producing B cells on CD4⁺ T cells, B cells from patients with SLE were co-cultured with CD4⁺ T cells. In addition, we thoroughly analyzed the surface markers of IFN-γ-producing B cells in HCPB and investigated whether this unique B cell subset coexists with CD4⁺ T cell subsets in the effusion of SLE patients with pleuritis.

Results: Among a panel of CD4⁺ T cell-related cytokines, IFN-γ and IL-21 significantly facilitated the generation of IFN-γ-producing B cells particularly from switched-memory (IgD^–CD27⁺) B cells.In the presence of anti-BCR/CD40L with IFN-γ and IL-21 which mimics stimulation of B cells by follicular helper CD4⁺ type 1 cells (Tfh1 cells), the CXCR3⁺ fraction of switched-memory B cells strongly produced IFN-γ. Consistent with this, circulating Tfh1 cells from HCPB induced IFN-γ production from CXCR3⁺ switched-memory B cells. IFN-γ-producing B cells were enriched in the CD226⁺PD-1⁺ fraction. The frequency of CXCR3⁺ switched-memory B cells was higher in patients with SLE than HC. Intriguingly, under Tfh1 conditions CXCR3⁺ switched-memory B cells from patients with SLE further accelerated IFN-γ production from CD4⁺ T cells. In the effusion of SLE patients with pleuritis, Tfh1 cells were the predominant Tfh subset and CD226⁺PD-1⁺CXCR3⁺ switched-memory B cells produced high amounts of IFN-γ.

Conclusion: Together, these findings clearly suggest the existence of IFN-γ-producing effector B cells in humans that are involved in the pathogenesis of SLE via closely interacting with CD4⁺ T cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-ifn-%ce%b3-producing-effector-b-cells-in-humans-their-relevance-to-the-pathogenesis-of-systemic-lupus-erythematosus/