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Abstract Number: 1115

B Cell-Intrinsic Interferon Gamma Signals Promote the Development of Systemic Lupus Erythematosus By Enhancing the Formation of Spontaneous Autoimmune Germinal Centers

Shaun Jackson, Nicole Scharping, Holly Jacobs, Tanvi Arkatkar, Socheath Khim and David Rawlings, Seattle Children's Research Institute, Seattle, WA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: autoantibodies, B cells, cytokines and interferons, Lupus

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Session Information

Date: Monday, November 9, 2015

Session Title: B cell Biology and Targets in Rheumatolid Arthritis and other Autoimmune Disease Poster

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Type 1 interferon (IFN) is strongly implicated in lupus pathogenesis, and SLE patients frequently express a “type 1 IFN gene signature”. The type 2 interferon, IFN gamma (IFN-γ), has also been implicated in lupus development via direct activation of autoreactive T cells. Although B cells are critical in lupus pathogenesis, whether these cytokines exert cell-intrinsic impacts on autoantibody-producing B cells has not been studied. We recently developed a chimeric murine lupus model in which Wiskott-Aldrich syndrome protein (WAS)-deficient B cells promote spontaneous humoral autoimmunity (Jackson, et al. J Immunol 2014). An important advantage of the WAS chimera model is that dysregulated immune responses are limited to the B cell compartment, allowing genetic manipulation in a B cell-intrinsic fashion. In the current study, we contrast the impact B cell-intrinsic type 1 interferon and IFN-γ signals on serum autoantibody titers, systemic inflammation and the development of lupus nephritis.

Methods: Using the WAS chimera model of spontaneous humoral autoimmunity, we deleted the type 1 IFN receptor (IFNAR) or IFN-γ receptor (IFNgR) on all hematopoietic cells (“global deletion”), or specifically on B cells (“B cell-intrinsic”). Chimeras were analyzed for autoantibodies, immune activation and immune-complex glomerulonephritis (IC GN) by ELISA, flow cytometry and immunohistochemistry.

Results: Surprisingly, although type 1 IFN enhanced B cell responses in vitro, B cell-intrinsic IFNAR deletion exerted minimal impacts on lupus pathogenesis. To address whether other cytokines promote B cell activation in this model, we quantified cytokine production ex vivo, and noted prominent CD4 T cell IFN-γ production in diseased WAS chimeras. Consistent with this, global IFNγR deletion prevented autoantibody (Ab) production and systemic inflammation in WAS chimeras. Strikingly, cell-intrinsic deletion of IFN-γR on either T cells or B cells recapitulated the phenotype of global IFNγR deficiency. Mechanistically, deletion of IFNγR on B cells prevented the formation of spontaneous germinal centers (GCs), required for class-switched Ab formation. Consistent with lack of serum autoantibodies, lupus nephritis was abrogated in B cell IFNγR-null chimeras.

In addition to Ab formation, B cells promote autoimmunity via antigen presentation and production of cytokines. Based on prominent B cell IFN-γ production in this model, we hypothesized that B cell-derived IFN-γ enhances spontaneous GC formation. In contrast, rendering B cells unable to produce IFN-γ did not alter the development of murine lupus suggesting that other cellular IFN-γ sources compensate for lack of B cell-derived IFN-γ.

Conclusion: We report the novel observation that IFN-γ, and not type 1 IFN, signals promote systemic lupus via direct actions on B cells. Mechanistically, IFN-γ promotes the formation of spontaneous autoimmune GCs via reciprocal activation of GC B cells and T follicular helper cells. To our knowledge, this study is the first to directly address the impact of B cell IFN-γ activation in murine lupus, of relevance to both the understanding of disease pathogenesis and to efforts to target IFN-γ therapeutically in SLE.


Disclosure: S. Jackson, None; N. Scharping, None; H. Jacobs, None; T. Arkatkar, None; S. Khim, None; D. Rawlings, None.

To cite this abstract in AMA style:

Jackson S, Scharping N, Jacobs H, Arkatkar T, Khim S, Rawlings D. B Cell-Intrinsic Interferon Gamma Signals Promote the Development of Systemic Lupus Erythematosus By Enhancing the Formation of Spontaneous Autoimmune Germinal Centers [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/b-cell-intrinsic-interferon-gamma-signals-promote-the-development-of-systemic-lupus-erythematosus-by-enhancing-the-formation-of-spontaneous-autoimmune-germinal-centers/. Accessed January 31, 2023.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-intrinsic-interferon-gamma-signals-promote-the-development-of-systemic-lupus-erythematosus-by-enhancing-the-formation-of-spontaneous-autoimmune-germinal-centers/

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