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Frances E. Lund, PhD

Charles H. McCauley Professor and Chair,

University of Alabama at Birmingham

Department of Microbiology

https://labs.uab.edu/flund/

Characterization of Chemokine Producing Effector B Cells in SLE

B cells of the immune system make antibodies that are essential for the body’s defense against infectious diseases; yet, in autoimmune diseases like lupus, some B cells mistakenly go on the offense and attack the body itself instead of focusing on taking out bacteria or viruses. Dr. Lund’s ultimate goal is to improve on existing therapies that remove all B cells from a person’s immune system—such therapies treat autoimmunity but also leave patients vulnerable to new infections. With her Novel Research Grant, Dr. Lund is learning as much as she can about a unique population of B cells found in some people with lupus, but not in people without lupus. These cells (“T-bethi B cells”) have high levels of a gene-controller protein called T-bet. Understanding how these particular B cells are different could reveal new targets for safer drug therapy in lupus.

What this study means for people with lupus

By fully characterizing a specific type of B cell found in some people with lupus, Dr. Lund’s research paves the way for developing better, targeted therapies that specifically block the B cells that make lupus-related antibodies without affecting B cells that produce antibodies to fight infections.

Systemic Lupus Erythematosus (SLE) is a prevalent and potentially devastating autoimmune disease with more than 5 million cases worldwide. Diagnosis and treatment of SLE is complicated as it is highly heterogeneous with up to 300 clinically distinct forms that range from mild to multi-organ life-threatening disease. Only one new therapy for SLE was FDA approved in the last 50 years and, while modestly efficacious in a subset of patients, there is a clear need to develop new medicines that can be used to treat patients with active and severe disease. B and T lymphocytes and auto-antibody (Ab) secreting cells (auto-ASCs) are major drivers of SLE. Therefore, identification and characterization of pathogenic B and ASC subset(s) have the potential to lead to new therapies that either eliminate these pathogenic populations or modify the development or activity of these cells. In this application, we will functionally characterize a novel population of B cells that is expanded in a subset of SLE patients, with the goal of determining whether these B cells represent a new therapeutic target. Studies from our lab and others revealed that IFNg and the IFNg-induced transcription factors, T-bet and STAT1, are required for the development of SLE in mouse models. B cells expressing the IFNgR and T-bet are also required, indicating that T-bet+ B cells contribute to SLE pathogenesis. We showed that T-bet expressing B cells are expanded in a subset of SLE patients and that the presence of these cells tightly correlates with pathogenic auto-Ab titers and systemic levels of IFNg and the IFNg-induced chemokine CXCL10. Using a variety of in vitro model systems, we demonstrated that the human T-bethi B cells, which develop in an IFNg-dependent manner, are efficient antigen presenting cells and induce the differentiation of IFNg-producing Th1 cells from naïve precursors. The T-bethi B cells also exhibit an “effector” phenotype and can rapidly produce inflammatory chemokines, including CXCL10, following TLR7 activation. Finally, T-bethi B effector cells are transcriptionally poised to rapidly differentiate into “inflammatory ASCs” (ASC1) that retain the capacity to produce CXCL10. Given prior publications showing that CXCL10 promotes the chemotaxis of CXCR3+ cells to sites of inflammation, is necessary for optimal vaccine Ab responses (all isotypes), regulates T cell activation and polarization into IFNg-producing Th1 cells and drives an IFNg-dependent feedforward loop, we will test the hypothesis that production of the inflammatory chemokine CXCL10 by T-bethi effector B cells and ASC1 cells perpetuates an IFNg-driven inflammatory feedforward loop that further amplifies the development of auto-ASCs and pathogenic Th1 and Tfh1 cells. The proposed experiments are significant as we expect to provide evidence that eliminating T-bethi B cells or blocking the CXCL10/IFNg axis may be advantageous in the subset of SLE patients with expanded T-bethi B cell populations.

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