B cells have important antibody-independent effector functions including cytokine production that parallels T cells in magnitude and regulation. It has also been established that B cell-mediated antibody-independent effector functions are central to the pathogenesis of autoimmune diseases. These observations highlight the need to understand the precise phenotype and function of human effector B cells and their disregulation in autoimmunity. However, both in mice and humans, effector B cells are ill-defined and poorly understood. Over the last 3 years, we have identified a previously unrecognized population of human B cells that while displaying isotype switch and bearing a significant degree of somatic hypermutation, are distinct from conventional memory cells in the lack of CD27 expression;lower degree of mutation;expression of activation markers;expression of markers of trafficking to systemic inflamed tissues;and dependence on BAFF for survival. All the evidence combined, we postulate that these cells represent effector B cells that are greatly expanded systemically in SLE and in the synovial fluid of patients with Rheumatoid Arthritis and contribute to the pathogenesis of these diseases in antibody-independent fashion. The overall goal of this project is to understand the ontology, homeostasis, selection and function of effector B cells in human autoimmune disease with particular emphasis in SLE. This goal will be accomplished through the following specific aims: 1) To define the ontology of effector B cells (Beff) in SLE;2) To understand the homeostasis of effector B cells in SLE;3) To understand the selection of autoreactivity within the Beff effector compartment;and 4) To understand division of labor in human effector B cells. The information obtained should substantially improve our ability to therapeutically target populations of interest either for enhancement (vaccine responses) or dampening (autoimmune responses and transplantation). Finally, the knowledge gained will also greatly facilitate investigators ability to understand the immunological mechanisms behind the benefit (or lack thereof) of clinical interventions such as vaccination or B cell targeting therapies. This project has great synergy with the studies of other unique regulatory and effector B cell populations studied in projects 1 (human transitional cells) and projects 3-4 (mouse effector and Bin cells).
B cell cells are critical players in orchestrating protective immune responses against infections. At the same time, they play important pathogenic roles that contribute to disease in multiple autoimmune conditions including SLE. It is unknown at this time whether the different functions are played by different B cell populations or by the same cells after they acquire different function in the disease environment. We have discovered novel human B cell subsets and have started to characterize their function regarding antibody and cytokine production. These cells, effector B cells, will be extensively characterized in this project in terms of homeostasis and function. The expected results will greatly help our ability to understand, diagnose and treat SLE and other human autoimmune diseases.
|Sun, Wen; Meednu, Nida; Rosenberg, Alexander et al. (2018) B cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation. Nat Commun 9:5127|
|Jenks, Scott A; Cashman, Kevin S; Zumaquero, Esther et al. (2018) Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Immunity 49:725-739.e6|
|Bouta, Echoe M; Kuzin, Igor; de Mesy Bentley, Karen et al. (2017) Brief Report: Treatment of Tumor Necrosis Factor-Transgenic Mice With Anti-Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress. Arthritis Rheumatol 69:1187-1193|
|Oleksyn, D; Zhao, J; Vosoughi, A et al. (2017) PKK deficiency in B cells prevents lupus development in Sle lupus mice. Immunol Lett 185:1-11|
|D'Angio, Carl T; Wyman, Claire P; Misra, Ravi S et al. (2017) Plasma cell and serum antibody responses to influenza vaccine in preterm and full-term infants. Vaccine 35:5163-5171|
|Bird, Anna K; Chang, Martin; Barnard, Jennifer et al. (2017) Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers. J Immunol 199:458-466|
|Rangel-Moreno, Javier; To, Jesi Y; Owen, Teresa et al. (2016) Inhibition of G Protein ?? Subunit Signaling Abrogates Nephritis in Lupus-Prone Mice. Arthritis Rheumatol 68:2244-56|
|Kuzin, Igor I; Kates, Stephen L; Ju, Yawen et al. (2016) Increased numbers of CD23(+) CD21(hi) Bin-like B cells in human reactive and rheumatoid arthritis lymph nodes. Eur J Immunol 46:1752-7|
|Meednu, Nida; Zhang, Hengwei; Owen, Teresa et al. (2016) Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis. Arthritis Rheumatol 68:805-16|
|Rahimi, Homaira; Bell, Richard; Bouta, Echoe M et al. (2016) Lymphatic imaging to assess rheumatoid flare: mechanistic insights and biomarker potential. Arthritis Res Ther 18:194|
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