Autoimmune patients undergoing B cell depletion therapy (BCDT) with Rituximab can enter clinical remission for years, while others experience only transient relief (months). Although we do not understand why some patients respond well to BCDT and others do not, it is clear that B cells are pathogenic in a subset of patients. Clinical data show that BCDT can be efficacious without significantly reducing autoantibody titer, suggesting that B cells cause pathology via by another mechanism. Therefore, it is important to identify the Ab-independent functions of B cells and understand how B cells performing these functions contribute to pathology in autoimmune disease. However, these efforts have been hampered because we understand so little about the Ab-independent effector functions of B cells. Our data show that one potentially important effector function of B cells is to secrete cytokines. Indeed, we know that cytokines made specifically by B lineage cells regulate humoral and cellular immune responses in vivo. Based on these data, we hypothesize that cytokine-producing B cell effectors (Beff) likely contribute to immune responses to pathogens as well as autoantigens and that Beff cells can be either protective or damaging depending on the immune microenvironment and the cytokine secreted by the Beff cells. However, without until recently, it has been difficult to experimentally address this hypothesis, as we were not able to track cytokine-producing Beff cells in vivo. Importantly, we have now identified a novel subset of IFN?-producing Beff cells that develop in response to influenza infection and are inappropriately expanded in a mouse model of SLE (YaaFcyRllb-/- or Yaa.R2 mice). These data now provide us with the unique opportunity to address our original hypothesis. Therefore goals of this proposal are to (i) determine the factors that regulate the development of IFN? Beff cells in infectious and autoimmune settings and (ii) identify the functional role(s) of these cells in immune responses directed against pathogens and autoantigens.
Approximately 3-5% of Americans suffer from autoimmune disease and effective treatments for many patients are lacking. One promising therapy for autoimmune disease is Rituximab, an antibody that depletes B cells from pro-B cells to plasmablasts. The goals of this proposal are to understand how B cells mediate pathology in autoimmune disease.
|Bouta, Echoe M; Banik, Peony D; Wood, Ronald W et al. (2015) Validation of power Doppler versus contrast-enhanced magnetic resonance imaging quantification of joint inflammation in murine inflammatory arthritis. J Bone Miner Res 30:690-4|
|León, Beatriz; Ballesteros-Tato, André; Randall, Troy D et al. (2014) Prolonged antigen presentation by immune complex-binding dendritic cells programs the proliferative capacity of memory CD8 T cells. J Exp Med 211:1637-55|
|Sanz, Iñaki (2014) Rationale for B cell targeting in SLE. Semin Immunopathol 36:365-75|
|Wang, Wensheng; Rangel-Moreno, Javier; Owen, Teresa et al. (2014) Long-term B cell depletion in murine lupus eliminates autoantibody-secreting cells and is associated with alterations in the kidney plasma cell niche. J Immunol 192:3011-20|
|Palanichamy, Arumugam; Bauer, Jason W; Yalavarthi, Srilakshmi et al. (2014) Neutrophil-mediated IFN activation in the bone marrow alters B cell development in human and murine systemic lupus erythematosus. J Immunol 192:906-18|
|Finak, Greg; Jiang, Wenxin; Krouse, Kevin et al. (2014) High-throughput flow cytometry data normalization for clinical trials. Cytometry A 85:277-86|
|Bouta, Echoe M; Wood, Ronald W; Brown, Edward B et al. (2014) In vivo quantification of lymph viscosity and pressure in lymphatic vessels and draining lymph nodes of arthritic joints in mice. J Physiol 592:1213-23|
|León, Beatriz; Bradley, John E; Lund, Frances E et al. (2014) FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun 5:3495|
|Zhang, Hengwei; Hilton, Matthew J; Anolik, Jennifer H et al. (2014) NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-?B. J Clin Invest 124:3200-14|
|Roberts, Mustimbo E P; Kaminski, Denise; Jenks, Scott A et al. (2014) Primary Sjögren's syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory B cells. Arthritis Rheumatol 66:2558-69|
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