The central goal of this proposal is to elucidate the mechanism(s) by which B cell depletion therapy (BCDT) and other targeted B cell therapies are efficacious and restore tolerance in systemic lupus erythematosus (SLE). It is hypothesized that loss of tolerance in SLE is due to an alteration in the balance of B cell survival signals (e.g. BAFF-B cell activator of the TNF family) relative to the numbers of transitional B cells emerging from the bone marrow (BM) (high BAFF/low numbers of emerging BM B cells), decreasing the stringency of negative selection. It is further postulated that a key dysregulated signal is interferon (IFN), with local production in the BM inhibiting BM B cell lymphopoiesis. On the other hand, we have found that a subset of SLE patients treated with BCDT experience restoration of B cell tolerance and have a unique pattern of B cell reconstitution characterized by exuberant B cell lymphopoiesis and a prominent expansion of circulating transitional cells. Thus, restoration of homeostatic mechanisms within the B cell transitional compartment may be critical for tolerance restoration in this group of subjects and, moreover, transitional B cells may play a physiological regulatory role that is dysregulated in SLE and restored after BCDT. This model will be tested through the following specific aims: 1. Define the factors regulating homeostasis of the transitional B cell compartment in SLE with a focus on BM B cell lymphopoiesis;2. Determine the consequences of B cell depletion therapy and targeted biologic antagonism of BAFF or IFN on transitional B cell homeostasis and tolerance;and 3. Elucidate the immunoregulatory roles of transitional B cells and the contribution of a transitional B cell expansion to disease improvement in SLE after BCDT. Specifically, BM lymphopoiesis and its regulation will be examined by multi-parameter flow cytometry of BM B cell subsets and delineation of the cytokine milieu (IFN BAFF via luminex, gene signature, and flow based signaling) in normal controls, untreated SLE, and SLE after BCDT, anti-BAFF, or anti-IFN therapy. The phenotype, survival, proliferation, and selection of transitional B cells emerging from the BM will be ascertained based on flow cytometry, annexin-V binding, proliferation antigen expression, and replication history relative to IFN and engagement by BAFF. Tolerance will be assessed as a decrease in the frequency of autoreactive B cells during maturation from the transitional to the mature stage using single cell PCR and ELISPOT technology. The ability of transitional B cells to express anti-inflammatory cytokines (IL10) and induce a T regulatory cell phenotype will be defined. These studies will illuminate the mechanisms that underlie SLE, the role of B cells in autoimmunity, and the ways in which targeted therapy may improve disease.
Lupus is a chronic autoimmune disease characterized by an abnormal immune response against self. B cells are a key immune cell in lupus in part because they play a central role in the production of auto-antibodies, a hallmark of the disease process. The research proposed here will help us understand the dysregulation that occurs in lupus in B cell development and censoring of autoreactive B cells and how B cell depletion and other targeted biologic therapies induce improvement. The knowledge gained from the present studies will help us understand the multiple functions of B cells in autoimmunity and develop better strategies for the treatment of lupus and other autoimmune diseases.
|Gao, Lin; Bird, Anna K; Meednu, Nida et al. (2017) Bone Marrow-Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence-Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein-Interferon-? Feedback Loop. Arthritis Rheumatol 69:1623-1635|
|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|
|Adlowitz, Diana G; Barnard, Jennifer; Biear, Jamie N et al. (2015) Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response. PLoS One 10:e0128269|
|Bird, Anna K; Meednu, Nida; Anolik, Jennifer H (2015) New insights into B cell biology in systemic lupus erythematosus and Sjögren's syndrome. Curr Opin Rheumatol 27:461-7|
|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|
|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|
|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|
|Anolik, J H (2013) B cell biology: implications for treatment of systemic lupus erythematosus. Lupus 22:342-9|
|Marian, Valentin; Anolik, Jennifer H (2012) Treatment targets in systemic lupus erythematosus: biology and clinical perspective. Arthritis Res Ther 14 Suppl 4:S3|
|Ichikawa, H Travis; Conley, Thomas; Muchamuel, Tony et al. (2012) Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum 64:493-503|
Showing the most recent 10 out of 17 publications