B cells as therapeutic targets in SLE
ABSTRACT The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.
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ABSTRACT: Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG) activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fcγ receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.Cell Reports 03/2014; 7(1). DOI:10.1016/j.celrep.2014.02.041 · 7.21 Impact Factor
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ABSTRACT: B-cell activating factor (BAFF) is involved in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. However, how excessive BAFF promotes aggressive B-cell proliferation and survival is not well understood. Here we show that excessive human soluble BAFF (hsBAFF) enhanced cell proliferation and survival in normal and B-lymphoid (Raji) cells, which was associated with suppression of PP2A, resulting in activation of Erk1/2. This is supported by the findings that pretreatment with U0126 or PD98059, expression of dominant negative MKK1, or overexpression of PP2A prevented hsBAFF-induced activation of Erk1/2 and cell proliferation/viability in the cells. It appears that hsBAFF-mediated PP2A-Erk1/2 pathway and B-cell proliferation/viability was Ca(2+)-dependent, as pretreatment with BAPTA/AM, EGTA or 2-APB significantly attenuated these events. Furthermore, we found that inhibiting CaMKII with KN93 or silencing CaMKII also attenuated hsBAFF-mediated PP2A-Erk1/2 signaling and B-cell proliferation/viability. The results indicate that BAFF activates Erk1/2, in part through Ca(2+)-CaMKII-dependent inhibition of PP2A, increasing cell proliferation/viability in normal and neoplastic B-lymphoid cells. Our data suggest that inhibitors of CaMKII and Erk1/2, activator of PP2A or manipulation of intracellular Ca(2+) may be exploited for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.Biochemical pharmacology 11/2013; 87(2). DOI:10.1016/j.bcp.2013.11.006 · 4.65 Impact Factor
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ABSTRACT: A primary function of B lymphocytes is immunoglobulin production; however, the therapeutic benefit of B cell depletion in autoimmune diseases previously thought to be T cell mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, a CD11b(+) subset constitutes ~1 out of every 8-10 B1 cells, whereas a CD11b(-) subset constitutes the remaining B1 cells. These B1 cell populations differ functionally. CD11b(-) B1 cells spontaneously secrete much more IgM than CD11b(+) B1 cells. In contrast, CD11b(+) B1 cells express more CD86, and more efficiently stimulate allogeneic CD4(+) T cell expansion, than CD11b(-) B1 cells. The frequency of these CD11b(+) B1 cells is markedly elevated in lupus patients. CD11b(+) B1 cells in lupus patients express more CD86 and have increased T cell-stimulating activity in disease. This work distinguishes a novel, T cell-interacting B1 cell population whose abundance and activity may be a reflection of, and a therapeutic target in, autoimmune disease.Journal of Experimental Medicine 11/2011; 208(13):2591-8. DOI:10.1084/jem.20110978 · 13.91 Impact Factor