B Cell Depletion Enhances T Regulatory Cell Activity Essential in the Suppression of Arthritis

Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2011; 187(9):4900-6. DOI: 10.4049/jimmunol.1101844
Source: PubMed


The efficacy of B cell-depletion therapy in rheumatoid arthritis has driven interest in understanding the mechanism. Because the decrease in autoantibodies in rheumatoid arthritis does not necessarily correlate with clinical outcome, other mechanisms may be operative. We previously reported that in proteoglycan-induced arthritis (PGIA), B cell-depletion inhibits autoreactive T cell responses. Recent studies in B cell-depletion therapy also indicate a role for B cells in suppressing regulatory mechanisms. In this study, we demonstrate that B cells inhibited both the expansion and function of T regulatory (Treg) cells in PGIA. Using an anti-CD20 mAb, we depleted B cells from mice with PGIA and assessed the Treg cell population. Compared to control Ab-treated mice, Treg cell percentages were elevated in B cell-depleted mice, with a higher proportion of CD4(+) T cells expressing Foxp3 and CD25. On a per-cell basis, CD4(+)CD25(+) cells from B cell-depleted mice expressed increased amounts of Foxp3 and were significantly more suppressive than those from control Ab-treated mice. The depletion of Treg cells with an anti-CD25 mAb concurrent with B cell-depletion therapy restored the severity of PGIA to levels equal to untreated mice. Although titers of autoantibodies did not recover to untreated levels, CD4(+) T cell recall responses to the immunizing Ag returned as measured by T cell proliferation and cytokine production. Thus, B cells have the capacity to regulate inflammatory responses by enhancing effector T cells along with suppressing Treg cells.

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    • "This may have lead to the development of long-lived antigenspecific plasma cells that would not be affected by the anti-CD20 therapy. The anti-CD20 dose we used was comparable to other murine studies that demonstrated B cell depletion with some studies depleting essentially all splenic B cells [27] [28]. Our experimental system resulted in only an 80% reduction of B cells in the spleen. "
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    ABSTRACT: Anti-CD20 depletion therapies targeting B cells are commonly used in malignant B cell disease and auto-immune diseases. There are concerns about the ability of B cells to respond to infectious diseases acquired either before or after B cell depletion. There is evidence that the B cell response to existing or acquired viral infections is compromised during treatment, as well as the antibody response to vaccination. Our laboratory has an experimental system using co-infection of C3H mice with both Leishmania major and Leishmania amazonensis that suggests that the B cell response is important to healing infected mice. We tested if anti-CD20 treatment would completely restrict the B cell response to these intracellular pathogens. Infected mice that received anti-CD20 B cell depletion therapy had a significant decrease in CD19 + cells within their lymph nodes and spleens. However, splenic B cells were detected in depleted mice and an antigen-specific antibody response was produced. These results indicate that an antigen-specific B cell response towards intracellular pathogens can be generated during anti-CD20 depletion therapy.
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    • "Thus, BAFF may affect Tregs in an indirect way. BAFF receptors were mainly expressed on B cells and it was reported that resting B cells can expand and maintain specific Tregs (17, 18), while activated B cells may involve inhibition of Treg function in an IL-2-dependent way (19, 20). Moreover, activated T cells also express the BAFF receptors TACI (21) and BR3 (22, 23). "
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    ABSTRACT: Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.
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