Regulatory B cells, allergic diseases and Autoimmune Diseases.

Regulatory B cells, allergic diseases and Autoimmune Diseases.

Widodo Judarwanto. Children Allergy Online Clinic, Jakarta Indonesia

B cells positively regulate immune responses through antibody production and optimal CD4(+) T cell activation. However, a specific and functionally important subset of B cells can also negatively regulate immune responses in mouse autoimmunity and inflammation models. The lack or loss of regulatory B cells has been demonstrated by exacerbated symptoms in experimental autoimmune encephalitis, chronic colitis, contact hypersensitivity, collagen-induced arthritis, and non-obese diabetic mouse models.

IL-10-producing regulatory B cells predominantly localize within a rare CD1d(hi)CD5(+) B cell subset that shares cell surface markers with both B-1 and marginal zone B cells. We have labeled this specific subset of regulatory B cells as B10 cells to highlight that these rare CD1d(hi)CD5(+) B cells only produce IL-10 and are responsible for most IL-10 production by B cells, and to distinguish them from other regulatory B cell subsets that may also exist. The recent progress in this field and the exciting opportunities for understanding how this unique B cell subset influences diverse immune functions.

Regulatory B cells as inhibitors of immune responses and inflammation

B cells positively regulate immune responses through antibody production and optimal CD4(+) T-cell activation. However, a specific and functionally important subset of B cells can also negatively regulate immune responses in mouse autoimmunity and inflammation models. The lack or loss of regulatory B cells has been demonstrated by exacerbated symptoms in experimental autoimmune encephalitis, chronic colitis, contact hypersensitivity, collagen-induced arthritis, and non-obese diabetic mouse models.

Accumulating evidence suggests that B cells exert their regulatory role through the production of interleukin-10 (IL-10) by either B-1, marginal zone (MZ), or transitional 2-MZ precursor B-cell subsets. We have recently found that IL-10-producing regulatory B cells predominantly localize within a rare CD1d(hi)CD5(+) B-cell subset that shares cell surface markers with both B-1 and MZ B cells. This specific subset of regulatory B cells as B10 cells to highlight that these rare CD1d(hi)CD5(+) B cells only produce IL-10 and are responsible for most IL-10 production by B cells and to distinguish them from other regulatory B-cell subsets that may also exist. The recent progress in this field and the exciting opportunities for understanding how this unique B-cell subset influences diverse immune functions.

Regulatory B cells and allergic diseases.

B cells are generally considered to positively regulate immune responses by producing antigen-specific antibodies. B cells are classified into classical CD5(-) conventional B cells and CD5(+) B1 cells. The latter produce multi-specific autoantibodies and are thought to be involved in autoimmune diseases.

However, evidence supporting a B cell negative regulatory function has accumulated over the past 30 years. Multiple reports have suggested that absence, or loss, of regulatory B cells exacerbates symptoms of both allergic (including contact hypersensitivity and anaphylaxis) and autoimmune (such as experimental autoimmune encephalomyelitis, chronic colitis, and collagen-induced arthritis) diseases, and in lupus-like models of autoimmunity.

Regulatory B cells are characterized by production of the negative regulatory cytokines, IL-10 and TGF-β. IL-10-producing B cells were the first regulatory B cells to be recognized and were termed ‘B10′ cells. IL-10-producing regulatory B cells are of the CD19(+)CD5(+)IgM(hi)IgD(lo)CD1d(hi) type. Recently, a TGF-β-producing regulatory B cell subset, Br3, has been shown to be related to immune tolerance in food allergies. Moreover, forkhead box P3 (Foxp3)-expressing B cells have also been identified in humans and may act as regulatory B cells (Bregs). The functional image of regulatory B cells is similar to that of regulatory T cells. Because of the proliferative and apoptotic responses of Br1 and Br3 cells in immune tolerance in non-IgE-mediated food allergy, reciprocal roles and counter-regulatory mechanisms of Br1 and Br3 responses are also suspected. Additionally, different roles for regulatory B and T cells at different time points during initiation and progression of autoimmune disease are described.

Regulatory B cells in skin and connective tissue diseases

While B cells are generally considered to be positive regulators of humoral immune responses due to their ability to differentiate into plasmablasts/plasma cells and produce antibodies, B cells also modulate immune responses through antigen presentation and cytokine secretion. Moreover, “regulatory B cells” that suppress immune responses have been recognized as an important new component of the immune system. In mice, the function of regulatory B cells is almost exclusively dependent on IL-10. The cell-surface phenotype of murine IL-10-producing regulatory B cells is reported to be CD1d(hi)CD5(+) or CD1d(hi)CD21(hi)CD23(+)IgM(hi), and thus their phenotype overlaps with that of CD5(+) B-1a cells, CD1d(hi)CD21(hi)CD23(lo)IgM(hi) marginal zone (MZ) B cells, and CD1d(hi)CD21(hi)CD23(hi)IgM(hi) T2-MZ precursor B cells. Contrary to earlier work that suggested a minor role for B cells in contact hypersensitivity, regulatory B cells are now known to have a critical inhibitory functions in this type of immune response. Furthermore, studies using murine disease models have demonstrated that regulatory B cells play a significant role in autoimmune connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as organ-specific autoimmune diseases including experimental autoimmune encephalomyelitis and inflammatory bowel disease. In comparison to mouse regulatory B cells, little is known regarding their human counterparts. One recent study demonstrates that human CD19(+)CD24(hi)CD38(hi) B cells possess regulatory capacity. Clarifying the molecular mechanisms by which regulatory B cells suppress immune responses will be of great benefit in the development of new B cell-targeted therapeutic strategies.

Allergen-specific transforming growth factor-β-producing CD19+CD5+ regulatory B-cell (Br3) responses in eczematous cow’s milk allergy reaction

CD19(+)CD5(+) regulatory B cells produce transforming growth factor β (TGF-β) in both mouse and human B-cell leukemias. In this study, TGF-β was uniquely produced by normal human regulatory B cells. TGF-β-producing regulatory B-cell (Br3) responses were characterized through allergic responses to cow’s milk. In total, 10 subjects allergic to milk and 13 milk-tolerant subjects were selected following double-blinded, placebo-controlled food challenges. Their peripheral blood mononuclear cells were stimulated in vitro with casein.

Following allergen stimulation, the percentage of Br3s among CD5(+) B cells decreased from 11.5% ± 13.7% to 8.0% ± 9.6% (P = 0.042, n = 5) in the milk-allergy group and increased from 14.7% ± 15.6% to 18.9% ± 20.1% (P = 0.006, n = 7) in the milk-tolerant group. However, the numbers of Br3s increased only in the milk-tolerant group, from 1,954 ± 1,058 to 4,548 ± 1,846 per well (P = 0.026), whereas the numbers of Br3s in the milk-allergy group were unchanged [2,596 ± 823 to 2,777 ± 802 per well (P = 0.734)]. The numbers of apoptotic events were similar to the numbers of total Br3 responses. The percentage of non-TGF-β-producing CD5(+) B cells with apoptotic changes increased from 13.4% ± 17.1% to 16.4% ± 20.3% (P = 0.047, n = 5) in the milk-allergy group and remained unchanged [from 9.9% ± 11.9% to 9.3% ± 11.4% (P = 0.099, n = 7)] in the milk-tolerant group. Using carboxyfluorescein succinimidyl ester labeling,

The percentage of proliferating Br3s among CD5(+) B cells was unchanged [from 6.1% ± 2.8% to 6.4% ± 2.9% (P = 0.145)] in the milk-allergy group and increased from 6.8% ± 3.9% to 10.2% ± 5.3% (P = 0.024) in the milk-tolerant group. In conclusion, Br3s proliferated in response to allergen stimulation in the milk-tolerant group and not in the milk-allergy group. TGF-β-producing regulatory B cells (Br3) may be involved in allergy tolerance by negatively regulating the immune system with TGF-β, and this negative regulation may be controlled by apoptosis.

Regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer

The ability of B cells to negatively regulate cellular immune responses and inflammation has only recently been described. Hallmark papers from a number of distinguished laboratories have identified phenotypically diverse B-cell subsets with regulatory functions during distinct autoimmune diseases, including IL-10-producing B cells, CD5+ B-1a cells, CD1d+ marginal zone B cells, and transitional-2-marginal zone precursor B cells.

Most recently, a numerically rare and phenotypically unique CD1dhiCD5+CD19hi subset of regulatory B cells has been identified in the spleens of both normal and autoimmune mice. CD1dhiCD5+ B cells with the capacity to produce IL-10 have been named B10 cells as they produce IL-10 exclusively and are the predominant B-cell source of IL-10. Remarkably, B10 cells are potent negative regulators of inflammation and autoimmunity in mouse models of disease in vivo.

B10-cell development and function is reviewed in the context of previous studies that have identified and characterized regulatory B cells, emerging evidence for B10-cell regulation of tumor immunity, and the likelihood that B10 cells exist in humans.

Regulatory B cells (B10 cells) have suppressive and B10 cell deficiency exacerbates systemic autoimmunity

B cells play critical roles in the pathogenesis of lupus. To examine the influence of B cells on disease pathogenesis in a murine lupus model, New Zealand Black and New Zealand White F(1) hybrid (NZB/W) mice were generated that were deficient for CD19 (CD19(-/-) NZB/W mice), a B cell-specific cell surface molecule that is essential for optimal B cell signal transduction.

The emergence of anti-nuclear Abs was significantly delayed in CD19(-/-) NZB/W mice compared with wild type NZB/W mice. However, the pathologic manifestations of nephritis appeared significantly earlier, and survival was significantly reduced in CD19(-/-) NZB/W mice compared with wild type mice. These results demonstrate both disease-promoting and protective roles for B cells in lupus pathogenesis. Recent studies have identified a potent regulatory B cell subset (B10 cells) within the rare CD1d(hi)CD5(+) B cell subset of the spleen that regulates acute inflammation and autoimmunity through the production of IL-10. In wild type NZB/W mice, the CD1d(hi)CD5(+)B220(+) B cell subset that includes B10 cells was increased by 2.5-fold during the disease course, whereas CD19(-/-) NZB/W mice lacked this CD1d(hi)CD5(+) regulatory B cell subset. However, the transfer of splenic CD1d(hi)CD5(+) B cells from wild type NZB/W mice into CD19(-/-) NZB/W recipients significantly prolonged their survival.

Regulatory T cells were significantly decreased in CD19(-/-) NZB/W mice, but the transfer of wild type CD1d(hi)CD5(+) B cells induced T regulatory cell expansion in CD19(-/-) NZB/W mice. These results demonstrate an important protective role for regulatory B10 cells in this systemic autoimmune disease.

Protective and pathogenic roles for B cells during systemic autoimmunity

Delineating the relative contributions of B lymphocytes during the course of autoimmune disease has been difficult. Therefore, the effects of depleting all mature B cells using a potent CD20 mAb, or of depleting circulating and marginal zone B cells using a ligand-blocking CD22 mAb, were compared in NZB/W F(1) mice, a model for human systemic lupus erythematosus. Single low-dose mAb treatments depleted B cells efficiently in both NZB/W F(1) and C57BL/6 mice.

Prophylactic B cell depletion by repeated CD20 mAb treatments prolonged survival during pristane-accelerated lupus in NZB/W F(1) mice, whereas CD22 mAb had little effect. Despite effective B cell depletion, neither mAb treatment prevented autoantibody generation. In addition, CD20, CD22, and control mAb-treated NZB/W F(1) mice developed anti-mouse IgG autoantibodies in contrast to parental NZB and NZW strains, which may have reduced the effectiveness of B cell depletion. Despite this, low-dose CD20 mAb treatment initiated in 12-28-wk-old mice, and administered every 4 wk thereafter, significantly delayed spontaneous disease in NZB/W F(1) mice. By contrast, B cell depletion initiated in 4-wk-old mice hastened disease onset, which paralleled depletion of the IL-10-producing regulatory B cell subset called B10 cells. B10 cells were phenotypically similar in NZB/W F(1) and C57BL/6 mice, but were expanded significantly in young NZB/W F(1) mice. Thus, B cell depletion had significant effects on NZB/W F(1) mouse survival that were dependent on the timing of treatment initiation. Therefore, distinct B cell populations can have opposing protective and pathogenic roles during lupus progression.

Regulatory B cells (B10 cells) roles in controlling experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a T lymphocyte-mediated autoimmune disease of the CNS. Significant roles for B cells and a rare IL-10-producing CD1d(high)CD5(+) regulatory B cell subset (B10 cells) have been identified during the initiation and progression of EAE. Whether and how the regulatory functions of B10 cells and FoxP3(+) T regulatory cells (Tregs) overlap or influence EAE immunopathogenesis independently has remained unanswered.

This study demonstrates that the number of endogenous or adoptively transferred B10 cells directly influenced EAE pathogenesis through their production of IL-10. B10 cell numbers expanded quickly within the spleen, but not CNS following myelin oligodendrocyte glycoprotein(35-55) immunization, which paralleled B10 cell regulation of disease initiation. The adoptive transfer of myelin oligodendrocyte glycoprotein(33-35)-sensitized B10 cells into wild-type mice reduced EAE initiation dramatically. However, B10 cells did not suppress ongoing EAE disease. Rather, Treg numbers expanded significantly within the CNS during disease progression, which paralleled their negative regulation of late-phase disease. Likewise, the preferential depletion of B10 cells in vivo during disease initiation enhanced EAE pathogenesis, whereas Treg depletion enhanced late-phase disease. B10 cells did not regulate T cell proliferation during in vitro assays, but significantly altered CD4(+) T cell IFN-gamma and TNF-alpha production. Furthermore, B10 cells downregulated the ability of dendritic cells to act as APCs and thereby indirectly modulated T cell proliferation.

B10 cells predominantly control disease initiation, whereas Tregs reciprocally inhibit late-phase disease, with overlapping B10 cell and Treg functions shaping the normal course of EAE immunopathogenesis.

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