Regulatory B cells that produce IL-10: A breath of fresh air in allergic airway disease
2010; Elsevier BV; Volume: 125; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2010.03.024
ISSN1097-6825
AutoresThomas F. Tedder, Takashi Matsushita,
Tópico(s)Allergic Rhinitis and Sensitization
ResumoIn this issue of the Journal, Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar demonstrate a significant role for IL-10–producing regulatory B (Breg) cells during murine models of allergic airway inflammation. The authors identified a Breg cell subpopulation that expands in vivo and in vitro in response to parasitic Schistosoma mansoni worm infection. The adoptive transfer of these Breg cells into allergen-sensitized mice suppresses anaphylaxis and allergen-induced airway hyperresponsiveness through IL-10–dependent mechanisms.1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar, 2Mangan N.E. Fallon R.E. Smith P. van Rooijen N. McKenzie A.N. Fallon P.G. Helminth infection protects mice from anaphylaxis via IL-10-producing B cells.J Immunol. 2004; 173: 6346-6356PubMed Google Scholar These important findings expand the clinical significance of studies showing that IL-10–competent Breg cells dramatically regulate inflammation and autoimmunity in murine models of contact hypersensitivity,3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar experimental autoimmune encephalomyelitis,4Fillatreau S. Sweenie C.H. McGeachy M.J. Gray D. Anderton S.M. B cells regulate autoimmunity by provision of IL-10.Nat Immunol. 2002; 3: 944-950Crossref PubMed Scopus (1274) Google Scholar, 5Matsushita T. Yanaba K. Bouaziz J.-D. Fujimoto M. Tedder T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.J Clin Invest. 2008; 118: 3420-3430PubMed Google Scholar collagen-induced arthritis,6Mauri C. Gray D. Mushtaq N. Londei M. Prevention of arthritis by interleukin 10-producing B cells.J Exp Med. 2003; 197: 489-501Crossref PubMed Scopus (699) Google Scholar and inflammatory bowel disease.7Mizoguchi A. Mizoguchi E. Takedatsu H. Blumberg R.S. Bhan A.K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation.Immunity. 2002; 16: 219-230Abstract Full Text Full Text PDF PubMed Scopus (750) Google ScholarThese studies focus on a relatively rare IL-10–competent murine B-cell subset that represents only 1% to 2% of splenic B cells in naive wild-type mice.8DiLillo D.J. Matsushita T. Tedder T.F. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer.Ann N Y Acad Sci. 2010; 1183: 38-57Crossref PubMed Scopus (350) Google Scholar We call these cells "B10 cells" because IL-10 secretion is universally recognized as their mechanism of regulatory function, they only produce IL-10 transcripts,3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar, 9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar and multiple other B-cell subsets with regulatory properties are likely to exist. B10 cells are predominantly contained within a phenotypically unique CD1dhiCD5+CD19hi B-cell subpopulation that normally represents only 2% to 7% of splenic B cells.3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar B10 cells appear to be functionally mature because they can be identified based on cytoplasmic IL-10 expression after only 5 hours of in vitro stimulation with phorbol 12-myristate 13-acetate and ionomycin. B10 progenitor (B10pro) cells have also been functionally identified within the splenic CD1dhiCD5+ B-cell subpopulation, but these cells require 48 hours of in vitro stimulation through CD40 or with LPS before they acquire the ability to express cytoplasmic IL-10 after 5 hours of phorbol 12-myristate 13-acetate and ionomycin stimulation.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar, 10Yanaba K. Bouaziz J.D. Matsushita T. Magro C.M. St Clair E.W. Tedder T.F. B-lymphocyte contributions to human autoimmune disease.Immunol Rev. 2008; 223: 284-299Crossref PubMed Scopus (269) Google Scholar Therefore purifying splenic CD1dhi or CD1dhiCD5+ B cells enriches for functionally potent B10 and B10pro cells that can be adoptively transferred into recipient mice to shift the normal balance of regulatory networks toward a more immunosuppressive phenotype.Parasitic infections with S mansoni worms in the current study drives both B-cell and B10-cell expansion in mice (Fig 1).1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar Transferring splenic CD1dhi B cells from worm-infected mice into ovalbumin (allergen)–challenged recipients inhibits both acute and established airway inflammation. Most likely, B10 cells expand more than other B cells in vivo because they proliferate more vigorously in response to polyclonal mitogens when compared with non-B10 cells.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar Because antigen-specific B10 cells are required to inhibit contact hypersensitivity and autoimmunity,3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar, 5Matsushita T. Yanaba K. Bouaziz J.-D. Fujimoto M. Tedder T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.J Clin Invest. 2008; 118: 3420-3430PubMed Google Scholar it is unlikely that worm antigen-specific B10 cells would inhibit ovalbumin-driven disease. Thus it will be important to determine whether S mansoni worms are driving polyclonal, antigen-specific, or cross-reactive B10- and B10pro-cell expansion/maturation. It will also be important to determine whether worm-driven B10-cell expansion can regulate contact hypersensitivity and autoimmunity. Regardless, helminth-driven B10-cell expansion supports the "hygiene hypothesis," whereby a decrease in helminth infections within a population is proposed to increase allergic disease incidence.11Yazdanbakhsh M. Kremsner P.G. van Ree R. Allergy, parasites, and the hygiene hypothesis.Science. 2002; 296: 490-494Crossref PubMed Scopus (1181) Google Scholar Thus B10-cell function and relative frequencies might also be important factors contributing to human allergic diseases.The authors propose to have identified a distinct IL-10+CD1dhiCD21hiCD23+IgD+IgMhiCD19+ splenic Breg cell subpopulation. However, there are currently no cell-surface markers that uniquely delineate all IL-10–competent B10 cells or B10pro cells. Rather, the ability of B10 cells to produce IL-10 is the single functional marker that unifies most current studies and identifies a population of cells with a fairly homogenous cell-surface phenotype.3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar Isolating B cells based on IL-10 expression alone is technically problematic because this selects for either IL-10–secreting cells or cytoplasmic IL-10+ cells that must be permeabilized, whereas functionally important B10pro cells are lost with these methods. Moreover, IL-10 competence is most frequently measured after phorbol 12-myristate 13-acetate and ionophore stimulation in vitro. As shown by Amu et al,1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar single markers, such as CD1dhi, CD21hi, CD23+, IgDlow, or IgMhi, could be used to enrich for B10 cells, but they also exclude a substantial proportion of functionally competent B10 cells that are then diluted within the remaining nonselected B-cell population. IL-10–competent B cells found within other murine tissues also differently express some of these cell-surface markers.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar Despite these technical issues, most studies within the evolving Breg cell field are likely to be examining the same rare and functionally unique B10- and B10pro-cell subset that regulates immune responses through the production of IL-10.B cells contribute to asthma pathogenesis by producing IgE.12Boyce J.A. Broide D. Matsumoto K. Bochner B.S. Advances in mechanisms of asthma, allergy, and immunology in 2008.J Allergy Clin Immunol. 2009; 123: 569-574Abstract Full Text Full Text PDF Scopus (35) Google Scholar However, Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar also identified B-cell subsets that either exacerbated or regulated allergic airway inflammation (Fig 1). Although most B cells express CD1d, a splenic CD1dlow B-cell subset was expanded in helminth-infected mice. Asthma was exacerbated when these CD1dlow B cells were adoptively transferred into allergen-sensitized mice. Although it was not determined whether these B cells contributed to IgE production, the future characterization of these cells might reveal a novel B-cell subset that preferentially contributes to disease pathogenesis through unknown mechanisms. Distinct B-cell subsets with opposing pathogenic and negative regulatory functions have also been observed during experimental autoimmune encephalomyelitis pathogenesis in mice.5Matsushita T. Yanaba K. Bouaziz J.-D. Fujimoto M. Tedder T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.J Clin Invest. 2008; 118: 3420-3430PubMed Google Scholar Mature B-cell depletion with CD20 mAb before experimental autoimmune encephalomyelitis induction exacerbates subsequent disease, whereas B-cell depletion during experimental autoimmune encephalomyelitis progression dramatically reduces disease symptoms. Exacerbated autoimmune disease results from B10-cell depletion before disease initiation, which is ameliorated by the adoptive transfer of splenic CD1dhiCD5+ B cells. B10 cells and other B cells have also been found to have opposing protective and pathogenic functions during murine models of systemic lupus erythematosus, respectively.13Haas K.M. Watanabe R. Matsushita T. Nakashima H. Ishiura N. Okochi H. et al.Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice.J Immunol. 2010; (In press)Google Scholar, 14Watanabe R. Ishiura N. Nakashima H. Kuwano Y. Okochi H. Tamaki K. et al.Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity.J Immunol. 2010; (In press)Google Scholar Therefore different B-cell subsets might display opposing protective and pathogenic functions during human asthma because B-cell depletion might improve atopic eczema.15Simon D. Hösli S. Kostylina G. Yawalkar N. Simon H.U. Anti-CD20 (rituximab) treatment improves atopic eczema.J Allergy Clin Immunol. 2008; 121: 122-128Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Thus future murine and patient studies are needed to further uncover the likely complexities of B-cell function during different stages of airway immunopathology.Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar demonstrate that IL-10 production by CD1dhi B cells is required to observe their regulatory effects, and they show that S mansoni–infected CD1d-deficient mice are highly susceptible to allergic airway inflammation. However, it remains essential to determine whether B-cell CD1d expression is required for B10- or B10pro-cell function because CD1d expression is not required for B10-cell development.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar Multiple leukocyte lineages and subsets produce IL-10, and the mechanisms by which IL-10 can inhibit or augment immune responses are equally complex. However, Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar propose that adoptively transferred CD1dhi B cells suppress airway inflammation by inducing natural forkhead box protein 3–positve CD4+ regulatory T (Treg) cell recruitment into the lungs, where they suppress lung inflammation (Fig 1). Whether B10 cells must enter the lung to induce these changes or whether they can exert these effects distally remains unknown. It is also unknown whether B10 cells actually control Treg cell migration or whether enhanced Treg cell emigration into the lung is an indirect consequence of reduced inflammation. Nonetheless, Treg cell numbers are significantly decreased in CD19-deficient NZB/W mice that have few B10 cells, whereas wild-type CD1dhiCD5+ B cells transferred into CD19−/− NZB/W mice induce Treg cell expansion.14Watanabe R. Ishiura N. Nakashima H. Kuwano Y. Okochi H. Tamaki K. et al.Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity.J Immunol. 2010; (In press)Google Scholar These independent studies suggest a potential link between B10-cell function and Treg cell frequencies that needs to be explored.Multiple laboratories have demonstrated that Breg cells are functionally significant in diverse diseases. It will be important to determine whether other parasites and infectious agents also drive B10-cell expansion as a potential mechanism for reducing host immune responses. This will further open the door for identifying B10 cell–directed therapies. Turning these laboratory observations into therapeutic targets for modulating immune responses and pathology will be a significant but important challenge for the future. In this issue of the Journal, Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar demonstrate a significant role for IL-10–producing regulatory B (Breg) cells during murine models of allergic airway inflammation. The authors identified a Breg cell subpopulation that expands in vivo and in vitro in response to parasitic Schistosoma mansoni worm infection. The adoptive transfer of these Breg cells into allergen-sensitized mice suppresses anaphylaxis and allergen-induced airway hyperresponsiveness through IL-10–dependent mechanisms.1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar, 2Mangan N.E. Fallon R.E. Smith P. van Rooijen N. McKenzie A.N. Fallon P.G. Helminth infection protects mice from anaphylaxis via IL-10-producing B cells.J Immunol. 2004; 173: 6346-6356PubMed Google Scholar These important findings expand the clinical significance of studies showing that IL-10–competent Breg cells dramatically regulate inflammation and autoimmunity in murine models of contact hypersensitivity,3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar experimental autoimmune encephalomyelitis,4Fillatreau S. Sweenie C.H. McGeachy M.J. Gray D. Anderton S.M. B cells regulate autoimmunity by provision of IL-10.Nat Immunol. 2002; 3: 944-950Crossref PubMed Scopus (1274) Google Scholar, 5Matsushita T. Yanaba K. Bouaziz J.-D. Fujimoto M. Tedder T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.J Clin Invest. 2008; 118: 3420-3430PubMed Google Scholar collagen-induced arthritis,6Mauri C. Gray D. Mushtaq N. Londei M. Prevention of arthritis by interleukin 10-producing B cells.J Exp Med. 2003; 197: 489-501Crossref PubMed Scopus (699) Google Scholar and inflammatory bowel disease.7Mizoguchi A. Mizoguchi E. Takedatsu H. Blumberg R.S. Bhan A.K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation.Immunity. 2002; 16: 219-230Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar These studies focus on a relatively rare IL-10–competent murine B-cell subset that represents only 1% to 2% of splenic B cells in naive wild-type mice.8DiLillo D.J. Matsushita T. Tedder T.F. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer.Ann N Y Acad Sci. 2010; 1183: 38-57Crossref PubMed Scopus (350) Google Scholar We call these cells "B10 cells" because IL-10 secretion is universally recognized as their mechanism of regulatory function, they only produce IL-10 transcripts,3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar, 9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar and multiple other B-cell subsets with regulatory properties are likely to exist. B10 cells are predominantly contained within a phenotypically unique CD1dhiCD5+CD19hi B-cell subpopulation that normally represents only 2% to 7% of splenic B cells.3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar B10 cells appear to be functionally mature because they can be identified based on cytoplasmic IL-10 expression after only 5 hours of in vitro stimulation with phorbol 12-myristate 13-acetate and ionomycin. B10 progenitor (B10pro) cells have also been functionally identified within the splenic CD1dhiCD5+ B-cell subpopulation, but these cells require 48 hours of in vitro stimulation through CD40 or with LPS before they acquire the ability to express cytoplasmic IL-10 after 5 hours of phorbol 12-myristate 13-acetate and ionomycin stimulation.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar, 10Yanaba K. Bouaziz J.D. Matsushita T. Magro C.M. St Clair E.W. Tedder T.F. B-lymphocyte contributions to human autoimmune disease.Immunol Rev. 2008; 223: 284-299Crossref PubMed Scopus (269) Google Scholar Therefore purifying splenic CD1dhi or CD1dhiCD5+ B cells enriches for functionally potent B10 and B10pro cells that can be adoptively transferred into recipient mice to shift the normal balance of regulatory networks toward a more immunosuppressive phenotype. Parasitic infections with S mansoni worms in the current study drives both B-cell and B10-cell expansion in mice (Fig 1).1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar Transferring splenic CD1dhi B cells from worm-infected mice into ovalbumin (allergen)–challenged recipients inhibits both acute and established airway inflammation. Most likely, B10 cells expand more than other B cells in vivo because they proliferate more vigorously in response to polyclonal mitogens when compared with non-B10 cells.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar Because antigen-specific B10 cells are required to inhibit contact hypersensitivity and autoimmunity,3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar, 5Matsushita T. Yanaba K. Bouaziz J.-D. Fujimoto M. Tedder T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.J Clin Invest. 2008; 118: 3420-3430PubMed Google Scholar it is unlikely that worm antigen-specific B10 cells would inhibit ovalbumin-driven disease. Thus it will be important to determine whether S mansoni worms are driving polyclonal, antigen-specific, or cross-reactive B10- and B10pro-cell expansion/maturation. It will also be important to determine whether worm-driven B10-cell expansion can regulate contact hypersensitivity and autoimmunity. Regardless, helminth-driven B10-cell expansion supports the "hygiene hypothesis," whereby a decrease in helminth infections within a population is proposed to increase allergic disease incidence.11Yazdanbakhsh M. Kremsner P.G. van Ree R. Allergy, parasites, and the hygiene hypothesis.Science. 2002; 296: 490-494Crossref PubMed Scopus (1181) Google Scholar Thus B10-cell function and relative frequencies might also be important factors contributing to human allergic diseases. The authors propose to have identified a distinct IL-10+CD1dhiCD21hiCD23+IgD+IgMhiCD19+ splenic Breg cell subpopulation. However, there are currently no cell-surface markers that uniquely delineate all IL-10–competent B10 cells or B10pro cells. Rather, the ability of B10 cells to produce IL-10 is the single functional marker that unifies most current studies and identifies a population of cells with a fairly homogenous cell-surface phenotype.3Yanaba K. Bouaziz J.-D. Haas K.M. Poe J.C. Fujimoto M. Tedder T.F. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses.Immunity. 2008; 28: 639-650Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar Isolating B cells based on IL-10 expression alone is technically problematic because this selects for either IL-10–secreting cells or cytoplasmic IL-10+ cells that must be permeabilized, whereas functionally important B10pro cells are lost with these methods. Moreover, IL-10 competence is most frequently measured after phorbol 12-myristate 13-acetate and ionophore stimulation in vitro. As shown by Amu et al,1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar single markers, such as CD1dhi, CD21hi, CD23+, IgDlow, or IgMhi, could be used to enrich for B10 cells, but they also exclude a substantial proportion of functionally competent B10 cells that are then diluted within the remaining nonselected B-cell population. IL-10–competent B cells found within other murine tissues also differently express some of these cell-surface markers.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar Despite these technical issues, most studies within the evolving Breg cell field are likely to be examining the same rare and functionally unique B10- and B10pro-cell subset that regulates immune responses through the production of IL-10. B cells contribute to asthma pathogenesis by producing IgE.12Boyce J.A. Broide D. Matsumoto K. Bochner B.S. Advances in mechanisms of asthma, allergy, and immunology in 2008.J Allergy Clin Immunol. 2009; 123: 569-574Abstract Full Text Full Text PDF Scopus (35) Google Scholar However, Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar also identified B-cell subsets that either exacerbated or regulated allergic airway inflammation (Fig 1). Although most B cells express CD1d, a splenic CD1dlow B-cell subset was expanded in helminth-infected mice. Asthma was exacerbated when these CD1dlow B cells were adoptively transferred into allergen-sensitized mice. Although it was not determined whether these B cells contributed to IgE production, the future characterization of these cells might reveal a novel B-cell subset that preferentially contributes to disease pathogenesis through unknown mechanisms. Distinct B-cell subsets with opposing pathogenic and negative regulatory functions have also been observed during experimental autoimmune encephalomyelitis pathogenesis in mice.5Matsushita T. Yanaba K. Bouaziz J.-D. Fujimoto M. Tedder T.F. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression.J Clin Invest. 2008; 118: 3420-3430PubMed Google Scholar Mature B-cell depletion with CD20 mAb before experimental autoimmune encephalomyelitis induction exacerbates subsequent disease, whereas B-cell depletion during experimental autoimmune encephalomyelitis progression dramatically reduces disease symptoms. Exacerbated autoimmune disease results from B10-cell depletion before disease initiation, which is ameliorated by the adoptive transfer of splenic CD1dhiCD5+ B cells. B10 cells and other B cells have also been found to have opposing protective and pathogenic functions during murine models of systemic lupus erythematosus, respectively.13Haas K.M. Watanabe R. Matsushita T. Nakashima H. Ishiura N. Okochi H. et al.Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice.J Immunol. 2010; (In press)Google Scholar, 14Watanabe R. Ishiura N. Nakashima H. Kuwano Y. Okochi H. Tamaki K. et al.Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity.J Immunol. 2010; (In press)Google Scholar Therefore different B-cell subsets might display opposing protective and pathogenic functions during human asthma because B-cell depletion might improve atopic eczema.15Simon D. Hösli S. Kostylina G. Yawalkar N. Simon H.U. Anti-CD20 (rituximab) treatment improves atopic eczema.J Allergy Clin Immunol. 2008; 121: 122-128Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Thus future murine and patient studies are needed to further uncover the likely complexities of B-cell function during different stages of airway immunopathology. Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar demonstrate that IL-10 production by CD1dhi B cells is required to observe their regulatory effects, and they show that S mansoni–infected CD1d-deficient mice are highly susceptible to allergic airway inflammation. However, it remains essential to determine whether B-cell CD1d expression is required for B10- or B10pro-cell function because CD1d expression is not required for B10-cell development.9Yanaba K. Bouaziz J.-D. Matsushita T. Tasubata T. Tedder T.F. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals.J Immunol. 2009; 182: 7459-7472Crossref PubMed Scopus (392) Google Scholar Multiple leukocyte lineages and subsets produce IL-10, and the mechanisms by which IL-10 can inhibit or augment immune responses are equally complex. However, Amu et al1Amu S. Saunders S.P. Kronenberg M. Mangan N.E. Atzberger A. Fallon P.G. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model.J Allergy Clin Immunol. 2010; : 1114-1124Abstract Full Text Full Text PDF Scopus (299) Google Scholar propose that adoptively transferred CD1dhi B cells suppress airway inflammation by inducing natural forkhead box protein 3–positve CD4+ regulatory T (Treg) cell recruitment into the lungs, where they suppress lung inflammation (Fig 1). Whether B10 cells must enter the lung to induce these changes or whether they can exert these effects distally remains unknown. It is also unknown whether B10 cells actually control Treg cell migration or whether enhanced Treg cell emigration into the lung is an indirect consequence of reduced inflammation. Nonetheless, Treg cell numbers are significantly decreased in CD19-deficient NZB/W mice that have few B10 cells, whereas wild-type CD1dhiCD5+ B cells transferred into CD19−/− NZB/W mice induce Treg cell expansion.14Watanabe R. Ishiura N. Nakashima H. Kuwano Y. Okochi H. Tamaki K. et al.Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity.J Immunol. 2010; (In press)Google Scholar These independent studies suggest a potential link between B10-cell function and Treg cell frequencies that needs to be explored. Multiple laboratories have demonstrated that Breg cells are functionally significant in diverse diseases. It will be important to determine whether other parasites and infectious agents also drive B10-cell expansion as a potential mechanism for reducing host immune responses. This will further open the door for identifying B10 cell–directed therapies. Turning these laboratory observations into therapeutic targets for modulating immune responses and pathology will be a significant but important challenge for the future. We thank Drs Cynthia Magro, David DiLillo, Michelle Schweitzer, Jonathan Poe, and Susan Smith for their comments. Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine modelJournal of Allergy and Clinical ImmunologyVol. 125Issue 5PreviewParasitic helminth infections of humans have been shown to suppress the immune response to allergens. Experimentally, infection of mice with the helminth Schistosoma mansoni prevents allergic airway inflammation and anaphylaxis via IL-10 and B cells. Full-Text PDF
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