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• W2013136108 abstract "Atopic dermatitis is an inflammatory cutaneous disorder characterized by dry skin and relapsing eczematous skin lesions. Besides antibody production, the contribution of B cells to the pathogenesis of atopic dermatitis is unclear. In mice, repeated epicutaneous sensitization with ovalbumin induces inflamed skin lesions resembling human atopic dermatitis and therefore serves as an experimental model for this condition. To investigate the role of B cells in a murine model of atopic dermatitis, ovalbumin-sensitized allergic skin inflammation was assessed in mice lacking CD19. In ovalbumin-sensitized skin from CD19-deficient mice, the number of eosinophils and CD4+ T cells was reduced, and both epidermal and dermal thickening were decreased. Following in vitro stimulation with ovalbumin, CD19 deficiency significantly reduced the proliferation of CD4+, but not CD8+, T cells from spleen and draining lymph nodes. Furthermore, splenocytes and draining lymph node cells from ovalbumin-sensitized CD19-deficient mice secreted significantly less IL-4, IL-13, and IL-17 than ovalbumin-sensitized wild-type mice. These results suggest that CD19 expression in B cells plays a critical role in antigen-specific CD4+ T-cell proliferation and T helper 2 and 17 responses in a murine model of atopic dermatitis. Furthermore, the present findings may have implications for B-cell–targeted therapies for the treatment of atopic dermatitis. Atopic dermatitis is an inflammatory cutaneous disorder characterized by dry skin and relapsing eczematous skin lesions. Besides antibody production, the contribution of B cells to the pathogenesis of atopic dermatitis is unclear. In mice, repeated epicutaneous sensitization with ovalbumin induces inflamed skin lesions resembling human atopic dermatitis and therefore serves as an experimental model for this condition. To investigate the role of B cells in a murine model of atopic dermatitis, ovalbumin-sensitized allergic skin inflammation was assessed in mice lacking CD19. In ovalbumin-sensitized skin from CD19-deficient mice, the number of eosinophils and CD4+ T cells was reduced, and both epidermal and dermal thickening were decreased. Following in vitro stimulation with ovalbumin, CD19 deficiency significantly reduced the proliferation of CD4+, but not CD8+, T cells from spleen and draining lymph nodes. Furthermore, splenocytes and draining lymph node cells from ovalbumin-sensitized CD19-deficient mice secreted significantly less IL-4, IL-13, and IL-17 than ovalbumin-sensitized wild-type mice. These results suggest that CD19 expression in B cells plays a critical role in antigen-specific CD4+ T-cell proliferation and T helper 2 and 17 responses in a murine model of atopic dermatitis. Furthermore, the present findings may have implications for B-cell–targeted therapies for the treatment of atopic dermatitis. Atopic dermatitis (AD) is one of the most common inflammatory cutaneous disorders, characterized by dry, itchy skin and relapsing eczematous skin lesions, which affects approximately 15% to 30% of children and 2% to 10% of adults.1Bieber T. Atopic dermatitis.N Engl J Med. 2008; 358: 1483-1494Crossref PubMed Scopus (1589) Google Scholar Histologically, AD is characterized by epidermal and dermal thickening with marked infiltration of activated T cells, eosinophils, and monocytes/macrophages within the dermis.1Bieber T. Atopic dermatitis.N Engl J Med. 2008; 358: 1483-1494Crossref PubMed Scopus (1589) Google Scholar Approximately 60% to 90% of patients with AD show increased serum total IgE against environmental and/or food allergens.2Ponyai G. Hidvegi B. Nemeth I. Sas A. Temesvari E. Karpati S. Contact and aeroallergens in adulthood atopic dermatitis.J Eur Acad Dermatol Venereol. 2008; 22: 1346-1355Crossref PubMed Scopus (49) Google Scholar, 3Mori T. Ishida K. Mukumoto S. Yamada Y. Imokawa G. Kabashima K. Kobayashi M. Bito T. Nakamura M. Ogasawara K. Tokura Y. Comparison of skin barrier function and sensory nerve electric current perception threshold between IgE-high extrinsic and IgE-normal intrinsic types of atopic dermatitis.Br J Dermatol. 2010; 162: 83-90Crossref PubMed Scopus (61) Google Scholar, 4Ott H. Stanzel S. Ocklenburg C. Merk H.F. Baron J.M. Lehmann S. Total serum IgE as a parameter to differentiate between intrinsic and extrinsic atopic dermatitis in children.Acta Derm Venereol. 2009; 89: 257-261Crossref PubMed Scopus (52) Google Scholar In addition, the expression of T helper (Th) 2 cytokines, such as IL-4, IL-5, and IL-13, is increased in the acute skin lesions of AD,5Hamid Q. Boguniewicz M. Leung D.Y. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis.J Clin Invest. 1994; 94: 870-876Crossref PubMed Scopus (737) Google Scholar, 6Hamid Q. Naseer T. Minshall E.M. Song Y.L. Boguniewicz M. Leung D.Y. In vivo expression of IL-12 and IL-13 in atopic dermatitis.J Allergy Clin Immunol. 1996; 98: 225-231Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar suggesting that Th2 cells play critical roles in disease development. Skin barrier dysfunction is a critical feature of AD. Recent studies have shown that more than 10% of patients with AD have mutations in the filaggrin gene, which is important for skin barrier function.7Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. Goudie D.R. Sandilands A. Campbell L.E. Smith F.J. O’Regan G.M. Watson R.M. Cecil J.E. Bale S.J. Compton J.G. DiGiovanna J.J. Fleckman P. Lewis-Jones S. Arseculeratne G. Sergeant A. Munro C.S. El Houate B. McElreavey K. Halkjaer L.B. Bisgaard H. Mukhopadhyay S. McLean W.H. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.Nat Genet. 2006; 38: 441-446Crossref PubMed Scopus (2315) Google Scholar, 8Akiyama M. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics.Br J Dermatol. 2010; 162: 472-477Crossref PubMed Scopus (125) Google Scholar It has been hypothesized that a disrupted skin barrier facilitates antigen penetration and epicutaneous sensitization, leading to allergic skin inflammation in patients with AD.9Barnes K.C. An update on the genetics of atopic dermatitis: scratching the surface in 2009.J Allergy Clin Immunol. 2010; 125: 16-31Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar Moreover, IL-4 and IL-13 reduce filaggrin gene and protein expression in keratinocytes.10Howell M.D. Kim B.E. Gao P. Grant A.V. Boguniewicz M. Debenedetto A. Schneider L. Beck L.A. Barnes K.C. Leung D.Y. Cytokine modulation of atopic dermatitis filaggrin skin expression.J Allergy Clin Immunol. 2007; 120: 150-155Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar Thus, a genetic and/or acquired defect in filaggrin is likely to play an important role in the development of AD. In mice, repeated epicutaneous sensitization of tape-stripped skin with ovalbumin (OVA), mimicking epicutaneous allergen exposure to epidermal barrier dysfunction, was found to induce the appearance of inflamed pruritic skin lesions at the application site, as well as local and systemic Th2 responses. Because of the resemblance of these lesions to human AD,11Spergel J.M. Mizoguchi E. Oettgen H. Bhan A.K. Geha R.S. Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis.J Clin Invest. 1999; 103: 1103-1111Crossref PubMed Scopus (320) Google Scholar, 12Spergel J.M. Mizoguchi E. Brewer J.P. Martin T.R. Bhan A.K. Geha R.S. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice.J Clin Invest. 1998; 101: 1614-1622Crossref PubMed Scopus (542) Google Scholar this experimental method can serve as a convenient experimental model. Historically, B cells have been considered to mediate humoral immune responses by differentiating into antibody (Ab)-secreting plasma cells.13Yanaba 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 (275) Google Scholar However, recent studies have revealed that B cells also serve as antigen-presenting cells,14Kurt-Jones E.A. Liano D. HayGlass K.A. Benacerraf B. Sy M.S. Abbas A.K. The role of antigen-presenting B cells in T cell priming in vivo. Studies of B cell-deficient mice.J Immunol. 1988; 140: 3773-3778Crossref PubMed Google Scholar secrete a variety of cytokines,15Harris D.P. Haynes L. Sayles P.C. Duso D.K. Eaton S.M. Lepak N.M. Johnson L.L. Swain S.L. Lund F.E. Reciprocal regulation of polarized cytokine production by effector B and T cells.Nat Immunol. 2000; 1: 475-482Crossref PubMed Scopus (682) Google Scholar provide costimulatory signals, and promote T-cell activation.15Harris D.P. Haynes L. Sayles P.C. Duso D.K. Eaton S.M. Lepak N.M. Johnson L.L. Swain S.L. Lund F.E. Reciprocal regulation of polarized cytokine production by effector B and T cells.Nat Immunol. 2000; 1: 475-482Crossref PubMed Scopus (682) Google Scholar, 16Linton P.J. Bautista B. Biederman E. Bradley E.S. Harbertson J. Kondrack R.M. Padrick R.C. Bradley L.M. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo.J Exp Med. 2003; 197: 875-883Crossref PubMed Scopus (206) Google Scholar Moreover, IL-10–producing B cell subsets can inhibit innate and adaptive immune responses, inflammation, and autoimmunity, demonstrating the existence of regulatory B cells.13Yanaba 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 (275) Google Scholar, 17Bouaziz J.D. Yanaba K. Tedder T.F. Regulatory B cells as inhibitors of immune responses and inflammation.Immunol Rev. 2008; 224: 201-214Crossref PubMed Scopus (364) Google Scholar, 18Yanaba K. Yoshizaki A. Asano Y. Kadono T. Tedder T.F. Sato S. IL-10-producing regulatory B10 cells inhibit intestinal injury in a mouse model.Am J Pathol. 2011; 178: 735-743Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 19Yanaba 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 (1005) Google Scholar Thus, in addition to Ab production, B cells have multiple diverse immune functions. The fate and function of B cells are controlled by signal transduction through B-cell receptors, which are further modified by other cell-surface molecules, including CD19, CD21, CD22, CD40, CD72, and Fcγ receptor IIb.20Tsubata T. Co-receptors on B lymphocytes.Curr Opin Immunol. 1999; 11: 249-255Crossref PubMed Scopus (64) Google Scholar CD19 is a general rheostat that defines signaling thresholds critical for humoral immune responses and autoimmunity.21Tedder T.F. Inaoki M. Sato S. The CD19/21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity.Immunity. 1997; 6: 107-118Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar CD19 is a B-cell–specific cell-surface molecule of the Ig superfamily expressed by early pre-B cells in humans and mice until plasma cell differentiation.22Sato S. Steeber D.A. Jansen P.J. Tedder T.F. CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19.J Immunol. 1997; 158: 4662-4669Crossref PubMed Google Scholar, 23Sato S. Ono N. Steeber D.A. Pisetsky D.S. Tedder T.F. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity.J Immunol. 1996; 157: 4371-4378Crossref PubMed Google Scholar Human CD19 and mouse CD19 are functionally equivalent in vivo.22Sato S. Steeber D.A. Jansen P.J. Tedder T.F. CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19.J Immunol. 1997; 158: 4662-4669Crossref PubMed Google Scholar B cells from CD19-deficient (CD19−/−) mice are hyporesponsive to a variety of transmembrane signals, including B-cell receptor ligation.22Sato S. Steeber D.A. Jansen P.J. Tedder T.F. CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19.J Immunol. 1997; 158: 4662-4669Crossref PubMed Google Scholar CD20, a B-cell–specific cell-surface molecule involved in the regulation of B-cell activation and Ca2+ transport, is initially expressed by pre-B cells in humans and mice with continued expression until plasma cell differentiation.24Stashenko P. Nadler L.M. Hardy R. Schlossman S.F. Characterization of a human B lymphocyte-specific antigen.J Immunol. 1980; 125: 1678-1685Crossref PubMed Google Scholar, 25Uchida J. Lee Y. Hasegawa M. Liang Y. Bradney A. Oliver J.A. Bowen K. Steeber D.A. Haas K.M. Poe J.C. Tedder T.F. Mouse CD20 expression and function.Int Immunol. 2004; 16: 119-129Crossref PubMed Scopus (201) Google Scholar Although the role of B cells, besides Ab production, in the pathogenesis of AD remains unclear, B-cell depletion in humans with the chimeric human anti-CD20 monoclonal antibody (mAb) rituximab results in an improvement of AD,26Ponte P. Lopes M.J. Apparent safe use of single dose rituximab for recalcitrant atopic dermatitis in the first trimester of a twin pregnancy.J Am Acad Dermatol. 2010; 63: 355-356Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 27Simon D. Hosli 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 (214) Google Scholar suggesting that B cells play important roles in the development of this condition. Therefore, in the present study, we examined the importance of B cells in an OVA-sensitized allergic skin inflammation model using CD19−/− and wild-type (WT) mice. WT C57BL/6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME). CD19−/− (C57BL/6 × 129) mice were generated as described previously28Engel P. Zhou L.-J. Ord D.C. Sato S. Koller B. Tedder T.F. Abnormal B lymphocyte development, activation and differentiation in mice that lack or overexpress the CD19 signal transduction molecule.Immunity. 1995; 3: 39-50Abstract Full Text PDF PubMed Scopus (494) Google Scholar and backcrossed for 7 to 12 generations onto the C57BL/6 background before use in this study. Lack of cell-surface CD19 expression was verified by two-color immunofluorescence staining with flow cytometric analysis. All mice were bred in a specific pathogen–free barrier facility and used at 8 to 12 weeks of age. All studies were approved by the Committee on Animal Experimentation (University of Tokyo, Japan). Epicutaneous sensitization of mice was performed as described previously.12Spergel J.M. Mizoguchi E. Brewer J.P. Martin T.R. Bhan A.K. Geha R.S. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice.J Clin Invest. 1998; 101: 1614-1622Crossref PubMed Scopus (542) Google Scholar Briefly, the dorsal skin of anesthetized mice was shaved and tape-stripped six times. Next, 100 μg of OVA (Grade V; Sigma-Aldrich, St. Louis, MO) in 100 μL of PBS or 100 μL of PBS alone was placed on a patch of 1 × 1-cm sterile gauze, which was secured to the dorsal skin with a transparent bio-occlusive dressing (Tegaderm; 3M Health Care, St. Paul, MN). Each mouse had a total of three 1-week exposures to the patch separated from each other by 2-week intervals. Mice were sacrificed 1 day after removal of the patch after the third sensitization (day 50). Skin samples were removed, and segments were fixed in 10% buffered formalin. After paraffin embedding, sections (5 μm thick) were cut and stained with H&E for eosinophil counting and with toluidine blue for mast cell counting. For immunohistochemistry, paraffin-embedded tissues were cut into 6-μm-thick sections, deparaffinized in xylene, and then dehydrated in PBS. Deparaffinized sections were treated with endogenous peroxidase blocking reagent (Dako, Glostrup, Denmark) and proteinase K (Dako) for 6 minutes at room temperature. Sections were then incubated with rat mAb specific to mouse CD4 (#2H9; ReliaTech, Wolfenbüttel, Germany), CD8 (D-9; Santa Cruz Biotechnology, Santa Cruz, CA), and B220 (RA3-6B2; BD Biosciences, San Jose, CA). Rat IgG (Southern Biotechnology Associates, Birmingham, AL) was used as a control for nonspecific staining. Sections were then incubated sequentially (20 minutes at 37°C) with a biotinylated rabbit anti-rat IgG secondary Ab followed by a horseradish peroxidase–conjugated avidin–biotin complex (Vectastain ABC kit; Vector Laboratories, Burlingame, CA). Sections were developed with 3,3′-diaminobenzidine tetrahydrochloride and hydrogen peroxide, and counterstained with methyl green. Stained cells were counted in 10 random grids under high magnification (×400) using a light microscope. Each section was examined independently by two investigators (K.Y. and M.K.) in a blinded manner. Mice were bled and serum samples were collected on day 50 (1 day after the end of epicutaneous sensitization). All serum samples were stored at −70°C until use. Serum levels of OVA-specific IgG1, IgG2a, and IgE Abs were measured with a specific enzyme-linked immunosorbent assay (ELISA) kit (Alpha Diagnostic International, San Antonio, TX), according to the manufacturer’s protocol. Each sample was tested in duplicate. Anti-mouse mAbs against B220 (RA3-6B2), CD19 (1D3), CD5 (53-7.3), CD1d (1B1), CD4 (H129.19), CD8 (53-6.7), and CD25 (PC61) were obtained from BD Biosciences. For intracellular staining, mAbs against FoxP3 (FJK-16s; eBiosciences, San Diego, CA) and the Cytofix/Cytoperm kit (BD Biosciences) were used. Single-cell suspensions of the spleen and draining lymph nodes (pooled bilateral axial and inguinal lymph nodes) were prepared by gentle dissection. Peritoneal cavity leukocytes were isolated with 10 mL of cold (4°C) PBS injected into the peritoneum of sacrificed mice followed by gentle massage of the abdomen. Viable cells were counted using a hemocytometer, with relative lymphocyte percentages determined by flow cytometry. Single-cell leukocyte suspensions were stained on ice using predetermined optimal concentrations of each Ab for 20 to 60 minutes and fixed as previously described.23Sato S. Ono N. Steeber D.A. Pisetsky D.S. Tedder T.F. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity.J Immunol. 1996; 157: 4371-4378Crossref PubMed Google Scholar Cells with the light scatter properties of lymphocytes were analyzed by immunofluorescence staining and a FACSVerse flow cytometer (BD Biosciences). Background staining was determined using unreactive isotype-matched control mAbs (Caltag Laboratories, San Francisco, CA) with gates positioned to exclude ≥98% of unreactive cells. Magnetic-activated cell sorting technology (Miltenyi Biotec, Bergisch Gladbach, Germany) was used to purify lymphocyte populations according to the manufacturer’s instructions. B220 mAb-coated microbeads and CD4+ and CD8+ T-cell isolation kits (Miltenyi Biotec) were used to purify B cells, CD4+ T cells, and CD8+ T cells, respectively. When necessary, the cells were enriched a second time using a fresh magnetic-activated cell sorting column to obtain purities >95%. On day 50, 3 × 105 purified CD4+ or CD8+ T cells harvested from the spleen or draining lymph nodes were cultured in 96-well plates in 200 μL of complete medium (RPMI 1640 containing 10% fetal calf serum, 200 μg/mL penicillin, 200 U/mL streptomycin, 4 mmol/L l-glutamine, and 5 × 10−5 mol/L 2-mercaptoethanol; all from Invitrogen, Carlsbad, CA) with 1.5 × 105 mitomycin C (Sigma-Aldrich)-treated splenic B cells and 200 μg/mL OVA. 5-Bromo-2′-deoxyuridine (BrdU; cell proliferation BrdU ELISA; Roche, Indianapolis, IN) was added during the final 2 hours of 4-day cultures. BrdU incorporation was then assessed by measuring absorbance at 450 nm. Single-cell suspensions of the spleen and draining lymph nodes were prepared in complete medium. Cells were cultured in complete medium at 2 × 106/mL in 24-well plates in the presence of 200 μg/mL OVA. Supernatant was collected after 96 hours of culture. The levels of IL-4, IL-10, IL-13, IL-17, and interferon (IFN)-γ in the supernatants were determined by ELISA according to the manufacturer instructions (R&D Systems, Minneapolis, MN). Splenic B cells were purified using CD19 mAb-coated microbeads (Miltenyi Biotech). The cells were enriched a second time using a fresh magnetic-activated cell sorting column to obtain purities >95%. Then, 2 × 107 CD19+ B cells from naive WT mice were transferred intravenously into CD19−/− mice. Two days later, the recipient mice were epicutaneously sensitized with OVA to induce allergic skin inflammation. All data are expressed as means ± SEM. The U-test was used for determining the level of significance of differences in sample means, and the Bonferroni test was used for multiple comparisons. To assess whether CD19 expression played a role in the pathogenesis of OVA-sensitized allergic skin inflammation, we sensitized CD19−/− and WT mice with OVA epicutaneously over 7 weeks, and the site of repeated sensitization was histopathologically assessed. Epicutaneous sensitization with OVA induced thickening of the epidermis and dermis in both WT and CD19−/− mice, but to a lesser degree in CD19−/− mice (Figure 1). Furthermore, OVA sensitization significantly increased the numbers of eosinophils, mast cells, and CD4+ and CD8+ T cells in both WT and CD19−/− mice, but the numbers of eosinophils and CD4+ T cells were significantly lower in CD19−/− than in WT mice after sensitization with OVA (Figure 2). There were no significant differences in the numbers of mast cells, B cells, and CD8+ T cells between WT and CD19−/− mice. These results show that allergic skin inflammation was suppressed in CD19−/− mice compared with WT mice.Figure 2CD19 deficiency reduced inflammatory cell infiltration in allergic skin inflammation. The numbers of eosinophils, mast cells, B220+ B cells, CD4+ T cells, and CD8+ T cells per field of view were counted. Original magnification, ×400. Values represent means ± SEM from n ≥ 5 mice per group. Significant differences between sample means are indicated as ∗P < 0.05, ∗∗P < 0.01. Results represent one of two independent experiments with similar results. HPF, high-power field.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The effect of CD19 deficiency on serum Ab responses was also assessed after repeated OVA sensitization. OVA-sensitized WT mice were able to mount OVA-specific IgG1, IgG2a, and IgE Ab responses following sensitization, whereas no OVA-specific Abs were detected in the serum of PBS-sensitized mice (Figure 3). By contrast, the serum levels of IgG1, IgG2a, and IgE anti-OVA Abs remained significantly lower in CD19−/− mice sensitized with OVA; levels in these animals were not significantly higher than those in WT mice sensitized with PBS. Thus, CD19 deficiency significantly attenuated OVA-specific Ab production in OVA-sensitized allergic skin inflammation. The effects of CD19 deficiency on the numbers of CD4+CD25+FoxP3+ regulatory T cells in the spleen and draining lymph nodes, peritoneal CD5+B220+ B1-a cells, and splenic CD1dhiCD5+ regulatory B cells (B10 cells)19Yanaba 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 (1005) Google Scholar were also assessed by flow cytometry after repeated OVA sensitization. Without OVA sensitization, CD19−/− mice had significantly reduced B220+ B cells in the spleen and peritoneal cavity compared with WT mice (P < 0.01), whereas B220+ B-cell numbers in the draining lymph nodes were comparable between WT and CD19−/− mice (Table 1). The numbers of B220+ B cells in the spleen, draining lymph nodes, and peritoneal cavity increased during OVA-sensitized allergic skin inflammation in both WT and CD19−/− mice, although these changes were not significant. The numbers of regulatory T cells in the spleen and draining lymph nodes were significantly increased during OVA-sensitized allergic skin inflammation in both WT and CD19−/− mice (P < 0.05 and P < 0.01, respectively). The numbers of regulatory T cells in the spleen and draining lymph nodes were comparable in OVA-sensitized WT and CD19−/− mice. The numbers of peritoneal B-1a cells were significantly decreased in CD19−/− mice compared with WT mice, as previously described,23Sato S. Ono N. Steeber D.A. Pisetsky D.S. Tedder T.F. CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity.J Immunol. 1996; 157: 4371-4378Crossref PubMed Google Scholar but there was no effect on these peritoneal B-1a cell numbers after OVA sensitization of either WT or CD19−/− mice. Moreover, OVA sensitization did not affect splenic regulatory B-cell numbers in WT mice, whereas no significant numbers of regulatory B cells were observed in CD19−/− mice, regardless of OVA sensitization as described.19Yanaba 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 (1005) Google Scholar Thus, repeated epicutaneous OVA sensitization affected the numbers of regulatory T cells, which did not correlate with the observed decreased disease severity in CD19−/− mice.Table 1Cell Numbers in Wild-Type and CD19−/− MiceTissueSubsetCell number (× 10−5)Wild-type PBSCD19−/− PBSWild-type OVACD19−/− OVASpleenB220+499 ± 45235 ± 32∗∗532 ± 58262 ± 39∗∗CD1d hiCD5+B220+16 ± 30.2 ± 0.1∗∗20 ± 40.3 ± 0.1∗∗CD4+CD25+FoxP3+15 ± 214 ± 321 ± 3∗20 ± 4∗Draining lymph nodeB220+11 ± 212 ± 314 ± 314 ± 2CD4+CD25+FoxP3+2.5 ± 0.42.3 ± 0.64.4 ± 0.8∗∗4.9 ± 1.0∗∗Peritoneal cavityB220+12 ± 1.82.5 ± 0.4∗∗11 ± 2.22.3 ± 0.1∗∗CD5+B220+1.5 ± 0.40.09 ± 0.02∗∗1.6 ± 0.30.08 ± 0.03∗∗Data are expressed as means ± SEM of at least four mice.∗P < 0.05, ∗∗P < 0.01 versus PBS-sensitized wild-type mice. Open table in a new tab Data are expressed as means ± SEM of at least four mice. ∗P < 0.05, ∗∗P < 0.01 versus PBS-sensitized wild-type mice. The effects of CD19 deficiency on OVA-specific CD4+ and CD8+ T cell responses was evaluated after repeated OVA sensitization. Spleen and draining lymph node CD4+ and CD8+ T cells were purified after OVA sensitization, and OVA-specific T-cell proliferation was quantified in vitro using purified mitomycin C–treated B cells from WT mice sensitized with OVA as antigen-presenting cells in the presence of PBS or OVA. Spleen and draining lymph node CD4+ T-cell recall responses to OVA in OVA-sensitized CD19−/− mice were reduced by 40% (P < 0.01) and 66% (P < 0.01) compared to OVA-sensitized WT mice, respectively (Figure 4A). By contrast, OVA-specific CD8+ T-cell proliferation was equivalent in WT and CD19−/− mice (Figure 4B). Thus, CD19 deficiency impaired the expansion of antigen-specific CD4+ T cells, but not CD8+ T cells, following OVA sensitization. Because CD19 regulates OVA-specific T-cell proliferation, it is possible that CD19 also affects cytokine production in response to OVA stimulation. Therefore, we stimulated OVA-sensitized splenocytes and draining lymph node cells with PBS or OVA in vitro and, using ELISA, examined whether the loss of CD19 affected cytokine secretion. OVA-sensitized WT splenocytes secreted more IL-4, IL-13, IL-17, and IL-10 than PBS-sensitized WT splenocytes (Figure 5A). OVA-sensitized CD19−/− splenocytes exhibited reduced secretion of IL-4, IL-13, IL-17, and IL-10 compared to OVA-sensitized WT splenocytes. Similarly, WT draining lymph node cells treated with OVA showed increased IL-4, IL-13, IL-17, and IL-10 production compared to cells treated with PBS, whereas draining lymph node cells from OVA-sensitized CD19−/− mice secreted significantly less IL-4, IL-13, IL-17, and IL-10 relative to those from OVA-sensitized WT mice (Figure 5B). Thus, CD19 deficiency decreased Th2 and Th17 cytokine secretion in an OVA-sensitized model of allergic skin inflammation. Genetic deficiency of CD19 may affect normal T-cell development and impair allergic skin inflammation. Therefore, we next assessed whether CD19 expression in B cells was responsible in vivo for allergic skin inflammation. B cells were purified from the spleen of naive WT mice and transferred to CD19−/− mice before OVA sensitization (2 × 107 cells, >95% CD19+). Transferring WT B cells into CD19−/− mice significantly enhanced thickening of the epidermis and dermis (P < 0.05 for both) (Figure 6). The CD19−/− mice that received WT B cells developed allergic skin inflammation of the same severity as that in WT mice. Therefore, reduced allergic skin inflammation of CD19−/− mice is enhanced to normal levels when spleen B cells from WT mice are transferred, indicating the pathogenic role of CD19 expression in B cells. Previous studies have shown that B-cell depletion with CD20 mAb reduces CD4+ T-cell activation during immune responses to low-dose, but not high-dose, antigens.29Bo" @default.
• W2013136108 created "2016-06-24" @default.
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• W2013136108 date "2013-06-01" @default.
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• W2013136108 title "CD19 Expression in B Cells Regulates Atopic Dermatitis in a Mouse Model" @default.
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