Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis
© Carter et al.; licensee BioMed Central Ltd. 2012
Received: 11 August 2011
Accepted: 8 February 2012
Published: 8 February 2012
Interleukin-10 (IL-10) producing B cells, also known as regulatory B (Breg) cells, play a key role in controlling autoimmunity. Our laboratory and others have demonstrated a pivotal role for Bregs in rheumatological disorders, including experimental models of arthritis and lupus. The aim of this study was to identify the role of endogenous IL-10 secreting B cells in vivo in controlling the induction and disease progression of collagen-induced arthritis (CIA).
We generated chimeric mice that had IL-10 knocked-out specifically in the B cell population. These mice were compared with wild-type (WT) B cell chimeric mice for their susceptibility to CIA.
Here we report that chimeric mice specifically lacking IL-10 producing B cells (IL-10-/- B cell) developed an exacerbated CIA compared to chimeric wild type B cell (WT B cell) mice. A marked increase in inflammatory Th1 and Th17 cells were detected in IL-10-/-B cell mice compared to WT B cell mice. Furthermore, there was a reduction in IL-10 secreting CD4+ Tr1 cells in these animals.
IL-10 producing B cells restrain inflammation by promoting differentiation of immuno-regulatory over pro-inflammatory T cells and, hence, act to maintain tolerance.
CIA-induced joint destruction is widely accepted to develop as a result of the secretion of pro-inflammatory Th1 cytokines, such as IFNγ and IL-12 [1–3]. These Th1 cytokines facilitate the infiltration of neutrophils and macrophages into the joint, which stimulates the production of both TNFα and IL-1 that ultimately results in joint destruction and pannus formation [4, 5]. In addition to this, CIA is mediated by pathogenic B cells, which produce anti-collagen antibodies that are indicative of disease development  and can induce arthritis upon transfer [6, 7]. This taken together with the fact that B cell deficient mice (μMT) are resistant to CIA  shows that CIA is both a T and B cell-mediated disease.
The role of IL-10 has been well documented in experimental arthritis [9–13] and other autoimmune disorders [14–18]. It has been shown that CIA is exacerbated in IL-10 deficient DBA mice , although the relevant contributions of IL-10 secreted by T cells and B cells cannot be revealed using IL-10-/- animals. The importance of B cell derived IL-10 in CIA has been confirmed by previous work in this laboratory [9, 10]. Several regulatory B cell subsets have now been identified and most share the release of IL-10 as a common mechanism of action. In experimental arthritis, we have shown that the transfer of the main producers of IL-10, namely CD19+CD21hiCD23hiCD1dhi transitional 2 marginal zone precursor B cells (T2-MZP), prevents or ameliorates established disease [9, 19]. Similarly, transfer of CD5+CD1dhi B cells (B10) controls the development of the contact hypersensitivity response (CHS) . In each instance, Bregs isolated from IL-10 deficient mice (IL-10-/-) mice failed to suppress the development of autoimmune diseases [21–25]. In order to assess the importance of all subsets of IL-10 secreting regulatory B cells, we generated chimeric mice that lack IL-10 specifically on all B cells. Thus, providing us with a unique environment to assess the role of B cell derived IL-10 in joint inflammation.
Previous work in this laboratory has shown a pivotal role for endogenous B cell-derived IL-10 in the context of antigen induced arthritis (AIA) . AIA is induced by immunization with mBSA emulsified in Complete Freunds Adjuvant (CFA), followed a week later by intra-articular injection with mBSA . The incidence of disease (that is, antigen-mediated joint swelling) is 100% and the disease is characterized by acute inflammation which is resolved within one month . In the latter stages of disease, anti-mBSA antibodies are also produced , hence, this model incorporates both the DTH response and the development of an autoimmune-like disease. IL-10-/- B cell mice have an exacerbated AIA arthritis phenotype, including increased clinical scores and knee swelling, enhanced Th17 and Th1 development and a reduction in regulatory T cells .
Next we wanted to elucidate and validate the role of IL-10 secreting Bregs in CIA, a polyarthritis model involving both severe inflammation and cartilage and bone erosion. CIA differs from AIA in several key areas. CIA cannot be induced in B cell deficient mice, whereas AIA is a predominantly T- cell mediated disease that can be induced in B cell deficient mice that develop an exacerbated AIA [8, 19]. Additionally, different genetic backgrounds and modes of immunizations are commonly used. The courses of these diseases are also significantly different. AIA is a monoarthritis, which can be resolved in under one month, whereas CIA can take several months to develop and can go into remission in one or more paws.
In this paper, we have shown that in animals lacking IL-10 specifically on their B cells, T cell differentiation is skewed to pro-inflammatory Th1 and Th17 subtypes, at the expense of the differentiation and maintenance of immune-regulatory Tr1 cells. These conditions result in exacerbated experimental arthritis in IL-10-/- B cell mice as compared to WT B cell mice.
Materials and methods
This work and NC is funded by Arthritis Research UK http://www.arthritisresearchuk.org/arthritis_research.aspx by the programme grant to CM (MP/17707) and by the equipment grant (19367) to CM and NC. ER is funded by ARUK PhD studentship (NE/PhD/19607) to CM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
These studies have been reviewed and approved by the Home Office U.K. This work was conducted under UK Home Office Project Licence number PPL 70/7108.
Animals and antibodies
IL-10-/- and μMT animals on the H2q background were generated by backcrossing the original IL-10/H2b and μMT/H2b with DBA/1 H2q mice. The mice were typed by PCR, and IL-10 KO-/-H2q were further backcrossed into DBA/1. Mice from the 15th generation (DBA/1IL-10 KO-/-) were used for experiments. All animals were bred and maintained under specific pathogen-free conditions at the animal facility at University College London, UK. All antibodies were purchased from BD Biosciences, Oxford, UK.
Generation of chimeric mice
Chimeric mice were generated as previously published . Briefly, recipient μMt mice received 800 cGy of γ-irradiation via a caesium source. Five hours following irradiation recipients received 2 × 106 donor bone marrow cells. Bone marrow preparations were depleted of T cells by negative selection with a MACS magnetic column (Miltenyi Biotech, Bergisch Gladbach, Germany). To generate mice where the absence of IL-10 was exclusively restricted to B cells, μMT mice were reconstituted with a mixture of bone marrow consisting of 80% from μMT (no B cell differentiation) with 20% from IL-10-/- mice. Control mice received 80% from μMT and 20% bone marrow from WT mice (to give a normal B cell compartment). Two additional control groups were included: 100% of bone marrow from μMT into WT recipients (control for the absence of B cells) or 80% WT and 20% IL-10-/- bone marrow into μMT recipients (this will assess the effect of 20% reduction in IL-10 production by non-B cell lymphocytes in the response observed). Chimeras were left to fully reconstitute their peripheral lymphoid system over at least eight weeks before use in CIA experiments. The absence of B cells (CD19-expressing splenocytes) in the group that received 100% μMT bone marrow confirmed the total ablation of the host bone marrow by irradiation. In contrast, the three other groups showed numbers of CD19+ B cells and CD4+T cells equivalent to numbers found in non chimeric WT B6 mice.
Induction and assessment of collagen-induced arthritis and histology of joints
Male DBA/1 mice were immunized with 100 μg of type II bovine collagen (CII) emulsified in CFA (Diffco Laboratories, Oxford, UK) as previously described . The development of arthritis was assessed daily for the duration of the experiment. The clinical severity of arthritis was graded as follows: 0, normal; 1, slight swelling and/or erythema; 2, pronounced edematous swelling; 3, pronounced edematous swelling plus joint rigidity; and 4, laxity. Each limb was graded, allowing a maximal clinical score of 16 for each animal. All clinical evaluations were performed in a blinded manner. All the mice are kept in accordance with the local guidelines.
Hind paws were removed post-mortem and fixed in 10% (w/v) buffered formalin and decalcified in 5% EDTA. After decalcification, the paraffin sections were stained with hematoxylin-eosin. Two independent observers evaluated the slides histologically. The slides were graded as: 0, normal, no damage; 1, minimal synovitis, cartilage loss, and bone erosion limited to discrete foci; 2, synovitis and erosion present, but normal joint architecture intact; and 3, extensive erosion and joint architecture disrupted.
Serum anti-collagen antibody levels
Anti-CII Abs were determined as previously described . Briefly, microplates (Nunc) were coated with (2 μg/ml) bovine CII overnight, blocked with 2% BSA and then incubated with serial dilutions of the testing sera. Bound IgG1 and IgG2a were detected by incubation with alkaline phosphatase-conjugated sheep anti-mouse IgG1 and IgG2a respectively (The Binding Site, Schwetzingen, Germany) followed by TMB (Sigma, St Louis, MO, USA).
Flow cytometric analysis of intracellular cytokine synthesis
Intracellular cytokine analysis was performed as previously described . Briefly, inguinal lymph node cultures were suspended at 5 × 105 cells/ml in complete medium with PMA (50 ng/ml Sigma-Aldrich, St Louis, MO, USA), ionomycin (500 ng/ml Sigma-Aldrich, St Louis, MO, USA) and GolgiPlug (BD Biosciences, Oxford, UK) for five hours. Cells were then stained with extracellular markers, followed by permeabilization and incubation with anti-mouse IL-10 APC, IFNγ APC or IL-17 PE mAbs. The cells were acquired with a BD LSR flow cytometer (BD Biosciences, Oxford, UK) and analysed using FlowJo software.
In vivo cytokine capture assay
This was carried out using BD in vivo IFNγ and IL-2 capture assay kits. Briefly, mice were injected intraperitoneally with 10 μg of NA/LE biotin-conjugated anti-mouse IFNγ antibody in 200 μL in sterile PBS. Blood samples were collected from injected mice after 12 hours, and serum was isolated. Serum cytokine levels were then analyzed using an ELISA based method.
Cytokine secretion assay
Lymph node cultures were suspended at 5 × 105 cells/ml in complete medium with anti-CD3 (1 μg/ml). After incubation at 37°C for 48 hours, the plates were centrifuged; the supernatants were collected and stored at - 80°C until further analysis. Cytokine concentration in the supernatants was determined using mouse Th1/Th2 cytokine FlowCytomix kit (Bender Medsystems, AachenGermany), following the manufacturer's instructions.
Regulatory T cell suppression assay/proliferation assay
Spleens were removed post-mortem and CD4+T cells, Treg and Teff cells were negatively isolated. Cells were cultured for 60 hours with either complete medium or with anti-CD3 (1 μg/ml). Cultures were then pulsed overnight with 1 μCi of (H3) thymidine, harvested and counted in a scintillation counter (LKB Instruments, Mt Waverley, Victoria, Australia).
For the statistical analysis of the data, the Mann-Whitney U test and the Fisher exact test were applied to analyze clinical results. Unpaired t tests were applied in all other experiments. P < 0.05 was considered significantly different.
IL-10 is essential for the regulation of experimental arthritis
It is well documented that mice lacking IL-10 have a predisposition to immune-driven colitis and inflammation of the gut [16, 30, 31]. Furthermore, it has been shown that CIA develops with increased incidence and severity in IL-10 deficient animals [12, 13]. Unlike the wild type animals, the IL-10-/- animals do not enter remission (when inflammation has subsided) and, as such, joint swelling and redness does not permanently recede. In order to unravel the relative contribution of endogenous B cell derived IL-10 in a polyarthritis model, we generated mixed bone marrow chimera mice with IL-10 knocked-out specifically on B cells. As a control we generated bone marrow chimera mice with a normal WT B cell compartment. We have previously published that both WT B cell and IL-10-/- B cell animals show no major differences in either T or B cell phenotypes either in naïve or immunized animals (Additional file 1 ). Furthermore, the WT B cell chimeric mice developed CIA with the same incidence and severity as WT mice that have not undergone any irradiation procedures.
Pro-inflammatory cytokines IFNγ and IL-17 are increased in arthritic IL-10-/-B cell animals
Additionally, investigation of IL-17 levels clearly demonstrated an increase in IL-17 production, as seen by both multiplex bead array and IL-17 intracellular staining, in the IL-10-/- B cell mice (Figure 2A-C). Th17 cells were only significantly increased in the LN, but not the spleen, of arthritic IL-10-/- B cell mice compared to WT B cell mice at days 12, 35 and 45 post-immunization with collagen (Additional file 2 and data not shown). Therefore, in addition to IFNγ, IL-17 could also play an important role in both the increased inflammation and tissue destruction seen in the IL-10-/- B cell mice. However, the percentage and number of CD4+ IFNγ+ IL-17+ double producing cells was not significantly different in the WT B cell and IL-10-/- B cell mice (data not shown).
Regulatory T cells are reduced in IL-10-/-B cell animals
It is interesting to note that FoxP3+Treg numbers are not reduced in the LN of IL-10-/- B cell mice with CIA (Figure 3C). We did not see any significant differences in FoxP3+Treg numbers in the LN of IL-10-/- B cell mice compared to WT B cell mice on days 12, 35 or 45 post-immunization with collagen (Additional file 2). We also compared FoxP3+Treg numbers in the spleen and were unable to see any differences in IL-10-/- B cell mice compared to WT B cell mice with CIA (data not shown). Moreover, neither the suppressive function of these Tregs (Figure 3D) nor in vivo levels of IL-2 (Figure 3E) were modulated in these animals. We have previously published that during the development of antigen-induced arthritis in IL-10-/- B cell mice we can see a decrease in FoxP3+ Treg numbers and expression of FoxP3 specifically at the site of inflammation (both the synovial membrane of the affected knee and the inguinal LN draining that knee) .
We did not see differences in number or function of FoxP3+ Tregs during CIA development in IL-10-/- B cell mice. It is important to note that splenocytes and lymph node cells from these IL-10-/- B cell animals do have normal proliferative responses to anti-CD3 (Additional file 1B). Taken together these data suggest that FoxP3- CD4+ IL-10 secreting Tr1 population is preferentially affected by B cell- derived IL-10 during CIA.
The importance of IL-10 in disease control has been clearly demonstrated by the use of IL-10-/- animals. We and others have shown that immune mediated colitis [16, 30], EAE  and experimental arthritis  are exacerbated in these animals. However, this does not resolve the question of which IL-10 producing cell types are able to control inflammation.
Our results take advantage of chimeric animals that lack IL-10 specifically in their B cells. These animals had increased pro-inflammatory cytokines and antibodies in circulation, firmly establishing the importance of B cell derived IL-10 in regulating disease (Figures 1B and 2).
In a colitis model, TCR-/- μMT mice develop a more severe disease than an only-TCR-/- mouse, indicating that B cells are as important as T cells in this inflammatory disease . Interestingly, the IL-10-/- B cell mice developed a "colitis-like" disease with symptoms including rectal pro-lapse with some bleeding, sticky stool consistency, increased intestinal-gas (seen by dissection) and loss of body weight (data not shown). This supports the idea that B cell derived IL-10 is an important component of the hierarchy that regulates and suppresses the immune system, a concept that has been proved numerous times in transfer experiments [9, 17] and disease induction in μMT mice [35, 36]. It even suggests that in certain inflammatory models IL-10 secreting Bregs can be apical to regulatory T cells in prevention of autoimmunity and the maintenance of tolerance .
It is well established that IL-10 producing Tr1 cells control the expansion of Teff cells and reduce the production of proinflammatory cytokines in vitro [38–42]. However, to date there is a scarcity of information about the stimuli promoting in vivo differentiation of Tr1 and whether they are promoted by other cells. Here, our data confirm and expand upon the importance of Bregs in the differentiation and maintenance of Tr1 cells in vivo in the context of chronic disorders [19, 34, 43]. Therefore, taking into account our data and those already available in the literature, it is feasible to speculate that IL-10 producing B cells may control the regulatory hierarchy, including the proper development of anti-inflammatory T cells, leading to the maintenance of tolerance. This combined information reveals a conflicting hypothesis to research that attributes Tregs as the most important component of immune regulation , and that B cells only have a pathogenic role in autoimmune disease .
Of interest, unlike in AIA where animals display a reduction in both the number of FoxP3+ Tregs and their expression of FoxP3+ in IL-10-/- B cell mice compared to WT B cell mice, the number of FoxP3+ Tregs and FoxP3+ expression were similar in both groups during CIA. The discrepancy between the results in these two models could be due to several reasons. The course of arthritis is very different in the two diseases. Mice immunized with collagen in CFA develop disease three-to-four weeks post-immunization, whereas mice with AIA are assessed five days post immunization. In addition, it is possible to obtain a sufficient number of cells for flow cytometry analysis from the synovia (obtained from the knee) in mice developing AIA, we were unable to assess the frequencies of Tregs in the synovia of mice with CIA. Thus, timing and location could account for the differential data on Tregs in the IL-10-/-B cell mice in the two models. Nevertheless, in both an acute inflammatory model and a systemic experimental arthritis, IL-10-/- B cell mice have an exacerbated arthritis phenotype.
These data shed some light on the mechanism of action of IL-10- secreting regulatory B cells. We have shown that in IL-10-/- B cell mice T cell differentiation is skewed to pro-inflammatory Th1 and Th17 subtypes, whereas regulatory Tr1 cells are reduced as compared to WT B cell animals (Figures 2 and 3A, B). These increased inflammatory conditions result in exacerbated arthritis in IL-10-/- B cell mice as compared to WT B cell mice (Figure 1). These data confirm previous findings from this laboratory, and others, establishing the power of B cell produced IL-10 in maintenance of tolerance and prevention of multiple experimental autoimmune diseases [9, 10, 19, 20, 34, 43, 46, 47].
regulatory B cells
complete Freund's adjuvant
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forkhead box P3
phorbol 12-myristate 13-acetate
transitional type 2-marginal zone precursor B cells
effector T cell
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tumor necrosis factor alpha
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regulatory T cell
- Mauri C, Williams RO, Walmsley M, Feldmann M: Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis. Eur J Immunol. 1996, 26: 1511-1518. 10.1002/eji.1830260716.View ArticlePubMedGoogle Scholar
- Mauritz NJ, Holmdahl R, Jonsson R, Van der Meide PH, Scheynius A, Klareskog L: Treatment with gamma-interferon triggers the onset of collagen arthritis in mice. Arthritis Rheum. 1988, 31: 1297-1304. 10.1002/art.1780311012.View ArticlePubMedGoogle Scholar
- Germann T, Szeliga J, Hess H, Storkel S, Podlaski FJ, Gately MK, Schmitt E, Rude E: Administration of interleukin 12 in combination with type II collagen induces severe arthritis in DBA/1 mice. Proc Natl Acad Sci USA. 1995, 92: 4823-4827. 10.1073/pnas.92.11.4823.PubMed CentralView ArticlePubMedGoogle Scholar
- Mussener A, Litton MJ, Lindroos E, Klareskog L: Cytokine production in synovial tissue of mice with collagen-induced arthritis (CIA). Clin Exp Immunol. 1997, 107: 485-493. 10.1046/j.1365-2249.1997.3181214.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Stasiuk LM, Abehsira-Amar O, Fournier C: Collagen-induced arthritis in DBA/1 mice: cytokine gene activation following immunization with type II collagen. Cell Immunol. 1996, 173: 269-275. 10.1006/cimm.1996.0277.View ArticlePubMedGoogle Scholar
- Holmdahl R, Jansson L, Larsson A, Jonsson R: Arthritis in DBA/1 mice induced with passively transferred type II collagen immune serum. Immunohistopathology and serum levels of anti-type II collagen auto-antibodies. Scand J Immunol. 1990, 31: 147-157. 10.1111/j.1365-3083.1990.tb02754.x.View ArticlePubMedGoogle Scholar
- Stuart JM, Tomoda K, Yoo TJ, Townes AS, Kang AH: Serum transfer of collagen-induced arthritis. II. Identification and localization of autoantibody to type II collagen in donor and recipient rats. Arthritis Rheum. 1983, 26: 1237-1244. 10.1002/art.1780261011.View ArticlePubMedGoogle Scholar
- Svensson L, Jirholt J, Holmdahl R, Jansson L: B cell-deficient mice do not develop type II collagen-induced arthritis (CIA). Clin Exp Immunol. 1998, 111: 521-526. 10.1046/j.1365-2249.1998.00529.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR, Mauri C: Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol. 2007, 178: 7868-7878.View ArticlePubMedGoogle Scholar
- Mauri C, Gray D, Mushtaq N, Londei M: Prevention of arthritis by interleukin 10-producing B cells. J Exp Med. 2003, 197: 489-501. 10.1084/jem.20021293.PubMed CentralView ArticlePubMedGoogle Scholar
- Keravala A, Lechman ER, Nash J, Mi Z, Robbins PD: Human, viral or mutant human IL-10 expressed after local adenovirus-mediated gene transfer are equally effective in ameliorating disease pathology in a rabbit knee model of antigen-induced arthritis. Arthritis Res Ther. 2006, 8: R91-10.1186/ar1960.PubMed CentralView ArticlePubMedGoogle Scholar
- Finnegan A, Kaplan CD, Cao Y, Eibel H, Glant TT, Zhang J: Collagen-induced arthritis is exacerbated in IL-10-deficient mice. Arthritis Res Ther. 2003, 5: R18-24. 10.1186/ar601.PubMed CentralView ArticlePubMedGoogle Scholar
- Johansson AC, Hansson AS, Nandakumar KS, Backlund J, Holmdahl R: IL-10-deficient B10.Q mice develop more severe collagen-induced arthritis, but are protected from arthritis induced with anti-type II collagen antibodies. J Immunol. 2001, 167: 3505-3512.View ArticlePubMedGoogle Scholar
- Bacchetta R, Bigler M, Touraine JL, Parkman R, Tovo PA, Abrams J, de Waal Malefyt R, de Vries JE, Roncarolo MG: High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med. 1994, 179: 493-502. 10.1084/jem.179.2.493.View ArticlePubMedGoogle Scholar
- Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK: IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol. 1998, 161: 3299-3306.PubMedGoogle Scholar
- Davidson NJ, Fort MM, Muller W, Leach MW, Rennick DM: Chronic colitis in IL-10-/- mice: insufficient counter regulation of a Th1 response. Int Rev Immunol. 2000, 19: 91-121. 10.3109/08830180009048392.View ArticlePubMedGoogle Scholar
- Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM: B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002, 3: 944-950.View ArticlePubMedGoogle Scholar
- Suri-Payer E, Fritzsching B: Regulatory T cells in experimental autoimmune disease. Springer Semin Immunopathol. 2006, 28: 3-16. 10.1007/s00281-006-0021-8.View ArticlePubMedGoogle Scholar
- Carter NA, Vasconcellos R, Rosser EC, Tulone C, Munoz-Suano A, Kamanaka M, Ehrenstein MR, Flavell RA, Mauri C: Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol. 2011, 186: 5569-5579. 10.4049/jimmunol.1100284.View ArticlePubMedGoogle Scholar
- Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF: A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008, 28: 639-650. 10.1016/j.immuni.2008.03.017.View ArticlePubMedGoogle Scholar
- Bouaziz JD, Yanaba K, Tedder TF: Regulatory B cells as inhibitors of immune responses and inflammation. Immunol Rev. 2008, 224: 201-214. 10.1111/j.1600-065X.2008.00661.x.View ArticlePubMedGoogle Scholar
- Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF: Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest. 2008, 118: 3420-3430.PubMed CentralPubMedGoogle Scholar
- Mauri C, Ehrenstein MR: The 'short' history of regulatory B cells. Trends Immunol. 2008, 29: 34-40. 10.1016/j.it.2007.10.004.View ArticlePubMedGoogle Scholar
- Watanabe R, Fujimoto M, Ishiura N, Kuwano Y, Nakashima H, Yazawa N, Okochi H, Sato S, Tedder TF, Tamaki K: CD19 expression in B cells is important for suppression of contact hypersensitivity. Am J Pathol. 2007, 171: 560-570. 10.2353/ajpath.2007.061279.PubMed CentralView ArticlePubMedGoogle Scholar
- Watanabe R, Ishiura N, Nakashima H, Kuwano Y, Okochi H, Tamaki K, Sato S, Tedder TF, Fujimoto M: Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol. 2010, 184: 4801-4809. 10.4049/jimmunol.0902385.PubMed CentralView ArticlePubMedGoogle Scholar
- Brackertz D, Mitchell GF, Mackay IR: Antigen-induced arthritis in mice. I. Induction of arthritis in various strains of mice. Arthritis Rheum. 1977, 20: 841-850. 10.1002/art.1780200314.View ArticlePubMedGoogle Scholar
- Boe A, Baiocchi M, Carbonatto M, Papoian R, Serlupi-Crescenzi O: Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis. Cytokine. 1999, 11: 1057-1064. 10.1006/cyto.1999.0502.View ArticlePubMedGoogle Scholar
- Busso N, Frasnelli M, Feifel R, Cenni B, Steinhoff M, Hamilton J, So A: Evaluation of protease-activated receptor 2 in murine models of arthritis. Arthritis Rheum. 2007, 56: 101-107. 10.1002/art.22312.View ArticlePubMedGoogle Scholar
- Williams RO, Mauri C, Mason LJ, Marinova-Mutafchieva L, Ross SE, Feldmann M, Maini RN: Therapeutic actions of cyclosporine and anti-tumor necrosis factor alpha in collagen-induced arthritis and the effect of combination therapy. Arthritis Rheum. 1998, 41: 1806-1812. 10.1002/1529-0131(199810)41:10<1806::AID-ART12>3.0.CO;2-9.View ArticlePubMedGoogle Scholar
- Berg DJ, Davidson N, Kuhn R, Muller W, Menon S, Holland G, Thompson-Snipes L, Leach MW, Rennick D: Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996, 98: 1010-1020. 10.1172/JCI118861.PubMed CentralView ArticlePubMedGoogle Scholar
- Rennick DM, Fort MM: Lessons from genetically engineered animal models. XII. IL-10-deficient (IL-10(-/-) mice and intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2000, 278: G829-833.PubMedGoogle Scholar
- Feldmann M, Brennan FM, Maini RN: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996, 14: 397-440. 10.1146/annurev.immunol.14.1.397.View ArticlePubMedGoogle Scholar
- Finkelman FD, Morris SC: Development of an assay to measure in vivo cytokine production in the mouse. Int Immunol. 1999, 11: 1811-1818. 10.1093/intimm/11.11.1811.View ArticlePubMedGoogle Scholar
- Blair PA, Chavez-Rueda KA, Evans JG, Shlomchik MJ, Eddaoudi A, Isenberg DA, Ehrenstein MR, Mauri C: Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice. J Immunol. 2009, 182: 3492-3502. 10.4049/jimmunol.0803052.PubMed CentralView ArticlePubMedGoogle Scholar
- Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK: Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med. 1997, 186: 1749-1756. 10.1084/jem.186.10.1749.PubMed CentralView ArticlePubMedGoogle Scholar
- Wolf SD, Dittel BN, Hardardottir F, Janeway CA: Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med. 1996, 184: 2271-2278. 10.1084/jem.184.6.2271.PubMed CentralView ArticlePubMedGoogle Scholar
- Mauri C, Carter N: Is there a feudal hierarchy amongst regulatory immune cells? More than just Tregs. Arthritis Res Ther. 2009, 11: 237-10.1186/ar2752.PubMed CentralView ArticlePubMedGoogle Scholar
- Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL: A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007, 8: 1380-1389. 10.1038/ni1541.View ArticlePubMedGoogle Scholar
- Groux H, Cottrez F: The complex role of interleukin-10 in autoimmunity. J Autoimmun. 2003, 20: 281-285. 10.1016/S0896-8411(03)00044-1.View ArticlePubMedGoogle Scholar
- Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG: Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood. 2005, 105: 1162-1169.View ArticlePubMedGoogle Scholar
- Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK: Type 1 T regulatory cells. Immunol Rev. 2001, 182: 68-79. 10.1034/j.1600-065X.2001.1820105.x.View ArticlePubMedGoogle Scholar
- Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK: Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006, 212: 28-50. 10.1111/j.0105-2896.2006.00420.x.View ArticlePubMedGoogle Scholar
- Gray M, Miles K, Salter D, Gray D, Savill J: Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci USA. 2007, 104: 14080-14085. 10.1073/pnas.0700326104.PubMed CentralView ArticlePubMedGoogle Scholar
- Paust S, Lu L, McCarty N, Cantor H: Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA. 2004, 101: 10398-10403. 10.1073/pnas.0403342101.PubMed CentralView ArticlePubMedGoogle Scholar
- Dorner T, Burmester GR: The role of B cells in rheumatoid arthritis: mechanisms and therapeutic targets. Curr Opin Rheumatol. 2003, 15: 246-252. 10.1097/00002281-200305000-00011.View ArticlePubMedGoogle Scholar
- Correale J, Farez M, Razzitte G: Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol. 2008, 64: 187-199. 10.1002/ana.21438.View ArticlePubMedGoogle Scholar
- Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK: Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002, 16: 219-230. 10.1016/S1074-7613(02)00274-1.View ArticlePubMedGoogle Scholar
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