Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 May 4.
Published in final edited form as: Curr Opin Organ Transplant. 2011 Feb;16(1):61–68. doi: 10.1097/MOT.0b013e328342551c

Novel functions of B cells in Transplantation

Jeffrey L Platt 1, Shoichiro Tsuji 1, Marilia Cascalho 1
PMCID: PMC4855507  NIHMSID: NIHMS287487  PMID: 21150607

Abstract

Purpose of review

This manuscript will review current knowledge and recent findings regarding antibody-independent functions of B cells in transplantation.

Recent findings

Until recently the functions of B cells in transplantation have been attributed almost entirely to the antibodies they produce. However, the results of recent trials of B cell depleting agents for treatment of antibody mediated rejection as well as auto-immune disease raised awareness that B cells mediate functions independent of antibody synthesis.

Summary

These “non-classical” functions place B cells at the center of immune regulation with the power to enhance or inhibit immunity.

Keywords: B cells, Transplantation, T cells, Regulatory B cells, B cell-depletion therapy

Introduction

The main biological hurdle to successful transplantation is the immune response of the recipient against the graft and the impact of that response on the graft. The immune response to allo-transplantation includes powerful B cell and T cell responses which cause rejection in the absence of immunosuppression and/or sometime protect grafts [1,2]. Suppression of immunity by administration of immunosuppressive agents enables more than 90% of transplants to survive longer than a year. However, conventional immunosuppressive agents are more affective at preventing responses by T cells than responses by B cells and hence conventional therapies have little impact on antibody mediated rejection. Furthermore, residual immunity, perhaps especially humoral immunity, can damage graft blood vessels over months to years leading to severe vascular disease, such as chronic rejection. Hence, much recent interest has focused on B cell responses to transplantation and the impact of antibodies on the well-being of grafts [3]. The reader is referred to recent symposia on antibody-mediated rejection for consideration of this and related subjects [3].

The relative importance of B cells in the outcome of transplants was first considered in classical studies that divided adaptive immunity into two distinct branches. Warner and Szenberg [4] compared immune responses of various types in normal chickens with immune responses in chickens from which either the bursa of Fabricius or the thymus was removed. Chickens lacking the bursa of Fabricius rejected skin grafts as quickly as chickens in which this structure was left intact while chickens lacking a thymus accepted skin grafts permanently. These results led to the conclusion that graft rejection is thymus-dependent and bursa independent, which was quickly embraced as a canon of immunology [5–7]. Recent experiments in animals and man challenge the segregation of graft rejection into the domain of thymus dependent functions. In fact, B cells produced by the bursa of Fabricius have the most profound impact on clinical organ graft transplants. Problems, such as acute and chronic humoral rejection, caused by alloreactive antibodies are among the greatest challenges in transplantation. Further, to the extent that antibodies induce accommodation, a condition in which the graft resists immunological injury [8,9], which may represent the most common outcome in transplantation, B cells determine the fate of most transplants.

B cells and/or antibodies contribute to the rejection of skin allografts or organ allografts by different mechanisms. Skin allografts are fed predominantly by host blood vessels [10] and as a consequence they do not present vascular targets for alloantibodies. Instead rejection of skin grafts is dominated by cellular rejection [11]. In contrast, organ grafts are fed by blood vessels of the donor, and thus small amounts of alloantibody can generate complement-mediated vascular diseases [12,13], such as hyperacute or acute vascular rejection. How antibodies determine organ graft rejection has been abundantly reviewed elsewhere and will not be discussed here [1,8,13–16].

B cells in transplantation

Recent work has generated contradictory evidence regarding the role of B cells in rejection of allografts. A recent study [17] identified a “B cell signature” associated with renal transplant tolerance in humans. Newell et al. [17] compared the gene expression profiles in peripheral blood lymphocyte subsets of tolerant renal transplant recipients (recipients with stable graft function who had taken no immunosuppressive agents for more than one year) with the profiles of subjects with stable graft function who had taken immunosupressive agents. The tolerant and non-tolerant subjects differed in the expression of 3 genes, IGKV4-1, IGLL1 and IGKV1D-13, which encode Ig light chain variable region gene segments. Newell et al. [17] suggested that expression of these genes may be utilized to identify transplant recipients to be weaned from immunosuppression. Since the expression of those genes in non-transplanted controls was comparable to their expression in tolerant subjects, expression may result from immunosuppression as well as tolerance.

Zarkhin et al. [18] found that reduced graft survival and resistance to steroid therapy was associated with the presence of B lineage cells in grafts. Because CD20-positive B cells in the graft expressed activation markers and MHC class-II, Zarkhin et al. [18] suggested that B cells in the grafts might present donor antigen to T cells, amplifying anti-graft immunity. These authors also found that presence of CD20-negative CD38-positive plasmablasts and plasma cells infiltrating the grafts correlated with circulating donor-specific antibody and concluded that these cells might contribute to antibody mediated rejection and steroid resistance.

How B cells impact in the immune responses to transplantation has been sought in mice by genetic engineering and in human subjects using B cell depleting agents. Experiments using B cell deficient mice have yet to generate definitive concepts regarding involvement of B cells in antibody dependent or antibody independent facets of allograft rejection. Studies in mice rendered B cell deficient by targeted deletion of heavy chain constant region µ membrane exons, the so called µMT mice [19], have failed to reveal any significant impact on the outcome of fully allogeneic skin transplants [20] or on the outcome of skin transplants disparate for minor histocompatibility antigens [20,21]. Because µMT mice produce some antibodies [22] Abbuatthieh et al. [20] investigated the outcome of skin grafts in JH-/- mice which lack B cells and immunoglobulin completely, owing to a gene targeted deletion of the JH gene segments of the heavy chain loci [23]. Abbuatthieh [20] and colleagues showed that JH-/- B cell deficient mice rejected skin grafts differing in major or minor histocompatibility antigens with the same kinetics as wild type. Normal rejection of skin grafts was even more surprising given the compromised lymphoid structures [24,25] and the severe contraction in the diversity of the T cell compartment [26]. The apparent lack of impact of B cell and immunoglobulin deficiency on skin graft rejection might at a first glance suggest that B cells and immunoglobulin do not contribute to rejection of allografts. This conclusion may be premature however.

B cells have been found by some to impact on the outcome of organ transplants [27–30], but not by others [31]. Wasowska and colleagues [28] found that only 85% of the cardiac allografts were rejected within 14 days in µMT B cell deficient recipients, while all cardiac allografts were rejected in wild type recipients. The authors further demonstrated that wild type rejection of cardiac allografts could be restored in µMT recipients by administering donor-specific antibodies [28,32]. Gareau and colleagues [30] studied the role of B cells in the development of vasculopathy of aortic grafts in mice and concluded that antibodies were required for vasculopathy. Kelishadi et al. [29] studied the outcome of heterotopic cardiac allografts in cynomologous monkeys following preemptive anti-CD20 monoclonal antibody (mAb) therapy combined with the calcineurin inhibitor cyclosporine A (CsA). These studies [29] showed that CD20-positive B cell depletion combined with CsA prolonged graft survival and attenuated allograft vasculopathy suggesting that B cells contribute both to acute and chronic rejection. Noorchashm et al. [27] compared the outcome of heterotopic cardiac transplants in mice engineered to prevent expression of MHC class II on B cells with the outcome in wild type mice. The former retained allogeneic grafts for > 70 days while the latter rejected grafts in 9.5 days. Noorchashm et al. [27] suggested that B cells contributed to rejection by presenting antigen. In contrast, Nozaki et al. [31] reached a different conclusion. Their studies found that mice of µMT stock rejected cardiac and skin allografts with the same kinetics as wild type mice; however, µMT mice from which CD8+ T cells were depleted retained cardiac allografts indefinitely, but still rejected skin grafts rapidly. Nozaki et al. [31] concluded that B cells are dispensable in CD4-T cell mediated organ graft rejection. However in all the examples cited, since µMT mice are not completely B cell deficient and produce switched Ig isotypes [22], one cannot exclude the possibility that antibodies could have influenced cardiac allograft survival in complex ways.

B cell depletion therapies (with anti-human CD20 antibodies) in transplant recipients have brought more controversy to the functions of B cells in transplantation. Anti-human CD20 (rituximab) is a chimeric monoclonal antibody (mAb), composed of variable regions isolated from a murine clone (IDEC-2B8) linked to human IgG1 heavy chain and kappa light chain constant regions [33]. Anti-CD20 mAb was first used to treat non-Hodgkin's lymphoma. Rituximab binds with high affinity to CD20 on the surface of malignant and normal B cells, but not on other cells. CD20 is a transmembrane protein that functions as a calcium channel and is expressed from pre-B cell to mature B cell stages [34,35]. Rituximab cross-links CD20 depleting B cells by inducing antibody-dependent cell-mediated cytotoxicity [36], complement–dependent cytotoxicity [35,37] and/or apoptosis [35,38]. Because the precursors of B cells and antibody secreting cells lack CD20, anti-CD20 mAb therapy spares developing B cells and plasma cells and preserves sera IgG [39]. A single administration of anti-CD20 mAb depleted peripheral human naïve B cells for 3 months to one year, but depletion was less complete in secondary lymphoid tissues [40]. Glennie et al. [36] provide an excellent review on the mechanisms of anti-CD20 mAb B cell depletion.

Anti-CD20 mAb therapy improved the outcome of antibody mediated rejection [41], reviewed in [42] and induction therapy of highly sensitized patients [42,43]. Although administration of anti-CD20 mAb is associated with a favorable outcome of transplants, it is unclear whether the clinical improvement observed was due to inhibition of production of donor-specific antibodies or inhibition of other functions of B cells.

Results of one trial using anti-CD20 mAb as induction therapy have challenged the idea that B cells play no role in cellular rejection [44]. Clatworthy et al. [44] found that 83% of subjects treated with anti-CD20 mAb (rituximab) experienced cellular rejection while only 14% of subjects treated with an anti-CD25 experienced that condition. Acute cellular rejection was confirmed by biopsy and occurred in the first three months after transplantation. These results suggested that B cells might regulate immunity in ways not completely understood. The grafts of subjects treated with anti-CD20 mAb contained higher concentrations of tumor necrosis factor α, interleukin 6 and interleukin 10 than grafts of controls. Clatworthy et al. [44] suggested that depletion of B cells with anti-CD20 mAb might cause release of pro-inflammatory cytokines, stimulating antigen presentation and T cell activation. However, the results are also consistent with the possibility that B cells suppress inflammation and immunity, both being heightened by depletion.

Novel functions of B cells

While antibodies produced by B cells clearly modify the outcome of organ grafts, other functions and products of B cells might do so as well. We refer to these functions as “antibody-independent” to denote independence from actions of antibodies. In some cases however, the functions of B cells may depend more or less on the presence or stimulation of the B cell receptor or on use of the B cell receptor to facilitate transport of antigen into the cell.

Lymphoid organogenesis

Lakkis and colleagues [45] found that rejection of organ allografts depends on the existence of lymphoid tissue which is necessary to permit T cell activation. However, development of lymphoid tissue depends absolutely on the function of B cells, which produce lymphotoxin and which in turn generate lymphoid organogenesis [46]. We consider involvement of B cells in lymphoid organogenesis to be an antibody-independent function of B cells; thus B cell deficient mice, i.e. JH-/-mice, µMT and RAG-deficient mice, have grossly abnormal lymphoid organs [24,46] which may impact the generation of immunity to transplants.

T cell repertoire development

Cell mediated immunity is thought to reflect at least in part the diversity of T cell antigen receptors (TCR). In support of this concept are aberrations in the TCR repertoire found in conditions of immunodeficiency such as AIDS. Although the development of T cells was always thought to be independent of B cells (hence the use of “B” and “T” in classifying lymphocytes) [47], Keshavarzi et al. [48] observed that mice lacking B cells have a reduced number of T cells in the thymus and periphery and suggested that B cells and/or immunoglobulins contribute to the selection of T cells in the thymus and their maintenance in the periphery. Based on this concept, João et al. [26] measured TCR diversity in B cell deficient mice or mice with oligoclonal B cell repertoires [26]. B cell deficient mice had TCR repertoires contracted more than 10,000 fold compared to wild type and mice with oligoclonal B cells had TCR repertoires contracted 100 fold compared to wild type. Because TCR diversity could be restored either by adoptive transfer of diverse B cells or by administration of diverse Ig, the authors concluded that Ig gene diversity generates TCR diversity. As one potential mechanism through which B cells diversify the developing T cell repertoire, João et al. [26] have proposed that B cell receptors and Ig provide diverse peptides for positive selection of T cells in the thymus to maintain T cells in the periphery [26,48].

The extent to which B cells establish the repertoire of T cells that respond to a transplant is unknown. Since cellular immunity is predicated on the availability of diverse peptide/self MHC specific T cell receptors, one might predict that contraction of the T cell repertoire should result in deficient cellular immunity. However, this prediction fails in some remarkable ways. As an example, children who undergo thymectomy and treatment with T cell-depleting agents as a result of heart transplantation in infancy have profound contraction of T cell diversity [49]. However, despite this contraction, recipients transplanted early in life are susceptible to rejection and do not suffer especially from opportunistic infection or other problems associated with immunodeficiency. In agreement with the conclusion that contractions of TCR do not cause defects in themselves, B cell and/or immunoglobulin deficient mice can reject primary skin allografts as rapidly as wild type counterparts [20]. Thus, contraction of the T cell repertoire may not by itself cause immunodeficiency because T cells adapt to repertoire contraction suffered early in life [49]. Rejection of allografts, however, can hardly be considered a sensitive test of cellular immunity since humans and mice with gross defects in cellular immunity such as DiGeorge or nude can still reject allografts [50]. However, defects in TCR diversity might yet be found to influence the outcome of allografts and the recipients of allografts in more subtle ways, especially when added to the impact of immunosuppressive therapy.

Antigen presentation

B cells can present antigen to T cells [51–53]. B cells express MHC class I and MHC class II complexes and co-stimulatory molecules, such as CD80 and CD86 [53] and OX40L [54]. B cells can prime and activate T cells almost as effectively as dendritic cells [51]. B cell antigen presentation can lead to the clonal expansion of both B and T cells and may be necessary for the generation and maintenance of B cell and T cell memory [55–58].

B cells activate T cells in the same way as other antigen presenting cells, that is, they take up and process proteins, present peptides associated with MHC class II to T cells and express co-stimulatory molecules. B cells can also activate T cells by a mechanism distinct from the mechanisms used by other antigen presenting cells. In contrast to other antigen presenting cells, B cells can take up antigen specifically via the B cell receptor into the endosomal compartment [52] and as a consequence increase presentation of peptides from an antigen to which they have a unique specificity [51,53]. Thus, MHC class II expressed by activated B cells can be enriched for peptides derived from the antigen recognized by the B cell repertoire (BCR). Lanzavecchia [59] showed that antigen-specific interaction between T cells and B cells required antigen-specific immunoglobulins and antigen processing, and promoted activation of MHC class II restricted T cells. Activation of T cells directed against fragments of the antigen internalized by the BCR and presented on the surface of B cells establishes a “cognate” link between the T cell and B cell [59]. Cognate interaction might coordinate, amplify and co-regulate the responses of B cells and T cells. Whether and to what extent cognate interactions account for immunity to transplantation is not known.

The role of B cells as antigen presenting cells has been confirmed by several research groups [60–62]. More recent studies have generated controversy about whether antigen presentation by B cells contributes to T cell priming in vivo. B cells may not be needed for presentation of protein and viral antigens that lead to priming CD4 T cell responses that are measured by proliferation and cytokine production [21,63,64]. However, B cells are important for generating some CD4 T cell responses to protein antigens [65,66]. Activated B cells have been shown to skew T cell responses towards Th2 and production of Th2-derived cytokines [67–69]. Thus B cells appear to influence the fate of T cells depending on the environment and stimuli. In transplantation the role of B cells in antigen presentation has been difficult to ascertain because B cells have a broad impact on development of lymphoid tissue and T cells, thus complete absence of B cells impacts in multiple facets of immunity.

Cytokine production

B cells produce multiple cytokines including IL-4, IL-6, IL-10, lymphotoxin-α, TGFβ and IFNγ [67,70,71]. How cytokine production by B cells is orchestrated in the regulation of immunity is not understood and the subject of current research.

B cells as regulators of T cell-dependent immunity and inflammation

How exactly the antibody-independent functions of B cells might influence the outcome of cellular immunity to transplants has not been studied beyond potential involvement in antigen presentation, mentioned above. However, some potential functions can be drawn from work testing antibody-independent functions of B cells in autoimmune diseases. For a comprehensive review we recommend articles by Yanaba et al. [72] and Bouaziz et al. [73].

Anti-CD20 mAb therapy has improved the outcome of autoimmune disorders with pathogenic antibodies such as neuropathies associated with auto-antibodies [74], anti-factor VIII syndrome [75], mixed cryoglobulinemia [76], myasthenia gravis [77], Graves disease [78] and Sjogren syndrome [79] to name a few. The possibility that antibody-independent functions of B cells might explain improvements in the manifestations of autoimmunity can be taken from investigation of the impact of anti-CD20 mAb on the outcome of T cell mediated auto-immune diseases such as diabetes and relapsing multiple sclerosis. Anti-CD20 mAb treatment has been found to preserve beta cell function in subjects with insulin-dependent diabetes mellitus. In this study patients treated with anti-CD20 mAb showed improved endogenous insulin production, better control of glycemia and fewer diabetic complications [39]. Similarly, anti-CD20 mAb treatment decreased inflammatory brain lesions and clinical relapses in multiple sclerosis [80] without changing significantly the levels of IgM, IgG and IgA [80]. These conclusions are consistent with a role for B cells in the regulation of immunity.

One antibody-independent function contributed by B cells in autoimmune disease may involve the interaction of B cells with T cells. Non-obese diabetes prone (NOD) mice develop diabetes owing to cellular immunity directed against insulin producing beta cells. NOD prone mice made B cell deficient by breeding with the µMT strain have a lower incidence of diabetes [81]. Support for the idea that B cells contribute to initial priming and expansion of auto-immune T cells is found in a recent study in AIRE-deficient mice, a model for auto-immune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [82]. Gavanescu et al. [82] found that AIRE-deficient µMT mice, AIRE-deficient JH-/-mice, and AIRE-deficient mice treated with anti-CD20 mAb do not develop or develop less severe autoimmune APECED than B cell proficient AIRE-deficient mice. Because depletion of B cells later in the course of disease ameliorated but did not reverse auto-immunity the authors propose that B cells contribute early in the development of disease, perhaps by helping to prime autoimmune T cells.

In an animal model of multiple sclerosis, the results of anti-CD20 mAb therapy were ambivalent. While anti-CD20 mAb therapy administered after disease induction ameliorated experimental auto-immune encephalitis symptoms, the same treatment given prior to disease induction induced a more severe course [83]. In a separate study, Haas and colleagues [84] examined the effect of depleting CD20-positive B cells in a mouse model of human systemic lupus erythematosus. These authors found that spontaneous disease was delayed when B cell depletion therapy was administered to mice aged between 12 and 18 weeks. In contrast, when B cell depletion was administered to 4 week old mice it hastened disease onset. These studies demonstrated that B cell depletion can have opposite effects in the induction of protection or pathology, depending on when it occurs in the course of auto-immunity.

Antibody-independent B cell functions might restrain some facets of immunity. As early as 1974, Katz et al. [85] compared the magnitude of delayed-type hypersensitive (DTH) reactions in cyclophosphamid treated recipients followed by transfer of ovalbumin primed B and/or T cells. These authors found that the magnitude of the DTH responses was decreased when B cells were transferred together with T cells compared to the magnitude of the DTH reactions obtained in recipients receiving T cells alone [85]. These studies suggested that B cells suppress cellular immunity. Mizoguchi et al. [86] used the term “regulatory B cells” for the first time to identify B cells with inhibitory properties. B cells that suppress immunity have now been identified by several groups including Harris et al. [67,70] and Matsushita et al. [83]. B cells expressing CD1dhi, CD5+ CD19hi regulate T cell activation and inflammation through the production of IL-10 in an antigen-specific manner [70,83,87–89]. IL-10 suppresses production of pro-inflammatory cytokines by T cells, monocytes and macrophages [90], inhibits proliferation of antigen specific T cells by decreasing antigen presentation by dendritic cells, macrophages, Langerhans cells and B cells [91]. Thus mice deficient in IL-10 spontaneously develop inflammatory bowel disease [92] and IL-10 deficiency enhances the severity of several auto-immune and inflammatory disorders [93–95]. However, DiLillo et al. proposed that IL-10 regulates immunity locally rather than systemically [96]. Whether the properties of B cells in the regulation of immunity depend only on the production of IL-10 remains to be investigated.

What causes differentiation of regulatory B cells with immunosuppressive and anti-inflammatory properties is not known. IL-10 producing B cells might be generated as a consequence of polyclonal B cell activation, but regulation of inflammation and autoimmunity by B cells appears to be antigen specific [70,83]. In fact, development of B regulatory cells requires a diverse B cell repertoire [73]. If the regulatory properties of B cells impact the fate of organ transplants, one would predict that B cell depletion should exacerbate cellular alloimmunity. Consistent with this possibility is the work by Clatworthy et al. [44] who observed enhanced cellular rejection following B cell depletion therapy. However, enhanced cellular immunity may remain hidden in most transplant recipients undergoing T-cell specific immunosuppression explaining why enhanced cellular immunity in the course of B cell depletion therapy has been reported only in a small number of cases.

Conclusion

Once B cells were thought merely to produce antibodies, however, recent studies indicate far more complex and sometimes contradictory functions of B cells. B cells organize lymphoid structures, generate T cell diversity, present antigen and regulate immunity. Therefore, B cell depleting therapies could benefit but also compromise the outcome of organ transplants. Most knowledge about the antibody-independent functions of B cells derives from investigation of autoimmune diseases. However, clinical and basic research on autoimmunity is hindered by uncertainty regarding the onset of autoimmune response and the nature of antigens which provoke it.

In transplantation, the effects of immunity on the graft start at transplantation, thus defining a window in time for therapeutic intervention. The field of transplantation offers many new emerging tools to gain further important insights about novel, antibody-independent functions of B cells.

Key points.

  1. B cells contribute to immunity by producing antibodies and by antibody-independent functions

  2. Antibody-independent functions of B cells include: Lymphoid organogenesis; T cell repertoire development; Antigen presentation; Production of cytokines and Regulation of T cell-dependent immunity and inflammation

  3. B cell depletion may enhance or inhibit cellular immunity and thus B cell depletion should be considered with the broader goal of regulating immunity, rather than simply to remove antibodies.

Acknowledgements

Supported by grants from the National Institutes of Health HL52297 and HL79067

List of abbreviations

AIRE

autoimmune regulator

APECED

autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

CsA

calcineurin inhibitor cyclosporine A

DTH

delayed-type hypersensitive

IgA

immunoglobulin A

IgG

immunoglobulin G

IgM

immunoglobulin M

IL

interleukin

mAb

monoclonal antibody

MHC

major histocompatibility complex

NOD

non-obese diabetes

TCR

T cell receptor

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Lynch RJ, Platt JL. Accommodation in organ transplantation. Curr Opin Organ Transplant. 2008;13:165–170. doi: 10.1097/MOT.0b013e3282f6391e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Platt JL. Antibodies in transplantation. Discov Med. 2010;10:125–133. [PMC free article] [PubMed] [Google Scholar]
  • 3.Solez K, Colvin RB, Racusen LC, et al. Banff '05 meeting report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN') American Journal of Transplantation. 2007;7:518–526. doi: 10.1111/j.1600-6143.2006.01688.x. [DOI] [PubMed] [Google Scholar]
  • 4.Szenberg A, Warner NL. Dissociation of immunological responsiveness in fowls with a hormonally arrested development of lymphoid tissues. Nature. 1962;194:146–147. [Google Scholar]
  • 5.Good RA, Dalmasso AP, Martinez C, et al. The role of the thymus in development of immunologic capacity in rabbits and mice. The Journal of Experimental Medicine. 1962;116:773. doi: 10.1084/jem.116.5.773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Cooper MD, Peterson RD, Good RA. Delineation of the Thymic and Bursal Lymphoid Systems in the Chicken. Nature. 1965;205:143–146. doi: 10.1038/205143a0. [DOI] [PubMed] [Google Scholar]
  • 7.Cooper MD, Raymond DA, Peterson RD, et al. The functions of the thymus system and the bursa system in the chicken. J Exp Med. 1966;123:75–102. doi: 10.1084/jem.123.1.75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Platt JL, Vercellotti GM, Dalmasso AP, et al. Transplantation of discordant xenografts: a review of progress. Immunol Today. 1990;11:450–456. doi: 10.1016/0167-5699(90)90174-8. discussion 456-457. [DOI] [PubMed] [Google Scholar]
  • 9.Koch CA, Khalpey ZI, Platt JL. Accommodation: preventing injury in transplantation and disease. J Immunol. 2004;172:5143–5148. doi: 10.4049/jimmunol.172.9.5143. [DOI] [PubMed] [Google Scholar]
  • 10.Pober JS, Bothwell AL, Lorber MI, et al. Immunopathology of human T cell responses to skin, artery and endothelial cell grafts in the human peripheral blood lymphocyte/severe combined immunodeficient mouse. Springer Semin Immunopathol. 2003;25:167–180. doi: 10.1007/s00281-003-0135-1. [DOI] [PubMed] [Google Scholar]
  • 11.Cerny A, Ramseier H, Bazin H, Zinkernagel RM. Unimpaired first-set and second-set skin graft rejection in agammaglobulinemic mice. Transplantation. 1988;45:1111–1113. doi: 10.1097/00007890-198806000-00022. [DOI] [PubMed] [Google Scholar]
  • 12.Parker W, Stitzenberg KB, Yu PB, et al. Biophysical characteristics of anti-Gal(alpha)1-3Gal IgM binding to cell surfaces: implications for xenotransplantation. Transplantation. 2001;71:440–446. doi: 10.1097/00007890-200102150-00018. [DOI] [PubMed] [Google Scholar]
  • 13.Platt JL. C4d and the fate of organ allografts. Journal of the American Society of Nephrology. 2002;13:2417. doi: 10.1097/01.asn.0000030140.74450.0b. [DOI] [PubMed] [Google Scholar]
  • 14.Platt JL. Antibodies in graft rejection. In: Bach FH, Auchincloss H, editors. Transplantation Immunology. Wiley-Liss Inc.; 1995. pp. 113–129. [Google Scholar]
  • 15.Cascalho M, Platt JL. The immunological barrier to xenotransplantation. Immunity. 2001;30:437–446. doi: 10.1016/s1074-7613(01)00124-8. [DOI] [PubMed] [Google Scholar]
  • 16.Wasowska BA. Mechanisms involved in antibody- and complement-mediated allograft rejection. Immunologic Research. 2010;47:25–44. doi: 10.1007/s12026-009-8136-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Newell KA, Asare A, Kirk AD, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. Journal of Clinical Investigation. 2010;120:1836–1847. doi: 10.1172/JCI39933.. The paper exemplifies a strategy to discover markers associated with certain outcomes in transplantation.
  • 18.Zarkhin V, Kambham N, Li L, et al. Characterization of intra-graft B cells during renal allograft rejection. Kidney International. 2008;74:664–673. doi: 10.1038/ki.2008.249. [DOI] [PubMed] [Google Scholar]
  • 19.Kitamura D, Roes J, Kuhn R, Rajewsky K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature. 1991;350:423–426. doi: 10.1038/350423a0. [DOI] [PubMed] [Google Scholar]
  • 20.AbuAttieh M, Rebrovich M, Wettstein PJ, et al. Fitness of cell-mediated immunity independent of repertoire diversity. The Journal of Immunology. 2007;178:2950–2960. doi: 10.4049/jimmunol.178.5.2950. [DOI] [PubMed] [Google Scholar]
  • 21.Epstein MM, Di Rosa F, Jankovic D, et al. Successful T cell priming in B cell-deficient mice. Journal of Experimental Medicine. 1995;182:915–922. doi: 10.1084/jem.182.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Macpherson AJ, Lamarre A, McCoy K, et al. IgA production without mu or delta chain expression in developing B cells. Nat Immunol. 2001;2:625–631. doi: 10.1038/89775. [DOI] [PubMed] [Google Scholar]
  • 23.Chen J, Trounstine M, Alt FW, et al. Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. International Immunology. 1993;5:647–656. doi: 10.1093/intimm/5.6.647. [DOI] [PubMed] [Google Scholar]
  • 24.Golovkina TV, Shlomchik M, Hannum L, Chervonsky A. Organogenic role of B lymphocytes in mucosal immunity. Science. 1999;286:1965–1968. doi: 10.1126/science.286.5446.1965. [DOI] [PubMed] [Google Scholar]
  • 25.Ngo VN, Cornall RJ, Cyster JG. Splenic T zone development is B cell dependent. Journal of Experimental Medicine. 2001;194:1649–1660. doi: 10.1084/jem.194.11.1649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. João CM, Ogle BM, Gay-Rabinstein C, et al. B cell-dependent TCR diversification. Journal of Immunology. 2004;172:4709–4716. doi: 10.4049/jimmunol.172.8.4709.. The authors showed that immunoglobulin diversity determine the diversity of the T cell compartment thus implicating B cells in the development and maintenance of the T cell compartment.
  • 27. Noorchashm H, Reed AJ, Rostami SY, et al. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol. 2006;177:7715–7722. doi: 10.4049/jimmunol.177.11.7715.. The paper tests the role of B cell antigen-mediated presentation in rejection of skin and organ allografts.
  • 28.Wasowska BA, Qian Z, Cangello DL, et al. Passive transfer of alloantibodies restores acute cardiac rejection in IgKO mice. Transplantation. 2001;71:727–736. doi: 10.1097/00007890-200103270-00007. [DOI] [PubMed] [Google Scholar]
  • 29.Kelishadi SS, Azimzadeh AM, Zhang T, et al. Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. Journal of Clinical Investigation. 2010;120:1275–1284. doi: 10.1172/JCI41861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Gareau A, Hirsch GM, Lee TD, Nashan B. Contribution of B cells and antibody to cardiac allograft vasculopathy. Transplantation. 2009;88:470–477. doi: 10.1097/TP.0b013e3181b076cc. [DOI] [PubMed] [Google Scholar]
  • 31. Nozaki T, Rosenblum JM, Ishii D, et al. CD4 T cell-mediated rejection of cardiac allografts in B cell-deficient mice. Journal of Immunology. 2008;181:5257–5263. doi: 10.4049/jimmunol.181.8.5257.. The paper suggests a complex role of B cells in rejection of allografts.
  • 32.Rahimi S, Qian Z, Layton J, et al. Non-complement- and complement-activating antibodies synergize to cause rejection of cardiac allografts. Am J Transplant. 2004;4:326–334. doi: 10.1111/j.1600-6143.2004.00334.x. [DOI] [PubMed] [Google Scholar]
  • 33.Grillo-Lopez AJ. Rituximab: an insider's historical perspective. Seminars in Oncology. 2000;27:9–16. [PubMed] [Google Scholar]
  • 34.Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Seminars in Oncology. 2000;27:17–24. [PubMed] [Google Scholar]
  • 35.Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83:435–445. [PubMed] [Google Scholar]
  • 36. Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Molecular Immunology. 2007;44:3823–3837. doi: 10.1016/j.molimm.2007.06.151.. This article provides an excellent review on the mechanisms of anti-CD20 B cell depletion.
  • 37.Golay J, Lazzari M, Facchinetti V, et al. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood. 2001;98:3383–3389. doi: 10.1182/blood.v98.12.3383. [DOI] [PubMed] [Google Scholar]
  • 38.Pedersen IM, Buhl AM, Klausen P, et al. The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism. Blood. 2002;99:1314–1319. doi: 10.1182/blood.v99.4.1314. [DOI] [PubMed] [Google Scholar]
  • 39. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. New England Journal of Medicine. 2009;361:2143–2152. doi: 10.1056/NEJMoa0904452.. Report of a clinical trial of anti-CD20 mab in insulin-dependent diabetes mellitus. The results suggest complex functions of B cells in auto-immune diabetes.
  • 40.Maloney DG. Mechanism of action of rituximab. Anti-Cancer Drugs. 2001;12(Suppl 2):S1–S4. [PubMed] [Google Scholar]
  • 41.Lefaucheur C, Nochy D, Andrade J, et al. Comparison of combination Plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection. Am J Transplant. 2009;9:1099–1107. doi: 10.1111/j.1600-6143.2009.02591.x. [DOI] [PubMed] [Google Scholar]
  • 42. Singh N, Pirsch J, Samaniego M. Antibody-mediated rejection: treatment alternatives and outcomes. Transplant Rev (Orlando) 2009;23:34–46. doi: 10.1016/j.trre.2008.08.004.. Excellent review of diagnstic and treatment of antibody mediated rejection.
  • 43.Vo AA, Peng A, Toyoda M, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation. 2010;89:1095–1102. doi: 10.1097/TP.0b013e3181d21e7f. [DOI] [PubMed] [Google Scholar]
  • 44. Clatworthy MR, Watson CJ, Plotnek G, et al. B-cell-depleting induction therapy and acute cellular rejection. New England Journal of Medicine. 2009;360:2683–2685. doi: 10.1056/NEJMc0808481.. The paper reports the outcome of anti-CD20 mab therapy before kidney transplantation. The authors document increase frequency of cellular mediated rejection in patients treated with anti-CD20 mab.
  • 45.Lakkis FG, Arakelov A, Konieczny BT, Inoue Y. Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med. 2000;6:686–688. doi: 10.1038/76267. [DOI] [PubMed] [Google Scholar]
  • 46.Fu YX, Huang G, Wang Y, Chaplin DD. B lymphocytes induce the formation of follicular dendritic cell clusters in a lymphotoxin alpha-dependent fashion. J Exp Med. 1998;187:1009–1018. doi: 10.1084/jem.187.7.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Roitt IM, Greaves MF, Torrigiani G, et al. The cellular basis of immunological responses. A synthesis of some current views. Lancet. 1969;2:367–371. doi: 10.1016/s0140-6736(69)92712-3. [DOI] [PubMed] [Google Scholar]
  • 48.Keshavarzi S, Rietz C, Simoes S, et al. The possibility of B-cell-dependent T-cell development. Scandinavian Journal of Immunology. 2003;57:446–452. doi: 10.1046/j.1365-3083.2003.01257.x. [DOI] [PubMed] [Google Scholar]
  • 49.Ogle BM, West LJ, Driscoll DJ, et al. Effacing of the T cell compartment by cardiac transplantation in infancy. Journal of Immunology. 2006;176:1962–1967. doi: 10.4049/jimmunol.176.3.1962. [DOI] [PubMed] [Google Scholar]
  • 50.Markert ML, Li J, Devlin BH, et al. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. Journal of Immunology. 2008;180:6354–6364. doi: 10.4049/jimmunol.180.9.6354. [DOI] [PubMed] [Google Scholar]
  • 51.Constant SL. B lymphocytes as antigen-presenting cells for CD4+ T cell priming in vivo. Journal of Immunology. 1999;162:5695–5703. [PubMed] [Google Scholar]
  • 52.Clark MR, Massenburg D, Siemasko K, et al. B-cell antigen receptor signaling requirements for targeting antigen to the MHC class II presentation pathway. Curr Opin Immunol. 2004;16:382–387. doi: 10.1016/j.coi.2004.03.007. [DOI] [PubMed] [Google Scholar]
  • 53.Constant S, Schweitzer N, West J, et al. B lymphocytes can be competent antigen-presenting cells for priming CD4+ T cells to protein antigens in vivo. Journal of Immunology. 1995;155:3734–3741. [PubMed] [Google Scholar]
  • 54.Linton PJ, Bautista B, Biederman E, et al. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. Journal of Experimental Medicine. 2003;197:875–883. doi: 10.1084/jem.20021290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Shimoda M, Koni PA. MHC-restricted B-cell antigen presentation in memory B-cell maintenance and differentiation. Crit Rev Immunol. 2007;27:47–60. doi: 10.1615/critrevimmunol.v27.i1.40. [DOI] [PubMed] [Google Scholar]
  • 56.Linton P, Harbertson J, Bradley LM. A critical role for B cells in the development of memory CD4 cells. Journal of Immunology. 2000;165:5558–5565. doi: 10.4049/jimmunol.165.10.5558. [DOI] [PubMed] [Google Scholar]
  • 57.van Essen D, Dullforce P, Brocker T, Gray D. Cellular interactions involved in Th cell memory. Journal of Immunology. 2000;165:3640–3646. doi: 10.4049/jimmunol.165.7.3640. [DOI] [PubMed] [Google Scholar]
  • 58.van Essen D, Dullforce P, Gray D. Role of B cells in maintaining helper T-cell memory. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences. 2000;355:351–355. doi: 10.1098/rstb.2000.0572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985;314:537–539. doi: 10.1038/314537a0.. First report testing the mechanism of T and B cell cognate interaction.
  • 60.Janeway CA, Jr, Ron J, Katz ME. The B cell is the initiating antigen-presenting cell in peripheral lymph nodes. Journal of Immunology. 1987;138:1051–1055. [PubMed] [Google Scholar]
  • 61.Kurt-Jones EA, Liano D, HayGlass KA, et al. The role of antigen-presenting B cells in T cell priming in vivo. Studies of B cell-deficient mice. Journal of Immunology. 1988;140:3773–3778. [PubMed] [Google Scholar]
  • 62.Ron Y, Sprent J. T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes. Journal of Immunology. 1987;138:2848–2856. [PubMed] [Google Scholar]
  • 63.Phillips JA, Romball CG, Hobbs MV, et al. CD4+ T cell activation and tolerance induction in B cell knockout mice. Journal of Experimental Medicine. 1996;183:1339–1344. doi: 10.1084/jem.183.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Topham DJ, Tripp RA, Hamilton-Easton AM, et al. Quantitative analysis of the influenza virus-specific CD4+ T cell memory in the absence of B cells and Ig. Journal of Immunology. 1996;157:2947–2952. [PubMed] [Google Scholar]
  • 65.Liu Y, Wu Y, Ramarathinam L, et al. Gene-targeted B-deficient mice reveal a critical role for B cells in the CD4 T cell response. International Immunology. 1995;7:1353–1362. doi: 10.1093/intimm/7.8.1353. [DOI] [PubMed] [Google Scholar]
  • 66.Rivera A, Chen CC, Ron N, et al. Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations. Int Immunol. 2001;13:1583–1593. doi: 10.1093/intimm/13.12.1583. [DOI] [PubMed] [Google Scholar]
  • 67.Harris DP, Haynes L, Sayles PC, et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nature Immunology. 2000;1:475–482. doi: 10.1038/82717. [DOI] [PubMed] [Google Scholar]
  • 68.Macaulay AE, DeKruyff RH, Umetsu DT. Antigen-primed T cells from B cell-deficient JHD mice fail to provide B cell help. Journal of Immunology. 1998;160:1694–1700. [PubMed] [Google Scholar]
  • 69.Stockinger B, Zal T, Zal A, Gray D. B cells solicit their own help from T cells. Journal of Experimental Medicine. 1996;183:891–899. doi: 10.1084/jem.183.3.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Yanaba K, Bouaziz JD, Haas KM, et al. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28:639–650. doi: 10.1016/j.immuni.2008.03.017. [DOI] [PubMed] [Google Scholar]
  • 71.Pistoia V. Production of cytokines by human B cells in health and disease. Immunol Today. 1997;18:343–350. doi: 10.1016/s0167-5699(97)01080-3. [DOI] [PubMed] [Google Scholar]
  • 72.Yanaba K, Bouaziz JD, Matsushita T, et al. B-lymphocyte contributions to human autoimmune disease. Immunological Reviews. 2008;223:284–299. doi: 10.1111/j.1600-065X.2008.00646.x. [DOI] [PubMed] [Google Scholar]
  • 73.Bouaziz JD, Yanaba K, Tedder TF. Regulatory B cells as inhibitors of immune responses and inflammation. Immunological Reviews. 2008;224:201–214. doi: 10.1111/j.1600-065X.2008.00661.x. [DOI] [PubMed] [Google Scholar]
  • 74.Levine TD, Pestronk A. IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using Rituximab. Neurology. 1999;52:1701–1704. doi: 10.1212/wnl.52.8.1701. [DOI] [PubMed] [Google Scholar]
  • 75.Wiestner A, Cho HJ, Asch AS, et al. Rituximab in the treatment of acquired factor VIII inhibitors. Blood. 2002;100:3426–3428. doi: 10.1182/blood-2002-03-0765. [DOI] [PubMed] [Google Scholar]
  • 76.Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood. 2003;101:3827–3834. doi: 10.1182/blood-2002-09-2856. [DOI] [PubMed] [Google Scholar]
  • 77.Zaja F, Russo D, Fuga G, et al. Rituximab for myasthenia gravis developing after bone marrow transplant. Neurology. 2000;55:1062–1063. doi: 10.1212/wnl.55.7.1062-a. [DOI] [PubMed] [Google Scholar]
  • 78.Heemstra KA, Toes RE, Sepers J, et al. Rituximab in relapsing Graves' disease, a phase II study. European Journal of Endocrinology / European Federation of Endocrine Societies. 2008;159:609–615. doi: 10.1530/EJE-08-0084. [DOI] [PubMed] [Google Scholar]
  • 79.Pijpe J, van Imhoff GW, Spijkervet FK, et al. Rituximab treatment in patients with primary Sjogren's syndrome: an open-label phase II study. Arthritis and Rheumatism. 2005;52:2740–2750. doi: 10.1002/art.21260. [DOI] [PubMed] [Google Scholar]
  • 80. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. New England Journal of Medicine. 2008;358:676–688. doi: 10.1056/NEJMoa0706383.. The authors report clinical improvement of patients with relapsing-remitting multiple sclerosis following anti-CD20 mab therapy.
  • 81.Silveira PA, Dombrowsky J, Johnson E, et al. B cell selection defects underlie the development of diabetogenic APCs in nonobese diabetic mice. Journal of Immunology. 2004;172:5086–5094. doi: 10.4049/jimmunol.172.8.5086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Gavanescu I, Benoist C, Mathis D. B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:13009–13014. doi: 10.1073/pnas.0806874105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Matsushita T, Yanaba K, Bouaziz JD, et al. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. Journal of Clinical Investigation. 2008;118:3420–3430. doi: 10.1172/JCI36030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Haas KM, Watanabe R, Matsushita T, et al. Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. Journal of Immunology. 2010;184:4789–4800. doi: 10.4049/jimmunol.0902391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Katz SI, Parker D, Turk JL. B-cell suppression of delayed hypersensitivity reactions. Nature. 1974;251:550–551. doi: 10.1038/251550a0. [DOI] [PubMed] [Google Scholar]
  • 86.Mizoguchi A, Bhan AK. A case for regulatory B cells. Journal of Immunology. 2006;176:705–710. doi: 10.4049/jimmunol.176.2.705. [DOI] [PubMed] [Google Scholar]
  • 87.Fillatreau S, Sweenie CH, McGeachy MJ, et al. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002;3:944–950. doi: 10.1038/ni833. [DOI] [PubMed] [Google Scholar]
  • 88.Evans JG, Chavez-Rueda KA, Eddaoudi A, et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. Journal of Immunology. 2007;178:7868–7878. doi: 10.4049/jimmunol.178.12.7868. [DOI] [PubMed] [Google Scholar]
  • 89.Gray M, Miles K, Salter D, et al. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:14080–14085. doi: 10.1073/pnas.0700326104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Fiorentino DF, Zlotnik A, Mosmann TR, et al. IL-10 inhibits cytokine production by activated macrophages. Journal of Immunology. 1991;147:3815–3822. [PubMed] [Google Scholar]
  • 91.Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy--review of a new approach. Pharmacological Reviews. 2003;55:241–269. doi: 10.1124/pr.55.2.4. [DOI] [PubMed] [Google Scholar]
  • 92.Kuhn R, Lohler J, Rennick D, et al. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  • 93.Bettelli E, Das MP, Howard ED, et al. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. Journal of Immunology. 1998;161:3299–3306. [PubMed] [Google Scholar]
  • 94.Johansson AC, Hansson AS, Nandakumar KS, et al. IL-10-deficient B10.Q mice develop more severe collagen-induced arthritis, but are protected from arthritis induced with anti-type II collagen antibodies. Journal of Immunology. 2001;167:3505–3512. doi: 10.4049/jimmunol.167.6.3505. [DOI] [PubMed] [Google Scholar]
  • 95.Berg DJ, Leach MW, Kuhn R, et al. Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses. Journal of Experimental Medicine. 1995;182:99–108. doi: 10.1084/jem.182.1.99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. DiLillo DJ, Matsushita T, Tedder TF. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Annals of the New York Academy of Sciences. 2010;1183:38–57. doi: 10.1111/j.1749-6632.2009.05137.x.. Recent review on regulatory B cells; their development and function in health and disease.

RESOURCES