Publications (28)292.35 Total impact
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Article: Intrinsic Toll-like receptor signalling drives regulatory function in B cells.
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ABSTRACT: B cells can contribute to immunity through production of antibodies, presentation of antigen to T cells, and secretion of cytokines. B cell activation can result in various outcomes for the host. In general B cell responses are beneficial during infections, and deleterious during autoimmune diseases. However, B cells can also limit host defence against pathogens, and protect from autoimmune pathologies. B cells can therefore act both as drivers and as regulators of immunity. Understanding how these opposite functions are mediated shall stimulate the elaboration of novel approaches for manipulating the immune system. B cells might acquire distinct functional properties depending on their mode of activation. Antigen-specific B cell responses require triggering of B cell receptor (BCR) by antigen, and provision of helper signals by T cells. B cells also express various innate immune receptors, and can directly respond to microbial products. Here, we discuss how intrinsic signalling via Toll-like receptors contributes to the suppressive functions of B cells during autoimmune and infectious diseases.Frontiers in bioscience (Elite edition) 01/2013; E5:78-86. -
Article: Activation of CD4⁺ Foxp3⁺ regulatory T cells proceeds normally in the absence of B cells during EAE.
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ABSTRACT: B cells and regulatory T (Treg) cells can both facilitate remission from experimental auto immune encephalomyelitis (EAE), a disease of the central nervous system (CNS) used as a model for multiple sclerosis (MS). Considering that B-cell-depletion therapy (BCDT) is used to treat MS patients, we asked whether Treg-cell activation depended on B cells during EAE. Treg-cell proliferation, accumulation in CNS, and augmentation of suppressive activity in the CNS were normal in B-cell-deficient mice, indicating that B cells are not essential for activation of the protective Treg-cell response and thus provide an independent layer of regulation. This function of B cells involved early suppression of the encephalitogenic CD4(+) T-cell response, which was enhanced in B-cell-deficient mice. CD4(+) T-cell depletion was sufficient to intercept the transition from acute-to-chronic EAE when applied to B-cell-deficient animals that just reached the peak of disease severity. Intriguingly, this treatment did not improve disease when applied later, implying that chronic disability was ultimately maintained independently of pathogenic CD4(+) T cells. Collectively, our data indicate that BCDT is unlikely to impair Treg-cell function, yet it might produce undesirable effects on T-cell-mediated autoimmune pathogenesis.European Journal of Immunology 05/2012; 42(5):1164-73. · 5.10 Impact Factor -
Article: B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells.
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ABSTRACT: B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6-secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell-specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6-sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6-producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell-driven pathogenesis in T cell-mediated autoimmune disease such as EAE and MS.Journal of Experimental Medicine 04/2012; 209(5):1001-10. · 13.85 Impact Factor -
Article: Functional interactions between B lymphocytes and the innate immune system.
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ABSTRACT: The immune system is composed of multiple cell types, which together improve the resistance of the organism against infections. The unfolding of a successful host response ensuring effective protection against pathogens requires an appropriate coordination of the different players of the immune system. Innate cells and T cells extensively communicate during immune reactions, providing multiple opportunities for the mutual coordination of these two defense pathways. Little is known about the functional interactions between B and innate cells, and it is generally assumed that they influence each other indirectly through effects on T cells. However, recent studies highlighted important roles for innate cells in initial presentation of antigen to B cells after immunization, and in long-term maintenance of antibody-producing cells in bone marrow after resolution of immune responses. Furthermore, it was found that activated B cells could regulate the activity of innate cells through production of cytokines. Here, we review how direct interactions between innate and B cells can contribute to orchestration of humoral and cellular immunity.Infectious disorders drug targets. 03/2012; 12(3):191-9. -
Article: Pathogenic and protective functions of TNF in neuroinflammation are defined by its expression in T lymphocytes and myeloid cells.
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ABSTRACT: TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS.The Journal of Immunology 11/2011; 187(11):5660-70. · 5.79 Impact Factor -
Article: Novel regulatory functions for Toll-like receptor-activated B cells during intracellular bacterial infection.
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ABSTRACT: Infections by intracellular bacterial pathogens remain a major cause of human diseases worldwide. Despite intensive efforts, the development of effective vaccines or immunotherapies against these diseases has largely remained unsuccessful, asking for the exploration of new aspects of the host response to these pathogens. Genetic studies have demonstrated beyond doubt that cell-mediated mechanisms of host defense involving innate immunity and T cells are of crucial importance for the control of these diseases. By contrast, the role of B cells during intracellular bacterial infection has so far received little attention besides their role as antibody-producing cells. However, the general knowledge of B-cell immunology and in particular of their antibody-independent functions has greatly increased during the last years. Recently, it was found in a model of Salmonella typhimurium infection that Toll-like receptor triggering on B cells resulted through interleukin-10 secretion in a marked suppression of innate defense mechanisms ultimately leading to uncontrolled growth of the bacteria and earlier death from the disease during both primary and secondary infections. This article reviews the protective and deleterious roles of B cells during intracellular bacterial infections and discusses how manipulating their antibody-independent functions may be a powerful means to therapeutically improve host resistance against these diseases.Immunological Reviews 03/2011; 240(1):52-71. · 11.15 Impact Factor -
Article: Reprogrammed quiescent B cells provide an effective cellular therapy against chronic experimental autoimmune encephalomyelitis.
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ABSTRACT: Activated B cells can regulate immunity and have been envisaged as a potential cell-based therapy for treating autoimmune diseases. However, activated human B cells can also propagate immune responses, and the effects resulting from their infusion into patients cannot be predicted. This led us to consider resting B cells, which in contrast are poorly immunogenic, as an alternative cellular platform for the suppression of unwanted immunity. Here, we report that resting B cells can be directly engineered with lentiviral vectors to express antigens in a remarkably simple, rapid, and effective way. Notably, this neither required nor induced activation of the B cells. With this approach we were able to produce reprogrammed resting B cells that inhibited antigen-specific CD4(+) T cells, CD8(+) T cells, and B cells upon adoptive transfer in mice. Furthermore, resting B cells engineered to ectopically express myelin oligodendrocyte glycoprotein antigen protected recipient mice from severe disability and demyelination in EAE, and even induced complete remission from disease in mice lacking functional natural Tregs, which otherwise developed chronic paralysis. In conclusion, our study introduces reprogrammed quiescent B cells as a novel tool for suppressing undesirable immunity.European Journal of Immunology 03/2011; 41(6):1696-708. · 5.10 Impact Factor -
Article: Eosinophils are required for the maintenance of plasma cells in the bone marrow.
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ABSTRACT: Plasma cells are of crucial importance for long-term immune protection. It is thought that long-lived plasma cells survive in specialized niches in the bone marrow. Here we demonstrate that bone marrow eosinophils localized together with plasma cells and were the key providers of plasma cell survival factors. In vitro, eosinophils supported the survival of plasma cells by secreting the proliferation-inducing ligand APRIL and interleukin-6 (IL-6). In eosinophil-deficient mice, plasma cell numbers were much lower in the bone marrow both at steady state and after immunization. Reconstitution experiments showed that eosinophils were crucial for the retention of plasma cells in the bone marrow. Moreover, depletion of eosinophils induced apoptosis in long-lived bone marrow plasma cells. Our findings demonstrate that the long-term maintenance of plasma cells in the bone marrow requires eosinophils.Nature Immunology 02/2011; 12(2):151-9. · 26.01 Impact Factor -
Article: Signaling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection.
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ABSTRACT: The myeloid differentiation primary response gene 88 (Myd88) is critical for protection against pathogens. However, we demonstrate here that MyD88 expression in B cells inhibits resistance of mice to Salmonella typhimurium infection. Selective deficiency of Myd88 in B cells improved control of bacterial replication and prolonged survival of the infected mice. The B cell-mediated suppressive pathway was even more striking after secondary challenge. Upon vaccination, mice lacking Myd88 in B cells became completely resistant against this otherwise lethal infection, whereas control mice were only partially protected. Analysis of immune defenses revealed that MyD88 signaling in B cells suppressed three crucial arms of protective immunity: neutrophils, natural killer cells, and inflammatory T cells. We further show that interleukin-10 is an essential mediator of these inhibitory functions of B cells. Collectively, our data identify a role for MyD88 and B cells in regulation of cellular mechanisms of protective immunity during infection.Immunity 11/2010; 33(5):777-90. · 21.64 Impact Factor -
Article: Memory B and memory plasma cells.
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ABSTRACT: Vaccination provides a powerful means to control infections. It exploits and exemplifies the ability of the immune system to preserve the information that a specific pathogen has been encountered in the past. The cells and molecular mechanisms of immunological memory are still being discussed controversially. Here, we review the current concepts of memory B cells, the signals involved in their maintenance, and their role in enhanced secondary reactions. Memory plasma cells, secreting protective antibodies over lifetime, have been recognized only recently. Their characterization as cells resting in terms of proliferation and migration, and surviving in dedicated stromal niches, in the absence of antigen, has generated new concepts of how memory cells in general are organized by stroma cells, the 'resting memory'. In autoimmunity and chronic inflammation, memory B cells and memory plasma cells can be essential players, and they require special attention, as they do not respond to most conventional therapies. Their selective targeting will depend on a molecular understanding of their lifestyle.Immunological Reviews 09/2010; 237(1):117-39. · 11.15 Impact Factor -
Article: Suppressive functions of activated B cells in autoimmune diseases reveal the dual roles of Toll-like receptors in immunity.
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ABSTRACT: B lymphocytes contribute to immunity through production of antibodies, antigen presentation to T cells, and secretion of cytokines. B cells are generally considered in autoimmune diseases as drivers of pathogenesis. This view is certainly justified, given the successful utilization of the B cell-depleting reagent rituximab in patients with rheumatoid arthritis or other autoimmune pathologies. In a number of cases, however, the depletion of B cells led to an exacerbation of symptoms in patients with autoimmune disorders. In a similar manner, mice lacking B cells can develop an aggravated course of disease in several autoimmune models. These paradoxical observations are now explained by the concept that activated B cells can suppress immune responses through the production of cytokines, especially interleukin-10. Here, we review the stimulatory signals that induce interleukin-10 secretion and suppressive functions in B cells and the phenotype of the B cells with such characteristics. Finally, we formulate a model explaining how this process of immune regulation by activated B cells can confer advantageous properties to the immune system in its combat with pathogens. Altogether, this review proposes that B-cell-mediated regulation is a fundamental property of the immune system, with features of great interest for the development of new cell-based therapies for autoimmune diseases.Immunological Reviews 01/2010; 233(1):146-61. · 11.15 Impact Factor -
Article: Activated B cells in autoimmune diseases: the case for a regulatory role.
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ABSTRACT: B lymphocytes contribute to immunity through organogenesis of secondary lymphoid organs, presentation of antigen to T cells, production of antibodies, and secretion of cytokines. Their roles in autoimmune diseases are complex. Clinical trials have shown that depleting B cells can significantly ameliorate such diseases, underlining the contributions of B cells to pathogenesis. Conversely, B-cell depletion can lead to exacerbation of symptoms in some patients. In mice, B cells can offer protection from chronic autoimmune pathologies. It is important to understand the mechanisms responsible for the distinct roles of B cells in autoimmune diseases, and investigation of these processes could highlight new therapeutic strategies. Here, we review recent progress in our understanding of the suppressive functions of activated B cells in mice, as well as the promising potential of B cells for use as cell-based therapy for experimental autoimmune diseases, and, finally, discuss the possibility of translating this cellular approach to treat human autoimmune diseases.Nature Clinical Practice Rheumatology 01/2009; 4(12):657-66. · 5.85 Impact Factor -
Article: Not always the bad guys: B cells as regulators of autoimmune pathology.
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ABSTRACT: When B cells react aggressively against self, the potential for pathology is extreme. It is therefore not surprising that B-cell depletion is seen as an attractive therapy in autoimmune diseases. However, B cells can also be essential for restraining unwanted autoaggressive T-cell responses. Recent advances have pointed to interleukin-10 (IL-10) production as a key component in B-cell-mediated immune regulation. In this Opinion article, we develop a hypothesis that triggering of Toll-like receptors controls the propensity of B cells for IL-10 production and immune suppression. According to this model, B cells can translate exposure to certain microbial infections into protection from chronic inflammatory diseases.Nature Reviews Immunology 06/2008; 8(5):391-7. · 32.25 Impact Factor -
Article: TLR-activated B cells suppress T cell-mediated autoimmunity.
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ABSTRACT: TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.The Journal of Immunology 05/2008; 180(7):4763-73. · 5.79 Impact Factor -
Article: Immune regulation by B cells and antibodies a view towards the clinic.
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ABSTRACT: B lymphocytes contribute to immunity in multiple ways, including production of antibodies, presentation of antigen to T cells, organogenesis of secondary lymphoid organs, and secretion of cytokines. Recent clinical trials have shown that depleting B cells can be highly beneficial for patients with autoimmune diseases, implicating B cells and antibodies as key drivers of pathology. However, it should be kept in mind that B cell responses and antibodies also have important regulatory roles in limiting autoimmune pathology. Here, we analyze clinical examples illustrating the potential of antibodies as treatment for immune-mediated disorders and discuss the underlying mechanisms. Furthermore, we examine the regulatory functions of activated B cells, their involvement in the termination of some experimental autoimmune diseases, and their use in cell-based therapy for such pathologies. These suppressive functions of B cells and antibodies do not only open new ways for harnessing autoimmune illnesses, but they also should be taken into account when designing new strategies for vaccination against microbes and tumors.Advances in Immunology 02/2008; 98:1-38. · 5.76 Impact Factor -
Article: A new role of CTLA-4 on B cells in thymus-dependent immune responses in vivo.
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ABSTRACT: The expression of CTLA-4 (CD152) on the cell surface of B cells and its consequences for the humoral immune response in vivo are unknown. We investigated the expression of CTLA-4 mRNA and protein in B cells in T cell-independent or -dependent ways. B cells in the presence of Ag-stimulated Th2 cells expressed mRNA of CTLA-4 and up-regulated intracellular CTLA-4 protein. Using a liposome-enhanced staining technique, we show for the first time, that surface CTLA-4 protein is expressed by 11-15% of B cells in a T cell-dependent culture system. To dissect the role of CTLA-4 on B cells in vivo, we used bone marrow chimeric mice in which only B cells were CTLA-4 deficient. These mice showed that early B cell development and homeostasis is not influenced by CTLA-4 deficiency of B cells. Ag-specific responses after immunization of the chimeric mice revealed elevated levels of IgM Abs in mice deficient for B cell CTLA-4. We propose that CTLA-4 signals on B cells determine the early fate of B cells in thymus-dependent immune responses.The Journal of Immunology 01/2008; 179(11):7316-24. · 5.79 Impact Factor -
Article: The role of ICOS in the development of CD4 T cell help and the reactivation of memory T cells.
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ABSTRACT: We have addressed the role of the inducible costimulator (ICOS) in the development of T cell help for B cells and in the generation, survival and reactivation of memory CD4 T cells and B cells. We find that while T cell help for all antibody isotypes (including IgG2c) is impaired in ICOS knockout (ICOS-KO) mice, the IFN-gamma response is little affected, indicating a defect in helper function that is unrelated to cytokine production. In addition, the ICOS-negative T cells do not accumulate in B cell follicles. Secondary (memory), but not primary, clonal proliferation of antigen-specific B cells is impaired in ICOS-KO mice, as is the generation of secondary antibody-secreting cells. Analysis of endogenous CD4 memory cells in ICOS-KO mice, using MHC class II tetramers, reveals normal primary clonal expansion, formation of memory clones and long-term (10 wk) survival of memory cells, but defective expansion upon reactivation in vivo. The data point to a role of ICOS in supporting secondary, memory and effector T cell responses, possibly by influencing cell survival. The data also highlight differences in ICOS dependency of endogenous T cell proliferation in vivo compared to that of adoptively transferred TCR-transgenic T cells.European Journal of Immunology 08/2007; 37(7):1796-808. · 5.10 Impact Factor -
Article: B-cell function in CNS inflammatory demyelinating disease: a complexity of roles and a wealth of possibilities.
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ABSTRACT: Multiple sclerosis is a heterogeneous disease associated with a rupture of immunological tolerance toward CNS antigens in both T- and B-lymphocyte compartments. The association of human leukocyte antigen genes with higher susceptibility to multiple sclerosis, and the capacity of immune-modulating drugs that block leukocyte transit into the CNS (e.g., natalizumab) to limit pathogenesis confirms that immune cells play important roles in disease progression. An immune therapy that depletes B cells selectively (rituximab) is in clinical trials for multiple sclerosis. Experiments performed in the multiple sclerosis animal model of experimental autoimmune encephalomyelitis have highlighted multiple possible roles for B cells, ranging from being crucial for pathogenesis to being necessary for recovery from clinical disease. Thus, we may expect that patients in whom B cells are key players in the pathogenic process should benefit from rituximab, whereas those in whom B cells are involved predominantly in regulation may show disease exacerbation.Expert Review of Clinical Immunology 07/2007; 3(4):565-78. · 2.07 Impact Factor -
Article: The role of ICOS in the development of CD4 T cell help and the reactivation of memory T cells
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ABSTRACT: We have addressed the role of the inducible costimulator (ICOS) in the development of T cell help for B cells and in the generation, survival and reactivation of memory CD4 T cells and B cells. We find that while T cell help for all antibody isotypes (including IgG2c) is impaired in ICOS knockout (ICOS-KO) mice, the IFN-γ response is little affected, indicating a defect in helper function that is unrelated to cytokine production. In addition, the ICOS-negative T cells do not accumulate in B cell follicles. Secondary (memory), but not primary, clonal proliferation of antigen-specific B cells is impaired in ICOS-KO mice, as is the generation of secondary antibody-secreting cells. Analysis of endogenous CD4 memory cells in ICOS-KO mice, using MHC class II tetramers, reveals normal primary clonal expansion, formation of memory clones and long-term (10 wk) survival of memory cells, but defective expansion upon reactivation in vivo. The data point to a role of ICOS in supporting secondary, memory and effector T cell responses, possibly by influencing cell survival. The data also highlight differences in ICOS dependency of endogenous T cell proliferation in vivo compared to that of adoptively transferred TCR-transgenic T cells.European Journal of Immunology 06/2007; 37(7):1796 - 1808. · 5.10 Impact Factor -
Article: T cell repertoire diversity is required for relapses in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.
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ABSTRACT: Comparison of TCRalphabeta repertoires of myelin oligodendrocyte glycoprotein (MOG)-specific T lymphocytes in C57BL/6 and TdT-deficient littermates (TdT(-/-)) generated during experimental autoimmune encephalomyelitis (EAE) highlights a link between a diversified TCRalphabeta repertoire and EAE relapses. At the onset of the disease, the EAE-severity is identical in TdT(+/-) and TdT(-/-) mice and the neuropathologic public MOG-specific T cell repertoires express closely similar public Valpha-Jalpha and Vbeta-Jbeta rearrangements in both strains. However, whereas TdT(+/+) and TdT(+/-) mice undergo successive EAE relapses, TdT(-/-) mice recover definitively and the lack of relapses does not stem from dominant regulatory mechanisms. During the first relapse of the disease in TdT(+/-) mice, new public Valpha-Jalpha and Vbeta-Jbeta rearrangements emerge that are distinct from those detected at the onset of the disease. Most of these rearrangements contain N additions and are found in CNS-infiltrating T lymphocytes. Furthermore, CD4(+) T splenocytes bearing these rearrangements proliferate to the immunodominant epitope of MOG and not to other immunodominant epitopes of proteolipid protein and myelin basic protein autoantigens, excluding epitope spreading to these myelin proteins. Thus, in addition to epitope spreading, a novel mechanism involving TCRalphabeta repertoire diversification contributes to autoimmune progression.The Journal of Immunology 04/2007; 178(8):4865-75. · 5.79 Impact Factor
Top co-authors
Top Journals
Institutions
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2002–2012
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The University of Edinburgh
- • Institute of Immunology and Infection Research
- • Institute of Cell Biology
Edinburgh, SCT, United Kingdom
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2007–2010
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Deutsches Herzzentrum Berlin
Berlin, Land Berlin, Germany
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2006
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German Rheumatism Research Centre
Berlin, Land Berlin, Germany
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