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The nature of the autoimmune T cell response to myelin oligodendrocyte glycoprotein (MOG), recently recognized as a potential target antigen in multiple sclerosis (MS), has not yet been characterized, in contrast to the T cell reactivity to other potential target antigens in MS such as myelin basic protein and proteolipid protein. Here, we show that the encephalitogenicity of the recombinant Ig-like domain of human MOG is associated, in H-2b mice, with an immunodominant T cell reactivity against a single region of MOG spanning amino acids 35–55, accounting for the previously reported strong encephalitogenic activity of pMOG 35–55. A single injection of pMOG 35–55 with or without administration of pertussis toxin was sufficient to induce severe clinical experimental autoimmune encephalomyelitis (EAE) in H-2b mice. Encephalitogenic pMOG 35–55-specific T cell lines derived from C3H.SW (Vβb) mice were diverse in their TCR Vβ gene usage (Vβ1, Vβ6, Vβ8 and Vβ15), although Vβ8.2 was most predominantly expressed (48%). However, Vβ8+ T cells may only be part of the encephalitogenic MOG-specific T cell repertoire in H-2b mice, as demonstrated by the susceptibility of C57L (Vβa) mice to disease induced by pMOG 35–55. Encephalitogenic T cell lines from Vβa mice were also diverse in their TCR Vβ gene usage (Vβ1, Vβ2, Vβ6, Vβ14 and Vβ16). Such a heterogeneous TCR Vβ gene expression by pMOG 35–55/I-Ab-reactive T cells from both Vβa and Vβb H-2b mice suggested multiple epitopes within pMOG 35–55. Analysis of the pattern of reactivity by pMOG 35–55-reactive T cells to a set of truncated peptides was not commensurate with independent nested epitopes, but revealed a requirement for recognition of a core sequence, YRSPFSRVV (pMOG 40–48). However, optimal stimulation was obtained with longer peptides, with each additional amino acid flanking either the N or the C terminus differentially increasing the stimulatory capacity of pMOG 40–48. Nonetheless, pMOG 40–48 was the minimal encephalitogenic epitope for both Vβa and Vβb mice. Thus, the T cell reactivity against the immunodominant encephalitogenic region of MOG is characterized by a diverse Vβ gene usage and a requirement for the same core epitope. This pattern of reactivity may favor epitope-directed, rather than TCR-targeted, approaches to immunospecific therapy for MOG-related autoimmune disease.  相似文献   

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Studies of experimental autoimmune encephalomyelitis (EAE) in rodents have revealed that encephalitogenic T cell lines reactive with myelin basic protein (BP) are frequently dominated by clones expressing a restricted T cell receptor repertoire. Using the rat EAE model, we have begun to examine the basis for clonal dominance within BP-reactive T cell lines. We find that variations introduced into the standard protocol of periodic antigen stimulation produce marked shifts in the representation of different clones within encephalitogenic T cell populations. For example, altering the source of antigen-presenting cells (APC), while holding antigen (BP) constant, and substituting BP from guinea pig (GPBP) for that of the rat antigen (RBP) with constant APC, both cause shifts in the composition of the dominant clones within BP-reactive T cell lines. Our results suggest that: (i) adherence to an invariant protocol of antigen challenge may lead to an underestimation of the diversity of BP-reactive encephalitogenic T cell populations; and (ii) the minor structural differences between GPBP and RBP not only cause the weak immunogenicity of RBP but also result in the alteration of different T cell subsets. These observations indicate that apparent restrictions upon the repertoire of autoimmune T cells should be interpreted with caution when such cells are elicited by immunization with foreign antigens.  相似文献   

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A predominant response to myelin oligodendrocyte glycoprotein (MOG) was recently observed in patients with multiple sclerosis (MS). To study the possible pathogenic role of T cell response to MOG in MS, we have investigated the encephalitogenic potential of MOG. Synthetic MOG peptides, pMOG 1-21, 35–55, 67–87, 104–117 and 202–218, representing predicted T cell epitopes, were injected into C57BL/6J and C3H.SW (H-2b) mice. The mice developed significant specific T cell responses to pMOG 1–21, pMOG 35–55 and pMOG 104–117. However, pMOG 35–55 was the only MOG peptide which could induce neurological impairment. The highly reproducible disease was chronic, with ascending paralysis and neuropathology comparable with those observed in experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein or proteolipid protein, except that in H-2b mice the disease was consistently non-remitting. These features differ markedly from those which we recently observed in PL (H-2u) mice with pMOG 35–55-induced disease. In PL mice, pMOG 35–55-induces atypical chronic relapsing EAE, the expression and progression of which are unpredictable. Hence, in different mouse strains, the same MOG peptide can induce typical EAE characterized by ascending paralysis, or atypical EAE with unpredictable clinical signs. pMOG 35–55-specific T cells from H-2b mice recognized an epitope within amino acids 40–55 of the MOG molecule, and pMOG 40–55-reactive T cell lines were encephalitogenic upon transfer into syngeneic recipients. The encephalitogenic pMOG 35–55-reactive C57BL/6J T cell lines expressed Vβ1, Vβ6, Vβ8, Vβ14 and Vβ15 gene segments, and the pMOG 35–55-reactive C3H.SW T cell lines expressed Vβ1, Vβ2, Vβ6, Vβ8, Vβ10, Vβ14, and Vβ15 gene segments. However, in both mouse strains, the utilization of the Vβ8 gene product was predominant (40–43 %). The highly reproducible encephalitogenic activity of pMOG 35–55 strongly suggests a pathogenic role for T cell reactivity to MOG in MS and supports the possibility that MOG may also be a primary target antigen in the disease.  相似文献   

7.
To determine the role of encephalitogenic T cells in the formation of lesions in the central nervous system (CNS), experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by immunization with either myelin basic protein (MBP) or the synthetic peptide which corresponds to the 87–100 sequence of guinea pig MBP, and T cells expressing T cell receptor (TcR) Vβ8.2, Vβ8.5, Vβ10 and Vβ16 in the lymphoid organs and CNS were localized and quantified by flow cytometry (FCM) and immunohistochemistry. In normal rats, the percentage of T cells expressing these Vβ phenotypes to the total number of TcR αβ+ T cells, as determined by FCM, ranged from 5% to 10% in the lymph node. Vβi6+ T cells were the most predominant population among the four Vβ subsets tested. Essentially the same findings were obtained from the analysis of the lymphoid organs of rats with EAE which had been induced by immunization with the same two antigens. In sharp contrast, 15–20% of the T cells isolated from lesions of MBP-induced EAE expressed Vβ8.2+. Thus, the percentage of Vβ8.2+ T cells in the EAE lesions was threefold higher than that in the lymph node, while the proportions of Vβ8.5+, Vβ10+ and Vβ16+ T cells were about the same in both organs. The predominance of Vβ58.2+ T cells in EAE lesions was confirmed by counts of immunohistochemically stained T cells in the spinal cord. Moreover, it was revealed that (i) the predominance of Vβ8.2+ T cells was greatest during the development of EAE and became less obvious at the recovery stage, and (ii) at the peak stage of EAE, approximately 85% of Vβ8.2+ T cells were distributed in the parenchyma while 15% were in the perivascular space of the CNS vessels. These findings indicate that encephalitogenic T cells which express Vβ8.2 infiltrate the CNS at a very early stage of EAE and become the predominant population in infiltrating T cells, and further suggest that encephalitogenic T cells, not only recruit inflammatory cells in the CNS, but also cause neural tissue damage, such as demyelination.  相似文献   

8.
<正>多发性硬化症(multiple sclerosis,MS)是由免疫细胞攻击中枢神经系统(central nervous system,CNS)而造成的一种自身免疫性疾病,其具有神经元脱髓鞘、神经胶质细胞增生和轴突损伤等病理特征[1]。NLRP3炎症小体作为一种能识别病原体和危险信号的传感器,近年来被发现与许多自身免疫性疾病的发病关系密切[2]。本文从NLRP3炎症小体激活的主要途径出发,综述了NLRP3炎症小体在MS及其动物模型——实验  相似文献   

9.
Serotonin (5-hydroxytryptamine, 5-HT) is one of the most extensively studied neurotransmitters of the central nervous system. It also has been identified in constituents of the immune system. Therefore serotonin has been suggested to serve as a mediator of bidirectional interactions between the nervous system and the immune system. We investigated this interaction in experimental autoimmune encephalomyelitis (EAE), a well-defined animal model of autoimmune disease of the central nervous system (CNS) mimicking features of the human disease multiple sclerosis. EAE was induced by immunization with the autoantigens myelin basic protein (MBP) or the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG) spanning amino acids 35-55 (MOGp 35-55). We studied EAE in knockout (KO) mice lacking the 5-HT transporter (5-HTT) on a C57.BL/6 background, in comparison with wild-type C57.BL/6 animals. After immunization with MOGp 35-55, or with rat MBP, the disease courses of the 5-HTT knockout mice were attenuated as compared to wildtype control mice. This difference was more pronounced in female animals. To dissect potential immune mechanisms underlying this phenomenon, histological studies of the CNS and cytokine measurements in mononuclear cells from the spleens of 5-HTT KO mice and wild-type controls were performed. We found a reduction of the inflammatory infiltrate in the CNS and of the neuroantigen-specific production of IFN-gamma in splenocytes, again accompanied by a gender difference. These findings suggest a potential role of extracellular 5-HT homeostasis in the fine-tuning of neuroantigen-specific immune responses.  相似文献   

10.
IL-2 is crucial for the production of CD4(+)CD25(+) T regulatory (Treg) cells while important for the generation of effective T cell-mediated immunity. How to exploit the capacity of IL-2 to expand Treg cells, while restraining activation of T effector (Teff) cells, is an important and unanswered therapeutic question. Dexamethasone (Dex), a synthetic glucocorticoid steroid, has been reported to suppress IL-2-mediated activation of Teff cells and increase the proportion of Treg cells. Thus, we hypothesized that glucocorticoids may be useful as costimulants to amplify IL-2-mediated selective expansion of Treg cells. We show in this study that short-term simultaneous administration of Dex and IL-2 markedly expanded functional suppressive Foxp3(+)CD4(+)CD25(+) T cells in murine peripheral lymphoid tissues. In a myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) mouse model, we observed that splenic CD4(+)CD25(+) T cells failed to suppress the proliferation of CD4(+)CD25(-) T cells. Pretreatment with Dex/IL-2 remarkably increased the proportion of CD4(+)FoxP3(+) cells and partially restored the function of splenic CD4(+)CD25(+) T cells, and inhibited the development of EAE. Therefore, the combination of glucocorticoid and IL-2, two currently used therapeutics, may provide a novel approach for the treatment of autoimmune diseases, transplant rejection and graft-vs.-host disease.  相似文献   

11.
By immunizing Lewis rats with myelin basic protein (MBP) peptide variants derived from the major encephalitogenic epitope of guinea pig (MBP(68–88) and then isolating encephalitogenic T cells from these animals, we demonstrated that the variant peptides do not elicit the same encephalitogenic T cell subsets as those induced by the wild-type peptide or by intact MBP. Rather, the pathogenic T cells differed in clonal composition as reflected by their heterogeneous responses to a panel of variant peptides and by their T cell receptor usage. Thus, molecules mimicking the MBP(68–88) autoantigen can elicit pathogenic T cell subsets without necessarily cross-reacting with T cells specific for the original autoantigen. This suggests that a more clonally diverse group of pathogenic T cells might be involved in EAE than has been apparent from studies with intact MBP or its unaltered peptides.  相似文献   

12.
In the present study, we have isolated and characterized five myelin basic protein (MBP)-reactive T cell lines directly from the brains of Lewis rats during the early paralytic phase of experimental autoimmune encephalomyelitis (EAE). Each T cell line responded to the dominant encephalitogenic epitope spanning residues 68–88, and did not react against the conserved encephalitogenic epitope [MBP(87–99)] or the nonencephalitogenic MBP epitope [MBP(50–69)]. We determined the T cell receptor (TcR) β chain usage by polymerase chain reaction, DNA sequencing analysis and by generation of MBP-reactive hybridomas from one of the T cell lines (BT74). The results revealed that brain-infiltrating, MBP-reactive T cells freshly isolated early in the course of the disease exhibit TcR diversity.  相似文献   

13.
Inflammation of the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE) starts in the subarachnoid space (SAS) and spreads later to the adjacent CNS parenchyma. To characterize the nature of lesion-forming T cells in situ in more detail, T cells were isolated from the SAS and their surface phenotype and the nucleotide sequence of the junctional region of the T cell receptor (TCR) was determined and compared with those of the lymph node (LN) and spinal cord (SC) T cells. Characteristically, more than 70% of SAS TCR αβ+ T cells isolated at the early stage of EAE lacked both CD4 and CD8 molecules, whereas those from LN and SC were either CD4+ or CD8+. Analysis of nucleotide sequences of the junctional region of TCR revealed that T cells bearing a sequence identical to that for encephalitogenic T cell clones were found in both SAS and SC. Furthermore, purified CD4?CD8? T cells expressed CD4 molecules after culture. At the same time, these T cells acquired reactivity to myelin basic protein and induced passive EAE in naive animals after adoptive transfer. Our results suggest that CD4?CD8? T cells in the SAS are precursors of lesion-forming T cells in the SC and that phenotype switching takes place during the process of T cell infiltration into the CNS parenchyma. The double-negative nature of these T cells may explain an escape of encephalitogenic T cells from negative selection in T cell differentiation.  相似文献   

14.
We have shown previously that administration of myelin basic protein (MBP)-reactive T cells to naive Lewis rats induces not only autoimmune encephalomyelitis (EAE) but also a near total resistance to subsequent disease. By isolating the effector cells that are responsible for the resistance, we demonstrated that disease protection paralleled with increased numbers of a CD8+ regulatory T cell (RTC) subset and that co-injection of this RTC subset with encephalitogenic T cells aborted the pathogenic activity of the latter cells. Here, we show that a radio-sensitive splenic population of RTC also exists in naive rats that can be recruited and activated to inhibit the onset of secondary episodes of adoptive EAE. In co-transfer experiments, this protective RTC subpopulation can be isolated to neutralize the pathogenic activity of stimulatory MBP-reactive T cells in vivo. We show that the frequency of RTC with specificity for MBP-reactive T cells in naive rats is two orders of magnitude higher than the frequency of MBP-specific precursors, the activity of RTC increases substantially with age and RTC frequencies increase as a consequence of immunization with MBP-reactive cells lines. In specificity studies, we show that RTC isolated from naive rats and RTC from animals primed with one MBP-reactive cell line show cross-reactive responses to a variety of different MBP-reactive T cell lines. However, following repeated stimulation with a given MBP line, these RTC display a more limited, clonotypic response to the selecting line and assume a uniform CD8 phenotype. Finally, functional studies with RTC indicate that proliferative and lytic specificities do not necessarily correlate and that activated rat RTC are especially lytic for a Fas-sensitive murine cell line.  相似文献   

15.
T‐cell migration across the blood‐brain barrier is a crucial step in the pathogenesis of EAE, an animal model for MS. Live cell imaging studies demonstrated that P‐selectin glycoprotein ligand‐1 (PSGL‐1) and its endothelial ligands E‐ and P‐selectin mediate the initial rolling of T cells in brain vessels during EAE. As functional absence of PSGL‐1 or E/P‐selectins does not result in ameliorated EAE, we speculated that T‐cell entry into the spinal cord is independent of PSGL‐1 and E/P‐selectin. Performing intravital microscopy, we observed the interaction of WT or PSGL‐1?/? proteolipid protein‐specific T cells in inflamed spinal cord microvessels of WT or E/P‐selectin?/? SJL/J mice during EAE. T‐cell rolling but not T‐cell capture was completely abrogated in the absence of either PSGL‐1 or E‐ and P‐selectin, resulting in a significantly reduced number of T cells able to firmly adhere in the inflamed spinal cord microvessels, but did not lead to reduced T‐cell invasion into the CNS parenchyma. Thus, PSGL‐1 interaction with E/P‐selectin is essential for T‐cell rolling in inflamed spinal cord microvessels during EAE. Taken together with previous observations, our findings show that T‐cell rolling is not required for successful T‐cell entry into the CNS and initiation of EAE.  相似文献   

16.
Intravenous (i.v.) injection of a soluble myelin antigen can induce tolerance, which effectively ameliorates experimental autoimmune encephalomyelitis (EAE). We have previously shown that i.v. myelin oligodendrocyte glycoprotein (MOG) induces tolerance in EAE and expands a subpopulation of tolerogenic CD11c+CD11b+ dendritic cells (DCs) with an immature phenotype having low expression of IA and co‐stimulatory molecules CD40, CD86, and CD80. Here, we further investigate the role of tolerogenic DCs in i.v. tolerance by injecting clodronate‐loaded liposomes, which selectively deplete CD11c+CD11b+ and immature DCs, but not CD11c+CD8+ DCs and mature DCs. I.v. MOG‐induced suppression of EAE was partially, yet significantly, blocked by CD11c+CD11b+ DC depletion. While i.v. MOG inhibited IA, CD40, CD80, CD86 expression and induced TGF‐β, IL‐27, IL‐10 production in CD11c+CD11b+ DCs, these effects were abrogated after injection of clodronate‐loaded liposomes. Depletion of CD11c+CD11b+ DCs also precluded i.v. autoantigen‐induced T‐cell tolerance, such as decreased production of IL‐2, IFN‐γ, IL‐17 and numbers of IL‐2+, IFN‐γ+, and IL‐17+ CD4+ T cells, as well as an increased proportion of CD4+CD25+Foxp3+ regulatory T cells and CD4+IL‐10+Foxp3? Tr1 cells. CD11c+CD11b+ DCs, through low expression of IA and costimulatory molecules as well as high expression of TGF‐β, IL‐27, and IL‐10, play an important role in i.v. tolerance‐induced EAE suppression.  相似文献   

17.
Maintenance of FOXP3 protein expression is crucial for differentiation and maturation of regulatory T (Treg) cells, which play important roles in immune homeostasis and immune tolerance. We demonstrate here that PDCD5 interacts with FOXP3, increases acetylation of FOXP3 in synergy with Tip60 and enhances the repressive function of FOXP3. In PDCD5 transgenic (PDCD5tg) mice, overexpression of PDCD5 enhanced the level of FOXP3 protein and percentage of CD4+CD25+FOXP3+ cells. Naïve CD4+ T cells from PDCD5tg mice were more sensitive to TGF-β-induced Treg polarization and expansion. These induced Tregs retained normal suppressive function in vitro. Severity of experimentally-induced autoimmune encephalomyelitis (EAE) in PDCD5tg mice was significantly reduced relative to that of wild-type mice. The beneficial effect of PDCD5 likely resulted from increases of Treg cell frequency, accompanied by a reduction of the predominant pathogenic Th17/Th1 response. Activation-induced cell death enhanced by PDCD5 was also linked to this process. This is the first report revealing that PDCD5 activity in T cells suppresses autoimmunity by modulating Tregs. This study suggests that PDCD5 serves as a guardian of immunological functions and that the PDCD5-FOXP3-Treg axis may be a therapeutic target for autoimmunity.  相似文献   

18.
Myelin basic protein (MBP) and proteolipid protein (PLP), the most abundant proteins of central nervous system (CNS) myelin, have been extensively studied as possible primary target antigens in multiple sclerosis (MS), a primary demyelinating autoimmune disease of the CNS. However, there is increasing evidence to suggest that autoimmune reactivity against the quantitatively minor myelin component, myelin oligodendrocyte glycoprotein (MOG), can also play a role in the pathogenicity of MS. We recently demonstrated a predominant response to MOG by peripheral blood lymphocytes from patients with MS tested for their reactivity against various myelin antigens, including MBP and PLP. To ascertain whether or not T cell reactivity to MOG in MS is a potentially pathogenic response, we have tested the ability of synthetic MOG peptides (pMOG) representing potential T cell epitopes, to induce neurological disease in mice. Both strains of mice tested (SJL/J and PL/J mice) were able to mount a primary T cell response to some of the five MOG peptides synthesized, pMOG 1–21, 35–55, 67–87, 104–117 and 202–218. T cell lines could be raised in both strains to pMOG 35–55 and 67–87, but epitope definition revealed that each strain recognized a different minimal epitope within these two peptides. T cell lines to pMOG 1–21 and 202–218 could also be raised in SJL/J and PL/J mice, respectively. T cell reactivity to pMOG 104–117 was not observed in either mouse strain. None of the peptides tested induced detectable clinical signs in SJL/J mice. In contrast, an MS-like chronic relasping-remitting disease could be induced in PL/J mice with pMOG 35–55. The disease presented with a delayed onset and with clinical signs which differed significantly in their progression and expression from the typical ascending paralysis of experimental autoimmune encephalomyelitis induced with other myelin components, such as MBP and PLP. Histological examination of CNS tissue from mice injected with pMOG 35–55 revealed only mild neuropathological signs with few inflammatory foci in brain and spinal cord. Some myelin splitting and edema were detected upon electron microscopic examination in the spinal cord and cerebellum. Transfer of pMOG 35–55 reactive T cells into naive PL/J mice resulted in pathological changes characterized by inflammatory foci in the brain and spinal cord. This passively induced disease was clinically silent, as was also reported for Lewis rats injected with T cells specific for the same MOG peptide. These data, which demonstrate unequivocally the encephalitogenic activity of MOG, support our contention that MOG may be as important as MBP or PLP in disease pathogenesis and could be a primary target antigen in autoimmune diseases of the CNS.  相似文献   

19.
A CD4+Vβ8.2+ T cell clone specific for the peptide 72–89 of guinea pig myelin basic protein (GMBP) was used to induce acute experimental autoimmune encephalomyelitis (EAE) in Lewis rats. To assess apoptosis in inflammatory cells infiltrating the central nervous system (CNS), we extracted cells from the spinal cord, enriched them for T cells and performed flow-cytometric analysis of their DNA stained with propidium iodide. The presence of apoptosis was confirmed by the demonstration of DNA fragmentation on gel electrophoresis. A gradual increase in the proportion of apoptotic cells was observed between 4 and 7 days after the transfer of the encephalitogenic T cells. The highest frequency of apoptotic cells (9.2 ± 1.2%) was observed 7 days after cell transfer, when clinical recovery commenced. Passive transfer of ovalbumin-specific cells resulted in only a background level (0.8%) of apoptosis in the CNS. We conclude that the apoptotic process selectively eliminates autoreactive T cells from the CNS as: (a) there was a selective disappearance of disease-relevant CD5+Vβ8.2+ cells from the CNS during the course of EAE; (b) there was a decrease in the frequency of CNS-infiltrating T cells reactive to the GMBP 72–89 peptide during the course of EAE, and in a standard proliferation assay there was a loss of in vitro reactivity of CNS-infiltrating cells to this peptide, but not to a non-CNS antigen (ovalbumin); (c) simultaneous surface labeling and DNA analysis of CNS-infiltrating cells revealed that the frequency of Vβ8.2+ cells was about sevenfold higher in the apoptotic T cell population than in the normal (non-apoptotic) T cell population; and (d) we were unable to detect recirculation of the Vβ8.2+ cells to lymphoid organs after their frequency decreased in the CNS. The selective apoptotic elimination of autoreactive T cells from the target organ of this spontaneously resolving autoimmune disease may have implications for the understanding of the mechanism by which an autoimmune attack is terminated and for the design of therapeutic strategies to facilitate this process.  相似文献   

20.
FoxP3(+) regulatory T (Treg) cells accumulate in the central nervous system (CNS) during experimental autoimmune encephalomyelitis and have been shown to limit the extent of neuroinflammation and to facilitate clinical recovery. The recent demonstration that Treg cells lose FoxP3 expression and assume effector cell characteristics upon stimulation with proinflammatory cytokines has raised questions about their stability in the inflamed CNS. In this issue of the European Journal of Immunology, O'Connor et al. [Eur. J. Immunol. 2012. 42: 1164-1173] show that CNS-infiltrating Treg cells maintain their suppressor phenotype by downregulating the IL-6 receptor. This commentary discusses the finding particularly with relevance to therapy of multiple sclerosis.  相似文献   

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