Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis.

Allegretta, Mark; Albertini, Richard J.; Howell, Mark D.; Smith, Lawrence R.; Martin, Roland; McFarland, Henry F.; Sriram, S; Brostoff, Steven W.; Steinman, Lawrence

doi:10.1172/jci117295

Cited by 42 publications

(18 citation statements)

References 32 publications

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“…Studies of the TCR expressed in the brains of DR15 Dw2' MS patients revealed a restricted group of CDR3 motifs [21]. Similar motifs have been found in MBP-specific T cell clones (TCC) activated in vivo derived from MS patients [22], in encephalitogenic TCC isolated from Lewis rats [23], and also in a cytotoxic, DR2a-restricted, MBP (87-99)-specific TCC derived from an MS patient [14]. These findings support the hypothesis of a pathogenic role of MBP (87-99)-specific T cells at least in a subgroup of DR15 Dw2' patients [24, 251.…”

Section: Introductionmentioning

confidence: 58%

Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99)

et al. 1996

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We have examined the functional consequences induced by interaction of DR2a-restricted myelin basic protein (MBP) (87-99)-specific T cell clones (TCC) with altered peptide ligands (APL) derived from MBP peptide (87-99). The immunodominant MBP peptide (87-99) has been implicated as a candidate antigen in multiple sclerosis (MS) by several lines of evidence. In the present study, we have defined the T cell receptor (TCR) contact residues for DR2a-restricted, (87-99)-specific T helper type 1 T cells to design APL suitable to modify the functions of such T cells potentially relevant for the pathogenesis of MS. We show that neutral (L-alanine substitutions) or conservative exchanges of the primary and secondary TCR contact residues lead to various alterations of T cell function, ranging from differences in interleukin-2 receptor up-regulation to anergy induction and TCR antagonism. The potential usefulness of APL as an immunomodulating therapy for DR2+ MS patients is discussed.

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Section: Introductionmentioning

confidence: 58%

Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99)

et al. 1996

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“…We have observed no increased association of HLA-DR2 in HAA patients. Differences in T-cell repertoire have been observed in other immune-mediated diseases, such as multiple sclerosis, 38,39 rheumatoid arthritis, 40,41 and autoimmune hepatitis, 42 where a limited number of T cells using a restricted diversity of the V ␤ subfamilies to proliferate dominantly is revealed in different patients, 21 but the TCR repertoire pattern is different among these diseases owing to the different antigenic triggers. 39,43,44 In summary, we show that in HAA there is an infiltration of both clonal and many nonclonal T cells, giving rise to a markedly skewed T-cell repertoire, as seen in both viral and autoimmune hepatitis.…”

Section: Discussionmentioning

confidence: 99%

Analysis of T-cell repertoire in hepatitis-associated aplastic anemia

Basu

Melenhorst

et al. 2004

Blood

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Hepatitis-associated aplastic anemia (HAA) is a syndrome of bone marrow failure following an acute attack of seronegative hepatitis. Clinical features and liver histology suggest a central role for an immune-mediated mechanism. To characterize the immune response, we investigated the T-cell repertoire (T-cell receptor [TCR] V ␤ chain subfamily) of intrahepatic lymphocytes in HAA patients by TCR spectratyping. In 6 of 7 HAA liver samples, a broad skewing pattern in the 21 V ␤ subfamilies tested was observed. In total, 62% ؎ 18% of HAA spectratypes showed a skewed pattern, similar to 68% ؎ 18% skewed spectratype patterns in 3 of 4 patients with confirmed viral hepatitis. Additionally, the T-cell repertoire had similarly low levels of complexity. In the peripheral blood lymphocytes (PBLs) of a separate group of HAA patients prior to treatment, 60% ؎ 15% skewed spectratypes were detected, compared with only 18% ؎ 8% skewed spectratypes in healthy controls. After successful immunosuppressive treatment, an apparent reversion to a normal T-cell repertoire with a corresponding significant increase in T-cell repertoire complexity was observed in the HAA samples. In conclusion, our data suggest an antigendriven T-cell expansion in HAA and achievement of a normal T-cell repertoire during recovery from HAA. IntroductionHepatitis-associated aplastic anemia (HAA), the development of hematopoietic failure with bone marrow hypocellularity within 6 months of an episode of hepatitis, is not uncommon, with hepatitis preceding the onset of bone marrow failure in 2% to 5% of aplastic anemia (AA) cases in Europe and the United States. 1 Aplastic anemia is also frequent following orthotopic liver transplantation for non-A, non-B, non-C hepatitis in young patients: 23% to 8% of non-A, non-B, non-C hepatitis patients receiving transplants developed aplastic anemia, compared with fewer than 1% of all liver transplant patients. 2,3 The hepatitis/aplastic anemia syndrome shows a stereotypical pattern; most often affecting young males, the hepatitis generally follows a benign course, but the onset of aplastic anemia 2 to 3 months later can be explosive and is usually fatal if untreated. 4 The presumed infectious cause of the hepatitis is unknown, but most cases are seronegative for known hepatitis viruses, including hepatitis A, B, C, and G (GB virus C[GBV-C]). [5][6][7] We previously reported 10 cases of HAA seen at the National Institutes of Health (NIH) that had evidence of lymphocyte activation; 70% responded to immunosuppression with antithymocyte globulin and cyclosporine. 8 Apart from case reports, the presence of lymphocyte activation, 9,10 and the clinical response to either immunosuppression or bone marrow transplantation, 11 little is known of the immunopathogenesis of this syndrome.The time interval between the occurrence of hepatitis and the onset of bone marrow failure suggests that the initial target organ of the immune response is the liver. For both hepatitis B and hepatitis C infection, large numbers of lymphocytes infilt...

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“…(ii) A number of studies have shown persistent clonal expansion of MBP-specific T cells either in the peripheral blood or in the cerebrospinal fluid of MS patients (3)(4)(5)(6). (iii) T cell infiltrates of MS plaques in the CNS and MBP-specific T cell clones share significant homologies in their T cell receptor (TCR) CDR3 sequences, implying that MBP-specific T cells contribute to the neuropathology of MS (7). (iv) An increase in the frequency and affinity of MBP-reactive T cells in the peripheral blood was shown to exacerbate disease and increase the number of plaques in the CNS of MS patients (8).…”

mentioning

confidence: 99%

Modified amino acid copolymers suppress myelin basic protein 85–99-induced encephalomyelitis in humanized mice through different effects on T cells

Illés

Stern

Reddy

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Human HLA-DR2, and specifically that encoded by the DRA͞DRB1*1501 alleles, is thought to be important in the presentation of the immunodominant epitope MBP 85-99 (9, 10). Although the association of the human MHC class II (MHC II) locus with MS has consistently been observed in genome-wide scans (11), an association of the HLA-DR2, DQ6 haplotype, including the DRB1*1501 allele, with susceptibility to MS has been suggested in several population-and family-based studies (12). The importance of the DRB1*1501-associated MBP 85-99 epitope in the pathogenesis of MS has been particularly proposed based on data that, in MS lesions, the microglia͞ macrophages were positive for the HLA-DR2͞MBP 85-99 complex detected by a monoclonal antibody specific for this complex (13). Moreover, mice transgenic (tg) for HLA-DR2 and the TCR from an MS patient develop EAE spontaneously in 6-12 months and the disease appearance can be accelerated by immunization with MBP 85-99 (14).Several clinical attempts have been made to interfere with the MHC II͞MBP 85-99͞TCR trimolecular complex with varying effectiveness (8,(15)(16)(17)(18)(19). Currently, Copolymer 1 (Cop1, Copaxone, glatiramer acetate) is used in MS patients as an immunomodulator (20)(21)(22). Cop1 is a random polypeptide synthesized from four amino acids, L-tyrosine, L-glutamic acid, L-alanine, and L-lysine [poly(Y,E,A,K)n], in a specific molar ratio of 1.0, 1.4, 4.2, and 3.4, respectively. Although the mechanism of action of Cop1 is not fully understood, several immunologic effects have been suggested (23,24). These include competition of Cop1 with the immunodominant MBP 85-99 peptide for binding to DRB1*1501 and competition of MHC II͞Cop1 and MHC II͞MBP complexes for binding to the TCR (23,(25)(26)(27)(28). Cop1 has also recently been shown to polarize T cells into a T helper 2 (Th2) phenotype. Splenocytes from Cop1-immunized mice transfer protection against EAE, and Cop1-specific Th2 cells capable of secreting IL-4 and IL-10 dominate in the CNS of protected mice (29). Similarly, MS patients treated with Cop1 have Cop1-specific T cells with a Th2 phenotype (30).Although widely used in the treatment of MS, Cop1 reduces the frequency of relapses by only Ϸ30% (21). We hypothesized that by improving the binding capacity of copolymers to HLA-DR2 relative to MBP 85-99, it may be possible to develop a more effective immunomodulator. Several random 4-aa copolymers were designed based on the knowledge of anchor residues used by the immunodominant MBP 85-99 epitope that bind to the DRB1*1501-encoded molecule. To determine the in vivo and in vitro effect of these copolymers, a humanized double-tg mouse

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Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis.

Abstract: The selection of T cell clones with mutations in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene has been used to isolate T cells reactive to myelin basic protein (MBP)

Cited by 42 publications

References 32 publications

Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99)

Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99)

Analysis of T-cell repertoire in hepatitis-associated aplastic anemia

Modified amino acid copolymers suppress myelin basic protein 85–99-induced encephalomyelitis in humanized mice through different effects on T cells

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