Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis. Restricted V alpha/beta rearrangements may indicate antigen-driven selection.

Mantegazza, Renato; Andreetta, Francesca; Bernasconi, Pia; Baggi, Fulvio; Oksenberg, Jorge R.; Simoncini, Ornella; Mora, Marina; Cornelio, F.; Steinman, Lawrence

doi:10.1172/jci116533

Cited by 149 publications

(66 citation statements)

References 38 publications

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“…Further, oligoclonal T cell accumulation was reported recently in such dominant BV families of muscle infiltrates in cases of iPM. 2,3,9 Our results in pPM also detected oligoclonal T cell expansion. This indicates that involvement of the superantigens would be unlikely in both iPM and pPM.…”

supporting

confidence: 65%

“…All the expanded TCR clonotypes in the muscle were characterized by possession of glutamic acid in their CDR3 regions, which were the main region of TCR for recognition of antigens. In this context, Mantegazza et al 9 reported that TCR ␤ chains of muscle-infiltrating T cells in cases of iPM frequently carried anionic amino acids of glutamic acid or aspartic acid in their CDR3 regions. Taken together, stimulating antigenic peptides derived from the muscle tissue may carry cationic amino acids both in the cases of iPM and pPM.…”

mentioning

confidence: 99%

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Clonal expansion of limited T cell clonotypes in affected muscle from a patient with post-transplant polymyositis

Kojima

Tanimoto

et al. 2002

Bone Marrow Transplant

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Summary:Critical roles of T cells in idiopathic polymyositis have been suggested, but, those in polymyositis occurring as GVHD after BMT are poorly understood. We thus investigated T cell clonality in a patient with posttransplant polymyositis. As a result, T cell receptor ␤ chains used various BV families in peripheral blood, but only one BV family (BV7) in affected muscle. Importantly, T cells proliferated oligoclonally both in the peripheral blood and the muscle, however, the expanded clonotypes were completely different. Taken Idiopathic polymyositis (iPM) is a systemic chronic inflammatory disease, which is pathologically characterized by infiltration of inflammatory cells into skeletal muscle fibers and subsequent degeneration of the fibers. Although the precise cause of iPM is still unclear, activated CD8 + T lymphocytes infiltrating into the muscle are thought to attack the muscle tissue. 1 In fact, muscle-infiltrating T cells have been found to display oligoclonal accumulation, suggesting that T cells stimulated by as yet unidentified autoantigens of the muscle proliferated clonally. 2,3 PM has been reported in approximately 30 long-term survivors with allogeneic bone marrow transplantion (BMT). This post-transplant PM (pPM) is considered as one of the manifestations of chronic graft-versus-host disease (cGVHD), since most of the patients with pPM were reported simultaneously to display cGVHD. cally, muscle specimens from patients with pPM show predominant infiltration of cytotoxic T cells. 6 This indicates that T cells attack muscle-specific antigens as speculated in the case of iPM. Clonotypic analyses of T cell receptors (TCR) on the muscle-infiltrating T cells would be a clue to estimate whether the T cells are antigen-specific or nonspecific, however, detailed analyses on the muscle-infiltrating T cells in pPM have not been available, mainly because of its rare occurrence.Here, we had a chance to investigate TCR clonotypes of T cells in peripheral blood (PB) and affected muscle of a patient with pPM. As a result, the muscle-infiltrating T cells showed clonal expansion of only one TCR ␤ chain variable region (BV) family and the expanded T cell clonotypes were completely different from those in PB. Our findings suggest that T cells infiltrating the muscle of the patient with pPM recognize very limited antigens, probably specific for the muscle tissue.A 38 year-old man with chronic myelogenous leukemia underwent allo-BMT from an HLA-matched unrelated donor. Cyclophosphamide (120 mg/kg) followed by total TCR V b 1 2 3 4 5 .1 5 .2 6 7 8 9 1 0 1 1 1 2 1 3 .1 1 3 .2 1 4 1 5 1 6 1 7 1 8 1 9 2 0 P C P M Figure 1 Southern hybridization of the amplified TCR ␤ genes. Amplified specific TCR ␤ genes electrophoresed and transferred to a nylon membrane were hybridized by a TCR ␤ probe. Results of the PBMCs (P) and the muscles (M) are shown.

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supporting

confidence: 65%

mentioning

confidence: 99%

Clonal expansion of limited T cell clonotypes in affected muscle from a patient with post-transplant polymyositis

Kojima

Tanimoto

et al. 2002

Bone Marrow Transplant

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“…The TCR repertoire in myositis patients has been investigated in a few studies using different methods, such as polymerase chain reaction (PCR), immunohistochemistry, TCR complementarity-determining region 3 (CDR3) length analysis, and flow cytometry, mainly on T cells from muscle tissue, and in some studies, a comparison with the TCR profile in blood was performed (9)(10)(11)(12)(13). A few studies have demonstrated a restricted TCR repertoire in muscle tissue from patients with PM, but without a consistent pattern of TCR V ␤ (BV) gene usage (9,10).…”

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confidence: 99%

Restricted T cell receptor BV gene usage in the lungs and muscles of patients with idiopathic inflammatory myopathies

Englund¹,

Wahlström²,

Fathi³

et al. 2007

Arthritis & Rheumatism

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Objective. To investigate T cell receptor (TCR) expression in 3 different compartments that could be involved in patients with myositis: muscle, lung, and peripheral blood.Methods. Nine patients with polymyositis (PM), dermatomyositis, or inclusion body myositis underwent bronchoscopy and bronchoalveolar lavage (BAL) as well as muscle biopsy and blood sampling. A panel of 19 monoclonal antibodies specific for TCR V ␤ (BV) and V ␣ (AV) were used to characterize the TCR profile in CD4؉ and CD8؉ T cell populations in BAL fluid and peripheral blood by flow cytometry. Muscle biopsy tissues were analyzed by immunohistochemistry. Patients were also typed for HLA-DRB1 and DRB3 alleles.Results. A total of 17 T cell expansions were detected in BAL fluid, 6 in the CD4؉ T cell population and 11 in the CD8؉ T cell population. Four T cell expansions were detected in peripheral blood. A selective TCR V usage was found in muscle. Two PM patients, both of whom had BAL fluid BV3؉ T cell expansions in the CD4 population and in whom BV3 was also a prominent TCR V segment in muscle tissue, shared the HLA-DRB1*03 allele. These 2 patients were the only ones who were positive for anti-Jo-1 antibody.Conclusion. We found a restricted accumulation of T lymphocytes expressing selected TCR V-gene segments in the target organ compartments (i.e., lung and muscle). The occurrence of shared TCR gene segment usage in muscle and lungs could suggest common target antigens in these organs.

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“…We then microdissected single T cells that expressed this particular V␤ element, and we amplified their corresponding ␣-chains by a multiplex PCR protocol. We successfully applied this method to muscle tissue from patients with inflammatory muscle diseases, which are known to be mediated by myocytotoxic CD8 ϩ T cells (15)(16)(17). This protocol, which eventually allows reconstruction of viable, TCR-expressing cells from frozen archival tissue, will be applicable to other inflammatory tissues, including reactions in transplants and tumors.…”

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confidence: 99%

Reconstitution of paired T cell receptor α- and β-chains from microdissected single cells of human inflammatory tissues

Seitz

Schneider

Malotka

et al. 2006

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

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We describe a strategy to ''revive'' putatively pathogenic T cells from frozen specimens of human inflammatory target organs. To distinguish pathogenic from irrelevant bystander T cells, we focused on cells that were (i) clonally expanded and (ii) in direct morphological contact with a target cell. Using CDR3 spectratyping, we identified clonally expanded T cell receptor (TCR) ␤-chains in muscle sections of patients with inflammatory muscle diseases. By immunohistochemistry, we identified those V␤-positive T cells that fulfilled the morphological criteria of myocytotoxicity and isolated them by laser microdissection. Next, we identified coexpressed pairs of TCR ␣-and ␤-chains by a multiplex PCR protocol, which allows the concomitant amplification of both chains from single cells. This concomitant amplification had not been achieved previously in histological sections, mainly because of the paucity of available anti-␣-chain antibodies and the great heterogeneity of the ␣-chain genes. From muscle tissue of a patient with polymyositis, we isolated 64 T cells that expressed an expanded V␤1 chain. In 23 of these cells, we identified the corresponding ␣-chain. Twenty of these 23 ␣-chains were identical, suggesting antigendriven selection. After functional reconstitution of the ␣␤-pairs, their antigen-recognition properties could be studied. Our results open avenues for combined analysis of the full TCR ␣-and ␤-chain repertoire in human inflammatory tissues.autoimmunity ͉ immunopathology ͉ myositis ͉ repertoire ͉ single-cell PCR

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Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis. Restricted V alpha/beta rearrangements may indicate antigen-driven selection.

Cited by 149 publications

References 38 publications

Clonal expansion of limited T cell clonotypes in affected muscle from a patient with post-transplant polymyositis

Clonal expansion of limited T cell clonotypes in affected muscle from a patient with post-transplant polymyositis

Restricted T cell receptor BV gene usage in the lungs and muscles of patients with idiopathic inflammatory myopathies

Reconstitution of paired T cell receptor α- and β-chains from microdissected single cells of human inflammatory tissues

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