Genetic control of T cell receptor BJ gene expression in peripheral lymphocytes of normal and rheumatoid arthritis monozygotic twins.

Nanki, Toshihiro; Kohsaka, Hitoshi; Mizushima, Noboru; Ollier, William; Carson, Dennis A.; Miyasaka, Nobuyuki

doi:10.1172/jci118953

Cited by 28 publications

(20 citation statements)

References 46 publications

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“…It has been reported that HLA-DR4ϩ healthy control subjects do not differ from HLA-DR4-healthy controls in terms of the size of clonal expansions or the families that were expanded, but the unaffected siblings of RA patients displayed clonal CD4ϩ T cell specificities (47), which suggests that the TCR repertoire may be intrinsically shaped by the broader genetic background (46,57).…”

Section: Discussionmentioning

confidence: 99%

“…First, both the V ␤ usage and the T cell clonality appeared to be skewed in RA (45). Second, this skewing is a primary event, rather than merely a consequence of inflamma- tion, since the unaffected siblings of RA patients also display expanded T cell clonotypes (46,47). Third, although alterations have been noted in the peripheral compartment (48), they are more pronounced in the joint, are similar in different joints in the same patient, and are stable over time (49,50).…”

Section: Discussionmentioning

confidence: 99%

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Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Cantaert¹,

Brouard²,

Thurlings³

et al. 2009

Arthritis & Rheumatism

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Objective. The association of HLA-DRB1 alleles with anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA-seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA؉ versus ACPA-RA patients.Methods. Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA؉ RA patients, 7 ACPA-RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis.Results. ACPA؉ and ACPA-RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA؉ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA-synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis.Conclusion. The T cell repertoire is specifically restricted in RA patients with ACPA؉ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPAseropositive RA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Cantaert¹,

Brouard²,

Thurlings³

et al. 2009

Arthritis & Rheumatism

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“…For TCRBV gene repertoire analysis, the cDNA was tailed with poly-dG and subjected to anchored polymerase chain reaction (APCR) amplification with biotinylated Cb-specific and anchour primers [1]. For TCRBV-BJ gene repertoire analysis, the cDNA was amplified using TCRBV-specific primers (BV5, BV13 and BV17) and biotinylated Cb-specific primer [2]. As was described previously [1,2], the PCR products were captured on streptavidincoated ELISA plates and hybridized with digoxigenin-labelled BV or BJ gene-specific oligonucleotide probes.…”

Section: Polymerase Chain Reaction and Elisamentioning

confidence: 99%

“…For TCRBV-BJ gene repertoire analysis, the cDNA was amplified using TCRBV-specific primers (BV5, BV13 and BV17) and biotinylated Cb-specific primer [2]. As was described previously [1,2], the PCR products were captured on streptavidincoated ELISA plates and hybridized with digoxigenin-labelled BV or BJ gene-specific oligonucleotide probes. The bound probes were detected with peroxidase-conjugated anti-digoxigenin antibody (Boehringer, Mannheim, Germany) and a tetramethylbenzidine (TMB) system (Kirkegaard & Perry Labs, Gaithersburg, MD).…”

Section: Polymerase Chain Reaction and Elisamentioning

confidence: 99%

“…The relative frequencies of the genes expressed by peripheral T cells vary among individuals. Our previous studies have disclosed that the peripheral TCRBV and TCRBJ repertoires of RA monozygotic twins were similar regardless of their disease status [1,2]. This suggested that the TCRB gene repertoire is controlled primarily by genetic factors.…”

Section: Introductionmentioning

confidence: 97%

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HLA-dependent peripheral T cell receptor (TCR) repertoire formation and its modification by rheumatoid arthritis (RA)

Mizushima

Kohsaka

Nanki

et al. 1997

Clinical and Experimental Immunology

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SUMMARYOur previous studies have disclosed that the peripheral T cell receptor b (TCRB) gene repertoires of RA monozygotic twins were similar. This suggested that the TCRBV repertoire is controlled primarily by genetic factors. Here, we examine how the combination of HLA and presence of RA influence the peripheral TCRB repertoire. Peripheral blood mononuclear cells from six pairs of healthy monozygotic twins, six pairs of monozygotic twins discordant for RA, and nine siblings of a large family, including three RA patients, were examined for their TCRB gene repertoires. Among healthy twins and siblings, the BV repertoires between HLA-identical pairs were significantly more similar than those of HLA-nonidentical pairs. When RA-affected members were included, the repertoires of the HLA-identical pairs discordant for RA were dissimilar compared with those of healthy pairs. TCRBV-BJ combination repertoire analysis of CD4 and CD8 T cell subsets from the twins showed that the dissimilarity was primarily confined to CD8 T cells in the healthy identical twins, whereas it was seen in both CD4 and CD8 T cell subsets in the RA-discordant twins. These results suggest (i) the presence of RA modifies the genetically controlled TCR repertoire of peripheral T cells, and (ii) the RA-associated alterations appear to occur more frequently in CD4 T cells than in CD8 T cells.

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Comparative sequence analysis of the human T cell receptor ? chain in juvenile rheumatoid arthritis and juvenile spondylarthropathies: Evidence for antigenic selection of T cells in the synovium

Thompson

Murray

Grom

et al. 1998

Arthritis & Rheumatism

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Objective. To identify features of the T cell receptors (TCRs) present on clonally expanded T cells in the joints of patients with similar types of childhood rheumatic disease. V,8 and V,20 TCRs were selected as prototypic for polyarticular juvenile rheumatoid arthritis (JRA) and pauciarticular/juvenile spondylarthropathy (SPA), respectively. Methods.The portion of the TCR p chain involved in antigen recognition in the synovial tissue, synovial fluid, and peripheral blood from patients with JRA and juvenile SPA was cloned and sequenced. The frequency of expanded clonotypes, size of expansions, the J, region, and sequence motifs were determined for >2,000 sequences.Results. The majority of V,20 and V,8 clonal expansions were found in the joint rather than the peripheral blood. While instances of both V,8 and Vp20 clonal expansion were detected in all disease types, the features of these expanded clonotypes were specific for disease type and V, family. For example, V,20 clonal expansion was characterized by many small expanded ~~~ ~~

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Genetic control of T cell receptor BJ gene expression in peripheral lymphocytes of normal and rheumatoid arthritis monozygotic twins.

Cited by 28 publications

References 46 publications

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

HLA-dependent peripheral T cell receptor (TCR) repertoire formation and its modification by rheumatoid arthritis (RA)

Comparative sequence analysis of the human T cell receptor ? chain in juvenile rheumatoid arthritis and juvenile spondylarthropathies: Evidence for antigenic selection of T cells in the synovium

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