T cells accumulating in the inflamed joints of a spontaneous murine model of rheumatoid arthritis become restricted to common clonotypes during disease progression (original) (raw)
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Journal of Clinical Investigation, 1995
To investigate the pathogenicity of T cells infiltrating in the rheumatoid joints, mononuclear cells (MNC), predominantly T cells, isolated from either synovial fluid or synovial tissues of the patients with RA were transferred into severe combined immunodeficient (SCID) mice by intraarticular injections. According to our observations in this experimental system, patients with RA could be classified into at least two groups. In one group of patients, the infiltrating MNC induced synovial hyperplasia in the recipient SCID mice (the positive group). Whereas, in the other group no synovial hyperplasia was observed (the negative group). The induction of synovial hyperplasia observed in the positive group was prevented by an anti-human CD3 antibody (OKT3), indicating T cell mediation. Analysis of T cell receptor (TCR) Vf8 usage by reverse transcriptase polymerase chain reaction in the infiltrating MNC transferred into SCID mice revealed a marked skew towards the preferential use of certain Vj3 genes, which was not seen in the peripheral blood MNC, in only the positive group. The patterns of TCR/V, skew were not uniform among the patients. The analysis of the PCR-amplified genes of such skewed TCR/ VfJ by single strand conformational polymorphism showed distinct bands, indicating that the T cell populations expanding in rheumatoid joints of the positive group were oligoclonal. Furthermore, the enrichment of the T cell populations expressing such skewed TCR/Vj3 by in vitro stimulation of peripheral blood MNC of the patients with the relevant superantigen enabled the induction of synovial hyperplasia in the SCID mice. These results suggest that the pathogenic T cells could be activated locally in rheumatoid joints by certain antigens in some, but not in all patients with RA. (J.
Clonal dominance among T-lymphocyte infiltrates in arthritis
Proceedings of the National Academy of Sciences, 1988
Synovial membranes in patients with rheumatoid arthritis as well as other types of chronic destructive inflammatory arthritis contain infiltrates of activated T lymphocytes that probably contribute to the pathogenesis of the disease. In an effort to elucidate the nature of these infiltrates, interleukin 2 (IL-2)-responsive T lymphocytes were grown out of synovial fragments from 14 patients undergoing surgery for advanced destructive inflammatory joint disease. Eleven of the samples examined were from patients with classical rheumatoid arthritis, while three others were obtained from individuals with clinical osteoarthritis. Southern blot analysis of T-cell receptor (TCR) 13-chain genes in 13 of 14 cultures showed distinct rearrangements, indicating that each culture was characterized by the predominance of a limited number of clones. T-cell populations from peripheral blood stimulated with a variety of activators and expanded with IL-2 did not demonstrate evidence of similar clonality in long-term culture.
Spread of clonal T-cell expansions in rheumatoid arthritis patients
Human Immunology, 1996
Despite a large number of studies identifying expanded T-cell clones among infiltrating lymphocytes, little is known about their distribution in patients suffering from rheumatoid arthritis. To evaluate the clonality of α/β T-cell populations in arthritic locations and PBL, we determined the CDR3 size lengths of TCR β-chain transcripts using BV (Vβ), BC (Cβ), BJ (Jβ), and clonotype-specific primers. Transcripts from
Clonal heterogeneity of synovial fluid T lymphocytes from patients with rheumatoid arthritis
Proceedings of the National Academy of Sciences, 1989
Although substantial evidence suggests that synovial T lymphocytes are critical in the pathogenesis of rheumatoid arthritis (RA), little is known regarding their antigenic specificities, antigen receptor gene rearrangements, and mechanisms of activation. To assess the extent ofexpansion of specific clones among RA synovial fluid T cells, Southern blot analyses of T-cell receptor (TCR) gene rearrangements were performed on 40 RA synovial fluid T-cell clones, as well as on both fresh and polydonally activated T cells from RA synovial fluid, RA peripheral blood, and normal peripheral blood. Two of the clones had identical TCR rearrangement patterns, but the remainder were unique. The nonclonal RA T-cell samples showed the same pattern of TCR fl-chain rearrangement that was observed among normal peripheral blood T cells, indicating no dominant clonal T-cell population in these samples. It was noted that with sufficient exposure of autoradiograms of the Southern blots, discrete TCR gene rearrangements, representing in some cases common DpJp (D, diversity; J, joining) rearrangements,. were evident in T cells from peripheral blood of normal individuals and patients with RA, as well as T cells from RA synovial fluid. Taken together, the findings indicate that only a minor degree of oligoclonality can be demonstrated among T lymphocytes from RA synovial fluid.
Clonal dominance among synovial tissue-infiltrating lymphocytes in arthritis
Human Immunology, 1990
T-cell receptor gene rearrangement using a C beta probe was evaluated in 12 patients with rheumatoid arthritis, 2 with juvenile rheumatoid arthritis, and 1 with systemic lupus erythematosus, and in all the samples a dominant T-cell receptor gene rearrangement was noted. In rheumatoid arthritis identical T-cell receptor gene rearrangement was noted in freshly isolated synovial tissue-infiltrating lymphocytes (TIL) and the corresponding interleukin 2-propagated culture. TIL from five different joints obtained from one rheumatoid arthritis patient shared one dominant band, and TIL from three joints had an identical rearrangement. Limiting dilution experiments showed that 10% of T-cell clones had rearrangements matching the corresponding bulk in one rheumatoid arthritis patient. These findings lend further support to the suggestion that the clonal dominance noted among synovial tumor-infiltrating lymphocytes is the result of an in vivo process reflecting a selective T-cell receptor gene usage.
Journal of immunology (Baltimore, Md. : 1950), 1999
We previously reported that inflammatory arthropathy resembling rheumatoid arthritis (RA) develops among transgenic mice carrying the long terminal repeat (LTR)-env-pX-LTR region of human T cell leukemia virus type I (LTR-pX-Tg mice). Because four genes are encoded in this region, we produced transgenic mice that only express the tax gene to examine its role in the development of arthritis. Transgenic mice were produced by constructing DNAs that express the tax gene alone under the control of either its own LTR or CD4 enhancer/promoter and by microinjecting them into C3H/HeN-fertilized ova. We produced seven transgenic mice carrying the LTR-tax gene and nine mice carrying the CD4-tax and found that one of the LTR-tax-Tg mice and five of CD4-tax-Tg mice developed RA-like inflammatory arthropathy similar to LTR-pX-Tg mice, indicating that the tax gene is arthritogenic. On the other hand, the other two LTR-tax-Tg mice had ankylotic changes caused by new bone formation without inflammat...
Biochemical and Biophysical Research Communications, 1999
Previously, we demonstrated the presence of at least two distinct subpopulations of patients with rheumatoid arthritis (RA) employing a cell-transfer experiment using severe combined immunodeficient (SCID) mice. One group of patients, whose T cells derived from the rheumatoid joints, induced synovial hyperplasia (SH) in the SCID mice (the positive group). The other group did not display the induction of SH (the negative group). TCR/V gene usage analysis indicated that some dominant T cell subpopulations were oligoclonally expanding only in the rheumatoid joints, and not in the periphery of the patients of the positive group. Moreover, these T cell subpopulations were not seen in the joints of patients in the negative group or in non-RA patients. In addition, the preferential uses of certain TCR/Vs (V8, V12, V13, and V14) genes were demonstrated in these T cells. In this study, to investigate whether these T cells are driven by a certain antigen(s), the third complementarity determining regions (CDR3s) of TCR/V, especially V8 and V14 PCR products, were cloned and sequenced. As a result, a dominant CDR3 sequence, CASS-PRERAT-YEQ, was found in V14؉ T cells from the rheumatoid joint of a patient (Patient 1) of the positive group with a V14 skew. The identical CDR3 sequence also predominated in V14؉ T cells from the rheumatoid joint of another patient (Patient 7) of the positive group with a V14 skew. In addition, in the patients (Patients 4, 7, 8) of the positive group with a V8 skew, other dominant CDR3 sequences, CASS-ENS-YEQ and CASS-LTEP-DTQ, were found as in the case of V14. However, no identical CDR3 sequences were detected dominantly in the joints of the patients in the negative group or in non-RA patients. A V14؉ T cell clone (TCL), named G3, with the identical CDR3 sequence, CASS-PRERAT-YEQ, was isolated successfully from Patient 1, and cell transfer of G3 with autologous irradiated peripheral mononuclear cells induced SH in the SCID mice. Taken together, these results suggest that T cells inducing SH, thought to be pathogenic for RA, might be driven by a certain shared antigen(s).
Rheumatology (Oxford, England), 2000
Autoreactive T cells may contribute to the pathogenesis of rheumatoid arthritis (RA). We studied the T-cell receptor (TCR) V-gene repertoire in the blood and synovium of early and chronic RA patients using polymerase chain reaction-enzyme-linked immunosorbent assay to evaluate possible differences between these patient groups. Over-represented TCR V genes were observed in the synovium, but not in the blood of all RA patients (n = 38). The number of over-represented V genes was higher in the synovium of chronic RA patients (n = 31) than in that of early RA patients (n = 7). The V-gene profile was different among patients, and similar in the two knees for patients with bilateral synovitis (n = 5). The clonal composition of over-represented TCR BV genes in a patient with early RA and a patient with chronic RA was further studied by CDR3 region sequence analysis. A high level of clonal diversity was found in the joints and the blood of the early RA patient, suggesting a polyclonal T-cel...