T cell receptors in rheumatoid arthritis

Struyk, Linda; Hawes, Gail E.; Chatila, M; Breedveld, Ferdinand C.; Kurnick, James T.; Elsen, Peter J. van den

doi:10.1002/art.1780380502

Cited by 94 publications

(42 citation statements)

References 71 publications

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“…Indeed, specific TCRBV mRNA levels are determined by three factors: the particular TCRBV gene involved, the number of cells producing that mRNA in the sample tested, and whether all, some, or none of those cells are being triggered by Ag. This may be one explanation why previous studies using TCRBV repertoire analysis have inconsistently identified the pathogenic T cells in a number of human diseases (34,35). Finally, our data support the contention that once normal ranges for Ag-triggered and basal transcription levels have been established for all the TCRBV genes, it should be possible to identify Ag-triggered T cells in vivo without prior knowledge of either the stimulating Ag or the responding TCR.…”

Section: Discussionsupporting

confidence: 84%

Antigen Triggering Selectively Increases TCRBV Gene Transcription

Lennon

Sillibourne

Furrie

et al. 2000

The Journal of Immunology

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When the TCR binds Ag it is phosphorylated, internalized, and degraded. We wished to examine whether this process was accompanied by a specific concomitant increase in TCR mRNA levels. To do this, PBMC and a T cell clone were cultured with a series of superantigens and an alloantigen. Only T cells specifically responding to an antigenic stimulus had increased levels of TCR β-chain variable (TCRBV)-specific mRNA. This response was apparent after 48 h, peaked around 72 h, and was still elevated after 7 days. Increased gene transcription appeared to be driven solely by Ag as specific Ag depletion prevented culture supernatants transferring this effect. The level of TCRBV mRNA elevation was not influenced by the stimulating Ag, but appeared dependent on the gene encoding the stimulated TCR. Reporter gene assays, using cloned TCRBV gene promoters, confirmed both that TCR gene transcription rises after stimulation and that basal and stimulated levels of TCR transcription vary between different TCRBV genes. These data conclusively demonstrate that there is no direct relationship between TCRBV mRNA and T cell number, and that future repertoire studies must take both factors into account.

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Section: Discussionsupporting

confidence: 84%

Antigen Triggering Selectively Increases TCRBV Gene Transcription

Lennon

Sillibourne

Furrie

et al. 2000

The Journal of Immunology

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“…During recent years, attention has focused on the search for appropriate T cell autoantigens. However, neither attempts to directly stimulate synovial T cells with (auto) antigens (6-11) nor a more indirect approach via analysis of T cell receptor V-gene usage by synovial T cells (12)(13)(14)(15) has provided satisfactory answers to this question.…”

mentioning

confidence: 99%

The B cell repertoire of patients with rheumatoid arthritis. II. Increased frequencies of IgG+ and IgA+ B cells specific for mycobacterial heat‐shock protein 60 or human type II collagen in synovial fluid and tissue

Rudolphi

Rzepka

Batsford

et al. 1997

Arthritis & Rheumatism

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Objective.A qualitative and quantitative analysis of the functional, antigen-specific B cell receptor repertoire of patients with rheumatoid arthritis (RA) in synovial and peripheral compartments.Methods. B cells were activated to grow and differentiate at high efficiency in vitro under limitingdilution conditions. Isotype and specificity of the secreted Ig were tested by enzyme-linked immunosorbent assay.Results. In contrast to peripheral B cells, most synovial B cells had already switched to IgG/IgA in vivo. The frequencies of B cells specifically recognizing foreign antigens were decreased within the synovial population, whereas the frequencies of B cells specific for type I1 collagen, mycobacterial heat-shock protein 60 (hsp60), or IgG Fc fragments were significantly increased, revealing a negative correlation in terms of frequencies.Conclusion. B cells specific for human type I1 collagen, hsp60, and IgG Fc fragments are produced and/or expanded locally within the affected joints of RA patients. Thus, the specific immune system is definitely involved in the local inflammatory and destructive processes.

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“…In some patients the TCR repertoire appeared to be restricted on the basis of TCR V-gene segment usage and clonal predominance. Other patients revealed a diverse TCRBV usage and clonality (Struyk et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…This technique has been used successfully in multiple studies on autoimmune disease, e.g. rheumatoid arthritis (Struyk et al, 1995) and insulin-dependent diabetes mellitus (Conrad et al, 1994). To obtain insight into the clonal composition of BM T cells we have utilized RT-PCR in conjunction with single-strand conformation polymorphism (SSCP) analysis.…”

mentioning

confidence: 99%

Analysis of T‐cell clonality in bone marrow of patients with acquired aplastic anaemia

Melenhorst¹,

Fibbe²,

Struyk

et al. 1997

Br J Haematol

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Summary. Acquired aplastic anaemia (AA) represents a state of bone marrow (BM) failure which is characterized by BM hypocellularity and pancytopenia. It has been hypothesized that in some AA patients, bone marrow failure is secondary to the targeted destruction of haemopoietic stem cells by autoreactive T cells. The response of T cells to antigenic stimulation has been shown, in a number of animal models and in autoimmune diseases, to result in the (oligo)clonal expansion of positively reacting T cells. For this reason, we studied the utilization of 24 T-cell receptor-variable gene segments (TCRBV) and the clonality in BM aspirates and peripheral blood (PB) of seven AA patients. BM from transplant donors served as controls. Determination of TCRBV gene segment usage revealed no significant differences between patients and controls.Clonality within each family was analysed by singlestrand conformation polymorphism (SSCP) analysis. Clonal and clonally predominant bands were seen in BM of three AA patients in five to eight TCRBV families. Clonal rearrangements were encountered less often in BM of control subjects. In conclusion, our results suggest an antigen-driven T-cell response in the BM of predominantly AA patients resulting in oligoclonal T-cell outgrowth.Keywords: aplastic anaemia, clonality, T-cell receptor-, SSCP, V usage.Aplastic anaemia (AA) is an acquired disorder affecting haemopoietic stem cells and is characterized by a reduced bone marrow (BM) cellularity and pancytopenia. Previously, we have studied the clonality of haemopoiesis in peripheral blood (PB) cells of female patients, who entered remission after anti-thymocyte globulin (ATG) therapy. Employing a PCR-based X-chromosome inactivation analysis, it was shown that about half of the patients exhibited clonal haemopoiesis (Van Kamp et al, 1991;Melenhorst et al, 1996). Analysis of the rearrangement patterns at the T-cell receptor-and immunoglobulin heavy chain loci by PCR revealed a polyclonal character of gene rearrangements, irrespective of the X-chromosome inactivation status of the lymphocyte populations.Clonal haemopoiesis in AA may result from a reduced stem cell pool to a clonal composition. It has been hypothesized that in a subgroup of AA patients this reduction is caused by autoreactive T lymphocytes (Young, 1992), recognizing an autoantigen expressed on haemopoietic progenitor cells. Evidence for the T-cellmediated pathogenesis of AA is found in the response of 70% of the patients treated with immunosuppressives, i.e. anti-lymphocyte globulin (ALG)/anti-thymocyte globulin (ATG) and cyclosporin A (Young & Barrett, 1995;Frickhofen et al, 1991). An increased percentage of CD8 HLA-DR T cells in PB and BM has been found (Zoumbos et al, 1985;Maciejewski et al, 1994) as well as a significant association of AA with the HLA-DR2 allele (Nimer et al, 1994;Nakao et al, 1994). The association of an HLA-allele with autoimmune disease predisposition is one of the most clearly established factors, and is related to the MHC-restricted T-cell response (T...

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T cell receptors in rheumatoid arthritis

Cited by 94 publications

References 71 publications

Antigen Triggering Selectively Increases TCRBV Gene Transcription

Antigen Triggering Selectively Increases TCRBV Gene Transcription

The B cell repertoire of patients with rheumatoid arthritis. II. Increased frequencies of IgG+ and IgA+ B cells specific for mycobacterial heat‐shock protein 60 or human type II collagen in synovial fluid and tissue

Analysis of T‐cell clonality in bone marrow of patients with acquired aplastic anaemia

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