Perforin and granzyme A expression identifying cytolytic lymphocytes in rheumatoid arthritis.

Griffiths, Gillian M.; Alpert, Susan; Lambert, Elaine; McGuire, James; Weissman, Irving L.

doi:10.1073/pnas.89.2.549

Cited by 70 publications

(42 citation statements)

References 31 publications

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“…These data offer three points of interest: (i) perforin-containing TCRa,3+ doublenegative T cells were present in this autoimmune disorder, though their percentage was much lower than in AITD; (ii) CD4+ perforn-containing cells were not detected in the synovial fluid, which contrasts with published, but indirect, findings [30]; (iii) most of perforn-containing cells were NK cells, indicating non-specific cytotoxicity at this disease site, while there is antigen-specific cytotoxicity in AITD.…”

Section: Discussioncontrasting

confidence: 54%

Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease

Podack

McKenzie

et al. 1994

Clinical and Experimental Immunology

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SUMMARY Infiltration of the thyroid gland by lymphocytes is a hall‐mark of autoimmune thyroid disease; it is particularly evident in Hashimoto's thyroiditis but is also seen in most patients with Graves’ disease. Infiltrating cells are comprised primarily of T lymphocytes., of which only a minority appears to be activated. Their precise pathogenic role is largely unknown. Since perforin has been a marker for functionally activated cytotoxic T cells in situ we elected to assess the presence of perforin‐containing cells in thyroid‐infiltrating lymphocytes and establish their phenotype. Cells were isolated from seven subtotal thyroidectomy specimens, five from patients with Graves” disease and two with Hashimoto's thyroiditis. The novel findings were as follows: CD4+ perforin‐containing T cells occurred only in Hashimoto's glands, suggesting a class II‐restricted component of cytotoxicity; in Graves' disease, and to a lesser extent in Hashimoto's, perforin‐expressing cells were primarily T cell receptor αβ+ CD4‐ CD8‐ (double negative); double negative perforin‐containing cells in peripheral blood of normal individuals were largely γδ+T cells. In Hashimoto's samples, the predominant population of T cells expressing perforin was CD8+. By comparison, in studies of the synovial fluid of knee joints from patients with rheumatoid arthritis only a minor population of the perforin‐containing cells was double‐negative. The data suggest significant differences in cytotoxic autoimmune mechanisms between the two autoimmune thyroid diseases. Functional characterization of double‐negative T cells is necessary to define their role in autoimmunity.

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Section: Discussioncontrasting

confidence: 54%

Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease

Podack

McKenzie

et al. 1994

Clinical and Experimental Immunology

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“…T cells from the synovial fluid and synovium of patients with RA, and to a lesser extent from patients with OA, contain these enzymes (55)(56)(57)(58)(59), and raised levels of granzyme B correlate with joint damage in RA (60,61). Extracellular granzyme A and granzyme B can also be found in the synovial fluid of patients with RA (62), but their role here is less well characterized than the intracellular cytotoxic function.…”

Section: Immune Cell-derived Serine Proteinasesmentioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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“…While this could be a disadvantage in protection against intracellular pathogens, the decrease of T EMRA cells may contribute to the clinical success of anti-TNF therapy. For example, complement-mediated lysis of T EMRA cells may be the mechanism by which the number of perforin + cells and elevated granzyme levels in fluids and tissues of RA patients (74,75) is normalized. Taken together, our own and others' studies (61,(76)(77)(78)(79)(80)(81)(82)(83) strongly suggest that the correction of inappropriate T cell responses is a key mechanism by which anti-TNF therapy antagonizes the hyperinflammatory state that accounts for autoimmune diseases.…”

Section: Figurementioning

confidence: 99%

Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humans

Bruns

Meinken²,

Schauenberg³

et al. 2009

J. Clin. Invest.

269

200

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The incidence of tuberculosis is increased during treatment of autoimmune diseases with anti-TNF antibodies. This is a significant clinical complication, but also provides a unique model to study immune mechanisms in human tuberculosis. Given the key role for cell-mediated immunity in host defense against Mycobacterium tuberculosis, we hypothesized that anti-TNF treatment impairs T cell-directed antimicrobial activity. Anti-TNF therapy reduced the expression in lymphocytes of perforin and granulysin, 2 components of the T cell-mediated antimicrobial response to intracellular pathogens. Specifically, M. tuberculosis-reactive CD8 + CCR7 -CD45RA + effector memory T cells (T EMRA cells) expressed the highest levels of granulysin, lysed M. tuberculosis, and infected macrophages and mediated an antimicrobial activity against intracellular M. tuberculosis. Furthermore, T EMRA cells expressed cell surface TNF and bound the anti-TNF therapeutic infliximab in vitro, making them susceptible to complement-mediated lysis. Immune therapy with anti-TNF was associated with reduced numbers of CD8 + T EMRA cells and decreased antimicrobial activity against M. tuberculosis, which could be rescued by the addition of CD8 + T EMRA cells. These results suggest that anti-TNF therapy triggers a reduction of CD8 + T EMRA cells with antimicrobial activity against M. tuberculosis, providing insight into the mechanism whereby key effector T cell subsets contribute to host defense against tuberculosis.

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Perforin and granzyme A expression identifying cytolytic lymphocytes in rheumatoid arthritis.

Cited by 70 publications

References 31 publications

Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease

Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease

Emerging roles of serine proteinases in tissue turnover in arthritis

Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humans

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