Rheumatoid arthritis synovial T cells regulate transcription of several genes associated with antigen-induced anergy

Ali, Manir; Ponchel, Frédérique; Wilson, Katherine E.; Francis, Michael J.; Wu, Xia; Verhoef, Adrienne; Boylston, Arthur W.; Veale, Douglas J.; Emery, Paul; Markham, Alexander F.; Lamb, Jonathan R.; Isaacs, John D.

doi:10.1172/jci8027

Cited by 38 publications

(27 citation statements)

References 54 publications

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“…In this study, most patients, despite receiving this type of therapy, responded to the TST, and some patients even presented high TST induration values. Therefore, the tuberculin anergy previously described in rheumatoid arthritis patients in other reports (36)(37)(38) was not observed in our study. The distribution of TST reactivity in our patient cohort showed that 31.1% of patients had a TST induration > 10 mm, whereas only two patients had indurations of 5-9 mm.…”

Section: Discussioncontrasting

confidence: 85%

Correlación de la respuesta a antígenos de Mycobacterium tuberculosis y la prueba cutánea tuberculina en pacientes con artritis reumatoide

et al. 2012

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Section: Discussioncontrasting

confidence: 85%

Correlación de la respuesta a antígenos de Mycobacterium tuberculosis y la prueba cutánea tuberculina en pacientes con artritis reumatoide

et al. 2012

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“…Strikingly, almost the entire population of joint-derived IFN-␥ ϩ Th cells in RA patients lacked 4-1BB expression, indicating that they had been induced by cytokines in a TCR-independent manner. The absence of 4-1BB was not the result of an intrinsic defect, for example, resulting from chronic activation of synovial Th cells leading to anergy, 37 because the activation marker could be induced among the majority of synovial IFN-␥ ϩ Th cells by TCR-dependent activation with immobilized ␣CD3 and ␣CD28 antibodies. Thus, we demonstrate here that a TCR-independent mechanism for IFN-␥ induction in human Th cells operates in vivo at a site of chronic autoimmune inflammation.…”

Section: Discussionmentioning

confidence: 99%

Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Sattler

Wagner

Rossol

et al. 2009

Blood

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IntroductionProduction of interferon-␥ (IFN-␥) by T-helper1 (Th1) cells is a key feature of both protective and pathologic immune responses. Control and clearance of bacterial and viral infections strictly depend on antigen-specific IFN-␥-secreting Th cells. 1,2 It is also undisputed that Th1 cells of the effector-memory phenotype predominate in inflamed tissues in human autoimmune diseases, such as rheumatoid arthritis (RA), [3][4][5] where they compose up to 80% of the T-cell infiltrate. 6 Nonetheless, how such cells get activated at sites of chronic inflammation remains an unsolved issue. Recent reports have challenged the concept that IFN-␥ release by T cells strictly depends on T-cell receptor (TCR) ligation: in in vitro-generated murine Th1-effector cells, IFN-␥ production is inducible in a TCR-independent manner by the cytokines interleukin-12 (IL-12) and IL-18. 7 IL-12R-downstream STAT4 and IL-18R-dependent GADD45-␤, which activates p38 mitogen-activated protein kinase (MAPK), were identified as essential signaling components. 8,9 Although infection models suggest that such a mechanism evolved to provide an early source of IFN-␥ contributing to host protection, 10,11 it was at the same time postulated to promote inflammatory circuits in autoimmunity. 12 In contrast to murine Th1 cells, however, stimulation of human resting Th cells with IL-12 and IL-18 induces only minute amounts of IFN-␥ 13 but boosts cytokine production in synergy with TCR ligation. 14 Th cells isolated from synovial infiltrates of RA patients exhibit a differentiated effector-memory Th1 phenotype, reflected, for example, by expression of IL-12R and IL-18R. 15 Because elevated levels of several proinflammatory mediators, including IL-12 and IL-18, were found to correlate with disease severity, 16,17 we wondered whether cytokine-induced IFN-␥ production in human Th cells in the absence of antigenic stimulation is functional at all in vitro and of relevance in vivo in human autoimmunity.We demonstrate here that a subset of human resting effectormemory Th cells, characterized by ex vivo expression of IL-18R␣, IL-12R, and CCR5, can be induced to secrete IFN-␥ by cytokines present at sites of chronic inflammation. IL-2R ␥-chain (␥ c ) signaling via JAK3, in addition to IL-12R and IL-18R ligation, is essential for TCR-independent induction of IFN-␥ production. Cytokine-induced IFN-␥ ϩ Th cells are sensitive to suppression by CD25 ϩϩ T regulatory cells and specifically lack 4-1BB (CD137) expression. Applying this activation marker, we provide evidence that almost all Th cells spontaneously secreting IFN-␥ ex vivo in synovial infiltrates from RA patients are cytokine-induced, for they characteristically lack 4-1BB expression. Our results support the notion that IFN-␥ production by Th cells in chronic autoimmune inflammation may be provoked solely by the cytokine environment, independent of triggering autoantigens. Methods Cell isolationPeripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of healthy donors by Ficoll-Hy...

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“…However, modulation or overexpression of calmodulin is not an attractive therapeutic target because of the myriad systems in which it acts (2,12,25,28,42,63). Therefore, stimulation of calmodulin or calcium signaling as a possible treatment for Pcp carries the high probability of disruption of other delicately balanced regulatory systems.…”

Section: Discussionmentioning

confidence: 99%

Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during Pneumocystis Pneumonia

et al. 2009

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Pneumocystis infection causes increased intracellular levels of reactive oxygen species (ROS) and the subsequent apoptosis of alveolar macrophages (Amø). Assessments of key prosurvival molecules in Amø and bronchoalveolar lavage fluids from infected rats and mice showed low levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and reduced activation of phosphoinositide-3 kinase (PI-3K). Ubiquitous calcium-sensing protein calmodulin protein and mRNA levels were also reduced in Amø during Pneumocystis pneumonia (Pcp). Calmodulin has been implicated in control of GM-CSF production and PI-3K activation in other immune cell types. Experiments to determine the control of GM-CSF and PI-3K by calmodulin in Amø showed that GM-CSF expression and PI-3K activation could not be induced when calmodulin was inhibited. Calmodulin inhibition also led to increased levels of ROS and apoptosis in cells exposed to bronchoalveolar lavage fluids from infected animals. Supplementation of Amø with exogenous calmodulin increased survival signaling via GM-CSF and PI-3K and reduced ROS and apoptosis. These data support the hypotheses that calmodulin levels at least partially control survival signaling in Amø and that restoration of GM-CSF or PI-3K signaling will improve host response to the organism.

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Rheumatoid arthritis synovial T cells regulate transcription of several genes associated with antigen-induced anergy

Cited by 38 publications

References 54 publications

Correlación de la respuesta a antígenos de Mycobacterium tuberculosis y la prueba cutánea tuberculina en pacientes con artritis reumatoide

Correlación de la respuesta a antígenos de Mycobacterium tuberculosis y la prueba cutánea tuberculina en pacientes con artritis reumatoide

Cytokine-induced human IFN-γ–secreting effector-memory Th cells in chronic autoimmune inflammation

Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during Pneumocystis Pneumonia

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