Treg Cell Function in Rheumatoid Arthritis Is Compromised by CTLA‐4 Promoter Methylation Resulting in a Failure to Activate the Indoleamine 2,3‐Dioxygenase Pathway

Cribbs, Adam P.; Kennedy, Alan; Penn, Henry; Read, Jordan E.; Amjadi, Parisa; Green, Patricia; Syed, Khaja Mohieddin; Manka, Szymon W.; Brennan, Fionula M.; Gregory, Bernard; Williams, Richard O.

doi:10.1002/art.38715

Cited by 128 publications

(109 citation statements)

References 45 publications

(59 reference statements)

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“…Depletion of Treg cells in mice aggravates the severity of experimental arthritis, whereas adoptive transfer CD4 + CD25 + cells protects against arthritis (Frey et al, 2005). In humans also, functional abnormalities of Treg cells have been identified in RA patients (Flores-Borja et al, 2008, Cribbs et al, 2014 B cells are the lymphocytes which, after antigen activation, can be transformed to plasma cells that produce antigen-specific immunoglobulins (antibodies) of different isotypes (IgM, IgD, IgG (subclasses 1-4), IgA (subclass 1 and 2), and IgE. Rituximab, a B-cell blocking drug, has been found effective to treat RA.…”

Section: Innate and Adaptive Immunity In Ramentioning

confidence: 99%

Immune tolerance by interferon-alpha in experimental arthritis

Chalise¹

2015

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Section: Innate and Adaptive Immunity In Ramentioning

confidence: 99%

Immune tolerance by interferon-alpha in experimental arthritis

Chalise¹

2015

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“…Функциональная активность Т рег зависит от набора поверхностных маркеров: CTLA-4 [27][28][29][30][31], ICOS [32][33][34][35][36][37][38][39][40], CD154 [41][42][43][44][45][46], CD274 [47][48][49][50][51][52][53] и ряда других, участвующих в контроле активации Т-клеток.…”

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“…Совсем недавно были получены новые данные, свидетельствующие о влиянии МТ на эпигенетические дефекты функции Т рег [30,101]. Напомним, что эпигене-тическая регуляция генов, в первую очередь метилирова-ние ДНК, играет существенную роль в контроле их функ-ции [23]; было продемонстрировано, что метилирование ДНК участвует в экспрессии транскрипционного регуля-тора Т рег -FoxP3 [23].…”

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“…Напомним, что эпигене-тическая регуляция генов, в первую очередь метилирова-ние ДНК, играет существенную роль в контроле их функ-ции [23]; было продемонстрировано, что метилирование ДНК участвует в экспрессии транскрипционного регуля-тора Т рег -FoxP3 [23]. Недавно получены данные о том, что снижение функции Т рег у пациентов с ранним РА, не получавших БПВП, ассоциируется со снижением экс-прессии CTLA-4 (cytotoxic T lymphocyte protein 4) [30]. Полагают, что механизм, определяющий этот феномен, связан с усилением метилирования фактора транскрип-ции NFAT (nuclear factor of activated T cells), располагаю-щегося в промоторном участке гена CTLA-4.…”

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“…Полагают, что механизм, определяющий этот феномен, связан с усилением метилирования фактора транскрип-ции NFAT (nuclear factor of activated T cells), располагаю-щегося в промоторном участке гена CTLA-4. Это приво-дит к нарушению транскрипционной активности и, как следствие, снижению экспрессии CTLA-4 [30]. На фоне лечения МТ отмечается усиление экспрессии FoxP3 и CTLA-4, что способствует нормализации супрессивной функции Т рег .…”

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The clinical and pathogenetic value of Foxp3+ T regulatory cells in rheumatoid arthritis

Авдеева¹,

Рубцов²,

Dyikanov³

et al. 2016

rsp

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Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis

Cribbs

Kennedy

Penn

et al. 2015

Arthritis & Rheumatology

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139

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Objective We have previously shown, in a cohort of untreated rheumatoid arthritis (RA) patients, that the suppressive function of Treg cells is defective. However, other studies in cohorts of patients with established RA have shown that Treg cell function is normal. We hypothesized that treatment may restore Treg cell function and lead to reduced disease activity. The aim of this study was to investigate whether treatment with methotrexate (MTX) can result in epigenetic changes that lead to restoration of the Treg cell suppressive function in RA. Methods Peripheral blood samples from RA patients were assessed using 3H‐thymidine incorporation to measure Treg cell suppression of T cell proliferation, and by enzyme‐linked immunosorbent assay to determine Treg cell suppression of interferon‐γ production. CTLA‐4 and FoxP3 expression was measured by flow cytometry and quantitative polymerase chain reaction (qPCR) in Treg cells from healthy individuals and RA patients. CD4+ T cells isolated from healthy individuals were cultured with interleukin‐2 (IL‐2), IL‐6, and tumor necrosis factor α in the presence or absence of MTX, and FoxP3 expression was determined using qPCR and flow cytometry. Methylation of the FOXP3 upstream enhancer was analyzed by bisulfite sequencing PCR. Results Defective Treg cell function was observed only in RA patients who had not been treated with MTX, whereas Treg cells from MTX‐exposed RA patients had restored suppressive function. This restored suppression was associated with increased expression of FoxP3 and CTLA‐4 in Treg cells. Bisulfite sequencing PCR of Treg cells cultured in MTX revealed a significant reduction in methylation of the FOXP3 upstream enhancer. Conclusion This study identifies a novel mechanism of action of MTX, in which treatment of RA patients with MTX restores defective Treg cell function through demethylation of the FOXP3 locus, leading to a subsequent increase in FoxP3 and CTLA‐4 expression.

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Treg Cell Function in Rheumatoid Arthritis Is Compromised by CTLA‐4 Promoter Methylation Resulting in a Failure to Activate the Indoleamine 2,3‐Dioxygenase Pathway

Cited by 128 publications

References 45 publications

Immune tolerance by interferon-alpha in experimental arthritis

Immune tolerance by interferon-alpha in experimental arthritis

The clinical and pathogenetic value of Foxp3+ T regulatory cells in rheumatoid arthritis

Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis

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