How signaling and gene transcription aberrations dictate the systemic lupus erythematosus T cell phenotype

Crispín, José C.; Kyttaris, Vasileios C.; Juang, Yuang-Taung; Tsokos, George C.

doi:10.1016/j.it.2007.12.003

Cited by 95 publications

(87 citation statements)

References 48 publications

(55 reference statements)

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“…Cellular levels of the catalytic subunit of PP2A are abnormally high in patients with SLE (8). This defect affects the activity of several transcription factors (8,43,44) and has been proposed to contribute to the altered phenotype of T cells from SLE patients (9). The fact that levels of PP2A Bβ are abnormally low in some patients with SLE underscores the notion that each component of the PP2A holoenzyme is regulated separately, and hints at its complex regulation (2).…”

Section: Discussionmentioning

confidence: 99%

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Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus

Crispín

Apostolidis

Finnell

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The activity and substrate specificity of the ubiquitously expressed phosphatase PP2A is determined by the type of regulatory (B) subunit that couples to the catalytic/scaffold core of the enzyme. We determined that the Bβ subunit (PPP2R2B) is expressed in resting T cells, its transcription is down-regulated during T-cell activation, and up-regulated in conditions of low IL-2. Specifically, high levels of PP2A Bβ were produced during IL-2 deprivation-induced apoptosis, whereas Fas ligation had no effect. Forced expression of the Bβ subunit in primary human T cells was sufficient to induce apoptosis, whereas silencing using siRNA protected activated T cells from IL-2 withdrawal-induced cell death. Because T-cell apoptosis is known to be altered in T cells from patients with systemic lupus erythematosus, we analyzed the regulation of PP2A Bβ in this autoimmune disease. We found that levels of PP2A Bβ did not increase upon IL-2 deprivation in 50% of the patients. Remarkably, this defect was accompanied by resistance to apoptosis. Importantly, kinetics of cell death were normal in cells of patients that up-regulated PP2A Bβ in a normal manner. We have identified a unique role for the phosphatase PP2A, particularly the holoenzyme formed by PP2A Bβ. Bβ appears to trigger apoptosis of T cells in the absence of IL-2 and probably contributes to the termination of a no-longer-needed immune response. We propose that defective production of PP2A Bβ upon IL-2 deprivation results in apoptosis resistance and longer survival of autoreactive T cells, in a subset of SLE patients.

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Section: Discussionmentioning

confidence: 99%

“…Patients with systemic lupus erythematosus (SLE), a chronic autoimmune condition (9), have abnormally high levels and activity of PP2A C in T cells (8). Increased PP2A expression has been shown to contribute to altered expression of transcription factors and cytokines (8).…”

mentioning

confidence: 99%

Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus

Crispín

Apostolidis

Finnell

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Frequently, the mutations involve a negative regulator such as SHP-1, CD22, or FCγRIIb (39-41); overexpression of a positive regulator such as CD19 or a mutation in CD45 that controls the activity of src kinases can also break tolerance and cause autoantibody production (42). Patients with systemic lupus erythematosus have a subset of T cells with FcRγ-Syk replacing ξ-ZAP70 in the TCR signaling complex, which induces a preferential calcium signal (43). The best example of T-cell hyperresponsiveness causing autoimmune disease is Cbl/Cbl-b doubledeficient mice (44).…”

Section: Discussionmentioning

confidence: 99%

K-RAS GTPase- and B-RAF kinase–mediated T-cell tolerance defects in rheumatoid arthritis

Singh

Deshpande

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Autoantibodies to common autoantigens and neoantigens, such as IgG Fc and citrullinated peptides, are immunological hallmarks of rheumatoid arthritis (RA). We examined whether a failure in maintaining tolerance is mediated by defects in T-cell receptor activation threshold settings. RA T cells responded to stimulation with significantly higher ERK phosphorylation ( P < 0.001). Gene expression arrays of ERK pathway members suggested a higher expression of KRAS and BRAF , which was confirmed by quantitative PCR ( P = 0.003), Western blot, and flow cytometry ( P < 0.01). Partial silencing of KRAS and BRAF lowered activation-induced phosphorylated ERK levels ( P < 0.01). In individual cells, levels of these signaling molecules correlated with ERK phosphorylation, attesting that their concentrations are functionally important. In confocal studies, B-RAF/K-RAS clustering was increased in RA T cells 2 min after T-cell receptor stimulation ( P < 0.001). Overexpression of B-RAF and K-RAS in normal CD4 T cells amplified polyclonal T-cell proliferation and facilitated responses to citrullinated peptides. We propose that increased expression of B-RAF and K-RAS lowers T-cell activation thresholds in RA T cells, enabling responses to autoantigens.

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“…Selain penurunan ekspresi CD3 dan CD26, beberapa abnormalitas penanda permukaan sel juga ditemukan pada limfosit pasien SLE seperti peningkatan ekspresi CD154 yang merupakan ligan CD40 pada sel B, penurunan sekresi IL-2, dan peningkatan IFN-γ. 16 Sebagai konsekuensinya, banyak limfosit T mengalami apoptosis dan juga merupakan sumber poten untuk mengaktifkan dan menginduksi antigen presenting cell imatur, meningkatkan kapasitas limfosit T yang autoreaktif, memproduksi sitokin, dan menstimulasi limfosit B yang autoreaktif. 15,16 Selanjutnya, interaksi CD154 dan CD40 akan mengaktifkan limfosit B untuk meningkatkan produksi autoantibodi yang disertai peningkatan sel-sel B dari berbagai tingkat perkembangan.…”

Section: Pembahasanunclassified

Ekspresi CD3 dan CD26 pada Limfosit T sebagai Biomarker Potensial Penyakit Systemic Lupus Erythematosus

Suselo¹,

Balgis²,

Indarto³

2016

mkb

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AbstrakSystemic lupus erythematosus (SLE) merupakan penyakit autoimun yang sering dijumpai pada wanita. Penyakit ini ditandai oleh hiperautoreaktivitas limfosit T dan B. Di dalam sistem imun, CD3 dibantu CD26 sebagai molekul kostimulator berkaitan erat dengan aktivasi dan migrasi limfosit T. Pada penyakit SLE, ekspresi CD3 dan CD26 serta aktivitas enzim CD26 belum diketahui. Tujuan penelitian ini adalah mengetahui ekspresi CD3 dan CD26 dalam darah serta kultur limfosit T pasien SLE. Rancangan penelitian ini bersifat eksperimen laboratorium dengan pendekatan studi retrospektif. Penelitian dilakukan di Laboratorium Biomedik, Fakultas Kedokteran Universitas Sebelas Maret Surakarta selama lima bulan (Mei-September 2012). Diagnosis SLE ditentukan menurut kriteria dari American College of Rheumatology (ACR). Darah vena diambil dari tiga pasien SLE dan dua orang sehat. Satu µg/mL phytohaemmaglutinin (PHA) digunakan untuk stimulasi kultur limfosit T. Ekspresi CD3 dan CD26 ditentukan dengan flows sytometry. Substrat H-Gly-Pro pNA digunakan untuk menguji aktivitas enzim CD26. Data yang terkumpul dianalisis dengan uji t. Ekspresi CD3 dan CD26 menurun dalam darah dan kultur limfosit T pada pasien SLE dibanding dengan kontrol, sedangkan aktivitas enzim CD26 pada kultur limfosit T pasien SLE lebih tinggi daripada kontrol (0.042 vs 0.030 U/mL), tetapi perbedaan tersebut tidak bermakna secara statistik (p>0.05). Simpulan, terdapat penurunan ekspresi CD3 dan CD26 baik dalam sirkulasi darah maupun di kultur limfosit T subtipe CD4+. CD3 dan CD26 berpotensi sebagai biomarker penting untuk SLE. Namun, riset lanjutan masih perlu dilakukan untuk menjelaskan peran keduanya dalam patogenesis penyakit SLE. [MKB. 2016;48(3):140-7] Kata kunci: CD3, CD26, systemic lupus erythematosus (SLE) CD3 and CD26 Expression on T Lymphocytes as a Potential Biomarker of Systemic Lupus Erithematosus AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease that is frequently found in women and characterized by hyperautoreactivity of T and B cells. In the immune system, expressions of CD 3 and CD26 (as co-stimulatory molecule) are related to T cells activation and migration. Co-expression of CD3 and CD26 in SLE patients has not been determined. The aim of this study was to investigate the co-expression of CD3 and CD26 in blood and T cell culture of SLE patients. This was an analytical descriptive study with a retrospective approach. This study was performed at the Biomedical laboratory, Faculty of Medicine, Sebelas Maret University, for five months (May-September 2012). SLE diagnosis was determined by using the criteria from the American College of Rheumatology (ACR). Vein blood was collected from three female patients with SLE and two healthy female controls. T cells isolated from the blood were cultured and stimulated with 1 µg/mL phytohaemmaglutinin (PHA). Flow cytometry was used to determine the coexpression of CD3 and CD26. CD26 enzyme activities in T cell culture were spectrophotometrically measured using H-Gly-Pro pNA substrate. Colle...

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How signaling and gene transcription aberrations dictate the systemic lupus erythematosus T cell phenotype

Cited by 95 publications

References 48 publications

Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus

Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus

K-RAS GTPase- and B-RAF kinase–mediated T-cell tolerance defects in rheumatoid arthritis

Ekspresi CD3 dan CD26 pada Limfosit T sebagai Biomarker Potensial Penyakit Systemic Lupus Erythematosus

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