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Immunol Cell Biol. 2014 Oct;92(9):752-60. doi: 10.1038/icb.2014.45. Epub 2014 Jun 17.

Upregulation of store-operated Ca(2+) entry in the naïve CD4(+) T cells with aberrant cytokine releasing in active rheumatoid arthritis.

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  • 1Department of Pharmacology, Ehime University Graduate School of Medicine, Ehime, Japan.
  • 21] Department of Bone and Joint Surgery, Ehime University Graduate School of Medicine, Ehime, Japan [2] Community Health Care Organization Uwajima Hospital, Ehime, Japan.
  • 3Department of Bioscience, Integrated Center for Sciences, Ehime University, Ehime, Japan.
  • 4Department of Molecular and Cellular Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
  • 5Department of Bone and Joint Surgery, Ehime University Graduate School of Medicine, Ehime, Japan.


The regulated control of Ca(2+) influx is essential for the activation and function of the adaptive immune response, as Ca(2+) is a key regulator of important transcription factors. To determine whether Ca(2+) release-activated Ca(2+) (CRAC) channels contribute to the abnormal behaviour of T cells in patients with rheumatoid arthritis (RA), we performed a cross-sectional study to characterize the expression and functional status of CRACM1 channels in RA patients. Peripheral blood was obtained from 50 RA patients, 50 osteoarthritis (OA) patients and healthy donors. We measured Ca(2+) influx and CRAC currents in naïve and memory CD4(+) T cells. CRACM1 expression was evaluated in T cells from each of the three groups. These cells were further characterized by flow cytometric analysis of interleukin-4 (IL-4), IL-17, interferon-γ and tumour necrosis factor-α. These cytokines were also measured in naïve CD4(+) T cells following the lentivirus-mediated silencing of CRACM1.There was a significant positive correlation between Ca(2+) influx in naïve T cells and RA activity. Functionally aberrant naïve CD4(+) T cells from patients with active RA showed the different cytokine release pattern and exhibited increased Ca(2+) influx as well as increased CRACM1 protein expression and function. Specific lentiviral-induced gene silencing of CRACM1 reversed the alterations in T-cell cytokine production. The data presented here indicate that an upregulation of CRACM1 expression and function may be responsible for the abnormal cytokine release of naïve CD4(+) T cells in RA patients. CRACM1 might therefore represent a new molecular target for RA therapies.

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