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Defective Regulatory T Cells In Patients with Severe Drug Eruptions: Timing of the Dysfunction Is Associated with the Pathological Phenotype and Outcome¹

Ryo Takahashi^2,*, Yoko Kano, Yoshimi Yamazaki, Momoko Kimishima, Yoshiko Mizukawa and Tetsuo Shiohara^*,

^* Division of Flow Cytometry, Kyorin University Graduate School of Medicine and Department of Dermatology, Kyorin University School of Medicine, Shinkawa, Mitaka, Tokyo, Japan

Toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS) represent two ends of a spectrum of severe drug eruptions: DIHS is unique in that severe epidermal damage seen in TEN is absent, sequential reactivations of herpesviruses occur, and autoimmunity often ensues. To investigate whether changes in regulatory T (Treg) cell function would contribute to variability in the clinical manifestations, we examined the frequency, phenotype, and function of Treg cells both during the acute stage and again long after clinical resolution of both diseases. Dramatic expansions of functional Treg cells were found in the acute stage of DIHS. In contrast, Treg function was profoundly impaired in TEN, although present in normal frequency. Skin homing addressins were more preferentially expressed on Treg cells in DIHS than in TEN. Indeed, Treg cells were more abundantly present in the skin lesions of DIHS. Surprisingly, Treg cells contracted upon resolution of DIHS became functionally deficient, whereas their functional defects in TEN were restored upon recovery. These findings indicate that a transitory impairment in their function during the acute stage of TEN may be related to severe epidermal damage, while a gradual loss of their function after resolution of DIHS may increase the risk of subsequently developing autoimmune disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology (to R.T., Y.K., and T.S.) and the Ministry of Health, Labor and Welfare of Japan (to T.S.), and Japanese Research Committee on Severe Cutaneous Adverse Reaction.

² Address correspondence and reprint requests to Dr. Ryo Takahashi, Division of Flow Cytometry, Kyorin University Graduate School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. E-mail address: ryo{at}ks.kyorin-u.ac.jp

³ Abbreviations used in this paper: SJS, Stevens-Johnson syndrome; DIHS, drug-induced hypersensitivity syndrome; TEN, toxic epidermal necrolysis; Treg, regulatory T, ESL, E-selectin ligand; CLA, cutaneous lymphocyte-associated Ag; Foxp3, forkhead box p3; CBZ, carbamazepine; PB, phenobarbital; IRS, immune reconstitution syndrome.