Akiko Nishioka

Tobacco smoke is related to Th17 generation with clinical implications for psoriasis patients

Abstract:  Environmental factors contribute to the increased prevalence of autoimmune diseases via T helper type‐17 cell (Th17) activation. Tobacco smoking increases the risk of psoriasis, but the mechanisms are not clear. We evaluated the percentage of circulating Th17 among CD3+ cells in peripheral blood mononuclear cells (PBMC) obtained from 27 healthy volunteers (2.58 ± 0.80%), 33 smoker (3.55 ± 1.33%) and 21 non‐smoker (3.10 ± 1.14%) patients with psoriasis to elucidate the relation between smoking and psoriasis. More smokers (19/33) than non‐smokers (6/21) had high Th17 levels (Th17/CD3 > 3.38%, mean + 1 SD of healthy volunteers). Tobacco smoke extract (TSE, 7 μl/ml) induced Th17 generation from central memory T cells in vitro. TSE increased interleukin 17 and 22 expression. These findings demonstrate the relation between tobacco smoke and IL‐17 and IL‐22, which exacerbate psoriasis.

Homeostasis of thymus-derived Foxp3+ regulatory T cells is controlled by ultraviolet B exposure in the skin.

Accumulating evidence shows that immunological tolerance induced by Ag administration together with UVB irradiation is dependent on Foxp3+ CD4+ regulatory T (Treg) cells. However, the mechanisms by which UVB controls Treg cells in the skin are currently unclear. In this study, we have shown that exposure to UVB induced expansion of Treg cells up to 50–60% of the CD4+ T cells in the irradiated skin. The Treg cell expansion in the skin lasted for 2 wk after exposure, which contributed to homeostasis of Treg cells in the periphery later. UVB-expanded Treg cells formed clusters with dendritic cells and proliferated in situ. Furthermore, the expanded Treg cells appeared to derive from neuropilin 1+ thymus-derived Treg (tTreg) cells in the periphery because UVB-expanded Treg cells possessed Treg cell–specific CpG hypomethylation pattern, as seen in tTreg cells. These results collectively indicate that homeostasis of tTreg cells is controlled by UVB exposure in the skin. UVB therapy may be useful for not only inflammatory skin disorders, but also autoimmunity, transplantation, and allergy.

Bath-PUVA therapy improves impaired resting regulatory T cells and increases activated regulatory T cells in psoriasis

BACKGROUND Bath-psoralen plus ultraviolet light A (PUVA) therapy is an effective, safe, and inexpensive treatment for psoriasis. Psoriasis might be due to an unbalanced ratio of Th17 cells and regulatory T cells (Treg). The Treg functional ratio is significantly lower in patients with psoriasis compared with controls and is inversely correlated with the Psoriasis Area and Severity Index score. We previously reported that bath-PUVA therapy significantly increases the number of Treg and restores Treg function to almost normal in most patients with psoriasis. OBJECTIVES We examined the effects of bath-PUVA therapy on three distinct Foxp3+ subsets: activated Treg (aTreg), resting Treg (rTreg), and cytokine-secreting non-suppressive T cells. METHODS We enrolled 15 patients with psoriasis and 11 healthy controls. We examined aTreg, rTreg, and cytokine-secreting non-suppressive T cells in peripheral blood obtained from the psoriasis patients before and after every fifth bath-PUVA therapy session. RESULTS Levels of aTreg, which are considered to have the strongest suppressive activity in patients with psoriasis, were significantly increased in the early bath-PUVA therapy sessions, and then diminished. Levels of rTreg were lower in psoriasis patients than in healthy controls, and increased during bath-PUVA therapy. CONCLUSIONS Bath-PUVA therapy induced aTreg and rTreg concomitantly with an improvement in the psoriatic lesions, suggesting a mechanism for the effectiveness of bath-PUVA therapy for psoriasis patients.

Ultraviolet B–Induced Maturation of CD11b-Type Langerin− Dendritic Cells Controls the Expansion of Foxp3+ Regulatory T Cells in the Skin

Skin dendritic cells (DCs) are divided into several subsets with distinctive functions. This study shows a previously unappreciated role of dermal CD11b-type Langerin− DCs in maintaining immunological self-tolerance after UVB exposure. After UVB exposure, dermal CD11b-type Langerin− DCs upregulated surface CD86 expression, induced proliferation of Foxp3+ regulatory T (Treg) cells without exogenous Ags, and upregulated a set of genes associated with immunological tolerance. This Treg-expansion activity was significantly hampered by CD80/CD86 blockade in vivo. These results indicate that CD11b-type Langerin− DCs from the UVB-exposed skin are specialized to expand Treg cells in the skin, which suppress autoimmunity.

RhoH deficiency induces psoriasis-like chronic dermatitis by promoting TH17 cell polarization

Background: Ras homolog gene family H (RhoH) is a membrane‐bound adaptor protein involved in proximal T‐cell receptor signaling. Therefore RhoH plays critical roles in the differentiation of T cells; however, the function of RhoH in the effecter phase of the T‐cell response has not been fully characterized. Objective: We sought to explore the role of RhoH in inflammatory immune responses and investigated the involvement of RhoH in the pathogenesis of psoriasis. Methods: We analyzed effector T‐cell and systemic inflammation in wild‐type and RhoH‐null mice. RhoH expression in T cells in human PBMCs was quantified by using RT‐PCR. Results: RhoH deficiency in mice induced TH17 polarization during effector T‐cell differentiation, thereby inducing psoriasis‐like chronic dermatitis. Ubiquitin protein ligase E3 component N‐recognin 5 (Ubr5) and nuclear receptor subfamily 2 group F member 6 (Nr2f6) expression levels decreased in RhoH‐deficient T cells, resulting in increased protein levels and DNA binding activity of retinoic acid–related orphan receptor &ggr;t. The consequential increase in IL‐17 and IL‐22 production induced T cells to differentiate into TH17 cells. Furthermore, IL‐22 binding protein/Fc chimeric protein reduced psoriatic inflammation in RhoH‐deficient mice. Expression of RhoH in T cells was lower in patients with psoriasis with very severe symptoms. Conclusion: Our results indicate that RhoH inhibits TH17 differentiation and thereby plays a role in the pathogenesis of psoriasis. Additionally, IL‐22 binding protein has therapeutic potential for the treatment of psoriasis. GRAPHICAL ABSTRACT Figure. No caption available.