乾癬のT細胞におけるケモカイン受容体発現およびサイトカイン産生の病因的役割

金沢大学附属病院尋常性乾癬の病変形成においてCD4^+T細胞が重要な役割を果たすと考えられている。乾癬病変部皮膚および血液中でそインターフェロンγ(IFN-γ)を産生するT1細胞がインターロイキン4(IL-4)を産生するT2細胞に比較して増加していると考えられているが,両者の頻度に差がないとの報告もある。そこでわれわれは尋常性乾癬の末梢血および病変部皮膚におけるTリンパ球のT1/T2バランスを検討した。乾癬患者の血液中で,IL-4産生CD8^+T(Tc2)細胞の頻度が4.8±3.2%対照の健常人と比較して優位に増加していた。T2細胞に特異的なケモカイン受容体CCR4を発現するCD8^+T細胞も乾癬患者末梢血中で健常人より有意に増加していた。さらにTc2細胞の頻度およびTc2細胞/Tc1細胞比は乾癬の重症度の指標であるpsoriasis area and severity indexと有意な正の相関を示した。それに対して乾癬患者血液中のIFN-γ産生CD4^+T(Th1)細胞,およびIFNγ産生CD8^+T(Tc1)細胞の頻度は健常人における頻度と差がなかった。T1細胞に特異的とされるケモカイン受容体CXCR3の発現も検討したが同様の結果が得られた。乾癬患者末梢血から分離したCD8^+T細胞は健常人由来の細胞より多くのIL-4を産生したが,IFN-γの産生は乾癬患者と健常人で差はなかった。病変部皮膚の免疫組織学検討により乾癬患者の表皮および真皮にCXCR3^+CD8^+T細胞と同様の頻度のCCR4^+CD8^+T細胞の浸潤が認められた。以上の結果から,尋常性乾癬患者の末梢血中にTc2細胞の頻度が増加していること,およびTc2細胞と乾癬の炎症との関連性が示唆された。Studies have suggested that psoriasis vulgaris is mediated by type 1 T cells. In this study, we examined both chemokine receptor expression and intracellular cytokine production by circulating T cells to check the type 1 / type 2 balance in psoriasis. CCR4^+ and CXCR3^+ T cells predominantly produced interleukin-4 and interferon-γ, respectively. The frequency of interferon-γ-producing cells and that of CXCR3^+ cells in circulating CD4^+ T cells were similar for psoriatic patients and healthy control subjects. By contrast, the frequency of CCR4^+ CD8^+ T cells and CCR4/CXCR3 ratio in circulating CD8^+ T cells were significantly higher in psoriatic patients than in healthy control subjects. Analysis of intracellular cytokine production also indicated relative increase of type 2 CD8^+ T (Tc2) cells in peripheral blood from psoriatic patients. The frequency of circulating Tc2 cells directly correlated with Psoriasis Area and Severity Index. Immunohistochemical analysis showed that not only CXCR3^+ CD8^+ T cells, but also a similar number of CCR4^+ CD8^+ T cells infiltrated the psoriatic epidermis and dermis. Our findings suggest an increase in Tc2 cell number in blood from psoriatic patients, and the association of Tc2 cells with inflammation in psoriasis.研究課題/領域番号:13670872, 研究期間(年度):2001-2002出典：研究課題「乾癬のT細胞におけるケモカイン受容体発現およびサイトカイン産生の病因的役割」課題番号13670872（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-13670872/136708722002kenkyu_seika_hokoku_gaiyo/）を加工して作

組換え型毒素を用いた黄色ブドウ球菌epidermolytic toxin Aの作用機序に関する研究

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第961号, 学位授与年月日：平成2年9月30日,学位授与年：199

Antiphospholipid antibodies in patients with autoimmune blistering disease

金沢大学医学部附属病院皮膚科Objective: Our purpose was to determine the serum levels and frequency of antiphospholipid antibodies (aPLs) and confirm the clinical importance of these antibodies in patients with autoimmune blistering disease (ABD). Methods: IgG and IgM anticardiolipin antibodies (aCL), IgG anticardiolipin-β2 glycoprotein I complex antibody (aCL/β2GPI), and IgG antiphosphatidylserine-prothrombin complex antibody (aPS/PT) were examined with an enzyme-linked immunosorbent assay in 71 patients with ABD, including pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid. Results: The prevalence of IgG aCL, IgM aCL, aCL/β2GPI, and IgG aPS/PT was positive for 22.4%, 9.1%, 9.9%, and 25.4% of the ABD patients, respectively, whereas these antibodies were not detected in any of the normal control subjects. Ten of 20 patients with ABD who were attending our hospital in 2004 tested positive for aPLs, and thromboembolism was detected in 7 of 10 patients with aPLs. Limitations: Follow-up studies, especially with a large patient group, will be needed to clarify the clinical relevance of aPLs in ABD. Conclusion: aPLs are frequently detected in patients with ABD. Careful examination and follow-up for thromboembolism may be necessary in ABD patients with aPLs. © 2007 American Academy of Dermatology, Inc

B Cell Activating Factor (BAFF) and T Cells Cooperate to Breach B Cell Tolerance in Lupus-Prone New Zealand Black (NZB) Mice

The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help

Low CD4/CD8 T-Cell Ratio Associated with Inflammatory Arthropathy in Human T-Cell Leukemia Virus Type I Tax Transgenic Mice

Human T-cell leukemia virus type I (HTLV-1) can cause an aggressive malignancy known as adult T-cell leukemia/lymphoma (ATL) as well as inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A transgenic mouse that expresses HTLV-1 Tax also develops T-cell leukemia/lymphoma and an inflammatory arthropathy that resembles rheumatoid arthritis. The aim of this study was to identify the primary T-cell subsets involved in the development of arthropathy in Tax transgenic mice. mRNA was strong in the spleen and joints of arthropathic mice, with a 40-fold increase compared with healthy transgenic mice.Our findings reveal that Tax transgenic mice develop rheumatoid-like arthritis with proliferating synovial cells in the joints; however, the proportion of different splenic T-cell subsets in these mice was completely different from other commonly used animal models of rheumatoid arthritis. The crucial T-cell subsets in arthropathic Tax transgenic mice appear to resemble those in HAM/TSP patients rather than those in rheumatoid arthritis patients