岩田 洋平

Experimental autoimmune encephalomyelitis (EAE) is a T lymphocyte-mediated autoimmune disease of the CNS. Significant roles for B cells and a rare IL-10-producing CD1dhighCD5+ regulatory B cell subset (B10 cells) have been identified during the initiation and progression of EAE. Whether and how the regulatory functions of B10 cells and FoxP3+ T regulatory cells (Tregs) overlap or influence EAE immunopathogenesis independently has remained unanswered. This study demonstrates that the number of endogenous or adoptively transferred B10 cells directly influenced EAE pathogenesis through their production of IL-10. B10 cell numbers expanded quickly within the spleen, but not CNS following myelin oligodendrocyte glycoprotein35-55 immunization, which paralleled B10 cell regulation of disease initiation. The adoptive transfer of myelin oligodendrocyte glycoprotein33-35-sensitized B10 cells into wild-type mice reduced EAE initiation dramatically. However, B10 cells did not suppress ongoing EAE disease. Rather, Treg numbers expanded significantly within the CNS during disease progression, which paralleled their negative regulation of late-phase disease. Likewise, the preferential depletion of B10 cells in vivo during disease initiation enhanced EAE pathogenesis, whereas Treg depletion enhanced late-phase disease. B10 cells did not regulate T cell proliferation during in vitro assays, but significantly altered CD4+ T cell IFN-γ and TNF-α production. Furthermore, B10 cells downregulated the ability of dendritic cells to act as APCs and thereby indirectly modulated T cell proliferation. Thus, B10 cells predominantly control disease initiation, whereas Tregs reciprocally inhibit late-phase disease, with overlapping B10 cell and Treg functions shaping the normal course of EAE immunopathogenesis. Copyright © 2010 by The American Association of Immunologists, Inc.

Objective. Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice. Methods. Tight skin (TSK/+) mice and bleomycin-induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts. Results. Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor beta 1, was attenuated by rapamycin. Hypergammaglobulinemia and anti-topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner. Conclusion. This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients.

Mice s.c. injected with bleomycin, an experimental model for human systemic sclerosis, develop skin and lung fibrosis, which is mediated by inflammatory cell infiltration. This process is highly regulated by multiple adhesion molecules and does not require Ag sensitization. To assess the role of adhesion molecules in this pathogenetic process, bleomycin-induced fibrosis was examined in mice lacking adhesion molecules. L-selectin and/or ICAM-1 deficiency inhibited skin and lung fibrosis with decreased Th2 and Th17 cytokines and increased Th1 cytokines. In contrast, P-selectin deficiency, E-selectin deficiency with or without P-selectin blockade, or P-selectin glycoprotein ligand 1 (PSGL-1) deficiency augmented the fibrosis in parallel with increased Th2 and Th17 cytokines and decreased Th1 cytokines. Furthermore, loss of L-selectin and/or ICAM-1 reduced Th2 and Th17 cell numbers in bronchoalveolar lavage fluid, whereas loss of P-selectin, E-selectin, or PSGL-1 reduced Th1 cell numbers. Moreover, Th1 cells exhibited higher PSGL-1 expression and lower expression of LFA-1, a ligand for ICAM-1, whereas Th2 and Th17 cells showed higher LFA-1 and lower PSGL-1 expression. This study suggests that L-selectin and ICAM-1 regulate Th2 and Th17 cell accumulation into the skin and lung, leading to the development of fibrosis, and that P-selectin, E-selectin, and PSGL-1 regulate Th1 cell infiltration, resulting in the inhibition of fibrosis. The Journal of Immunology, 2010, 185: 2502-2515.

Objective. To determine serum concentrations and clinical association of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with systemic sclerosis (SSc). Methods. Serum sTREM-1 levels from 17 patients with limited cutaneous SSc (ISSc), 24 patients with diffuse cutaneous SSc (dSSc), and 29 healthy control individuals were examined by ELISA. Results. Total SSc patients exhibited significantly elevated serum sTREM-1 levels relative to controls (p < 0.01). Serum sTREM-1 levels were significantly elevated in patients with dSSc compared to controls (p < 0.005) and ISSc patients (p < 0.05). By contrast, sTREM-1 levels in ISSc were similar to those in controls. Serum sTREM-1 levels were significantly elevated in SSc patients with decreased percentage vital capacity (%VC). Consistent with this, serum sTREM-1 levels in SSc patients correlated negatively with %VC (r = -0.24, p < 0.005). Among SSc patients with pulmonary fibrosis, sTREM-1 levels were significantly increased in patients with decreased %VC or decreased percentage of diffusion capacity for carbon monoxide relative to those with normal values (p < 0.05). Conclusion. Serum sTREM-1 levels were elevated in dSSc patients and correlated with severity of pulmonary fibrosis, suggesting that serum sTREM-1 is a novel serological marker for the disease severity of SSc. (First Release Feb 152010; J Rheumatol 2010;37:787-91; doi:10.3899/jrheum.090664)

壊死性筋膜炎は、致死率の高い疾患で、予後の改善には早期診断が重要である。壊死性筋膜炎の診断は特徴的な皮膚所見、試験穿刺所見、画像所見などから総合的に行われるが、近年、血液生化学検査データをもとにしたLRINEC scoreが補助的な診断ツールとして提唱されている。そこで自験例の壊死性筋膜炎9例と蜂窩織炎35例についてretrospectiveに、LRINEC scoreを用いて検討した。その結果、壊死性筋膜炎患者のLRINEC score(平均8.1±1.0点)は蜂窩織炎患者(平均1.7±0.3点)に比較して有意に高値であった。また、壊死性筋膜炎と診断するためのcut off値を6点以上と設定した場合には、LRINEC scoreの感度、特異度はそれぞれ100%、97%と優れたものであった。以上より、LRINEC scoreは壊死性筋膜炎の診断において有用であると考えられた。(著者抄録)

Platelets have been shown to be important in inflammation, but their role in the cutaneous Arthus reaction remains unclear. To assess the role of platelets in this pathogenetic process, the cutaneous Arthus reaction was examined in wild-type mice and mice lacking E-selectin, P-selectin, or P-selectin glycoprotein ligand-1 (PSGL-1) with or without platelet depletion by busulfan, a bone marrow precursor cell-specific toxin. Edema and hemorrhage induced by immune complex challenge significantly decreased in busulfan-treated wild-type mice compared with untreated mice. Busulfan treatment did not affect edema and hemorrhage in P-selectin- or PSGL-1-deficient mice, suggesting that the effect by busulfan is dependent on P-selectin and PSGL-1 expression. The inhibited edema and hemorrhage paralleled reduced infiltration of neutrophils and mast cells and reduced levels of circulating platelets. increased cutaneous production of interleukin-6, tumor necrosis factor-alpha, and platelet-derived chemokines; during Arthus reaction was inhibited in busulfan-treated wild-type mice relative to untreated mice, which paralleled the reduction in cutaneous inflammation. Flow cytometric analysis showed that immune complex challenge generated blood platelet-leukocyte aggregates that decreased by busulfan treatment. in thrombocytopenic mice, the cutaneous inflammation after immune complex challenge was restored by platelet infusion. These results suggest that platelets induce leukocyte recruitment into skin by forming platelet-leukocyte aggregates and secreting chemokines at inflamed sites, mainly through the interaction of P-selectin on platelets with PSGL-1 on leukocytes. (Am J Pathol 2010, 176:259-269; DOI: 10.2353/ajpath.2010.081117)

Painting subsensitizing doses of contact sensitizers on skin (low-dose tolerization) induces antigen (Ag)-specific tolerance, known as low zone tolerance (LZT), which has been experimentally demonstrated by the inhibition of contact hypersensitivity (CHS). Although LZT resulted from the inhibition of the sensitization phase, the effects on the effector/elicitation phase remain unknown. L-selectin and ICAM-1 regulate leukocyte influx into inflamed tissues during the elicitation phase of CHS. LZT was investigated in mice lacking either L-selectin or ICAM-1 to evaluate the roles these leukocyte receptors play in LZT during the elicitation phase. Low-dose tolerization effectively suppressed CHS in wild-type and L-selectin-deficient mice, but not in ICAM-1-deficient mice. Low-dose-tolerized ICAM-1-deficient splenocytes effectively suppressed the elicitation phase in naive wild-type recipients. Sensitized ICAM-1-deficient splenocytes showed normal proliferative responses to the sensitizing Ag and generated normal CHS in wild-type recipients. Thus, ICAM-1 deficiency did not affect sensitization. LZT was associated with a lack of ICAM-1 upregulation after elicitation, suggesting a potentially mechanistic role for ICAM-1. The blockade of IL-10, a possible mediator of LZT, produced by hapten-specific suppressor cells, abrogated LZT and restored ICAM-1 upregulation. These results indicate that low-dose tolerization controls CHS by abrogating ICAM-1 upregulation during the elicitation phase.

Objective To determine the prevalence and clinical correlation of autoantibody to activating transcription factor (ATF)-2, a transcription factor of ATF/CREB family, in patients with systemic sclerosis (SSc). Methods Anti-ATF-2 Ab was examined by ELISA and immunoblotting using human recombinant ATF-2. ATF-2 activity, to bind target DNA was evaluated by ELISA using a plate coated with oligonucleotide containing the consensus binding site for ATF-2. Results IgG anti-ATF-2 Ab levels in SSc patients (n=69) were significantly higher than those in normal controls (n=26). SSc patients positive for IgG anti-ATF-2 Ab had significantly, longer disease duration, more frequent presence of decreased %VC and %DLco, and elevated levels of serum IgG, serum IgA, and erythrocyte sedimentation rates than those negative. More-over, IgG anti-ATF-2 Ab levels correlated inversely with %VC or %DLco. The presence of anti-ATF-2 Ab in SSc patients was confirmed by immunoblotting analysis. IgG isolated from serum samples of SSc patients positive for IgG anti-ATF-2 Ab by ELISA slightly but significantly inhibited ATF-2 activity compared with normal controls. Conclusions These results suggest that anti-ATF-2 Ab is a new autoantibody in SSc and that it serves as a novel serological marker for inflammation and lung involvement in SSc.

Cell adhesion molecules are critical to wound healing through leukocyte recruitment. Although P-selectin glycoprotein ligand-1 (PSGL-1) regulates leukocyte rolling by binding P-selectin, but also binding E-and L-selectins with lower affinity, little is known about a role of PSGL-1 in wound healing. To clarify a role of PSGL-1 and its interaction with E-and P-selectins in wound healing, we investigated cutaneous wound healing in PSGL-1-deficient (PSGL-1(-/-)) mice in comparison with E-selectin(-/-), P-selectin(-/-), and P-selectin(-/-) mice treated with an anti-E-selectin antibody. PSGL-1 deficiency inhibited early wound healing, which was accompanied by decreased inflammatory cell infiltration and growth factor expression. By contrast, E-selectin deficiency did not affect wound healing. In general, the inhibitory effect of PSGL-1 deficiency on wound healing was similar to that of P-selectin deficiency either alone or with E-selectin blockade. However, early granulation tissue formation, late angiogenesis, and early infiltration of neutrophils and macrophages in PSGL-1(-/-) mice were inhibited beyond the inhibition in P-selectin(-/-) mice, but to a similar level of inhibition in P-selectin(-/-) mice with E-selectin blockade. These results suggest that PSGL-1 contributes to wound healing predominantly as a P-selectin ligand and partly as an E-selectin ligand by mediating infiltration of inflammatory cells.

Immune cells are critical to the wound-healing process, through both cytokine and growth factor secretion. Although previous studies have revealed that B cells are present within wound tissue, little is known about the role of B cells in wound healing. To clarify this, we investigated cutaneous wound healing in mice either lacking or overexpressing CD19, a critical positive-response regulator of B cells. CD19 deficiency inhibited wound healing, infiltration of neutrophils and macrophages, and cytokine expression, including basic and acidic fibroblast growth factor, interleukin-6, platelet-derived growth factor, and transforming growth factor-beta. By contrast, CD19 overexpression enhanced wound healing and cytokine expression. Hyaluronan (RA), an endogenous ligand for toll-like receptor (TLR)-4, stimulated B cells, which infiltrates into wounds to produce interleukin-6 and transforming growth factor-beta through TTR4 in a CD19-dependent manner. CD19 expression regulated TLR4 signaling through p38 activation. RA accumulation was increased in injured skin tissue relative to normal skin, and exogenous application of RA promoted wound repair in wild-type but not CD19-deficient mice, suggesting that the beneficial effects of HA to die wound-healing process are CD19-dependent. Collectively, these results suggest that increased RA accumulation in injured skin induces cytokine production by stimulating B cells through TLR4 in a CD19-dependent manner. Thus, this study is die first to reveal a critical role of B cells and novel mechanisms in wound healing. (Am J Pathol 2009,175.-649-660, DOI: 10.2353/ajpath.2009.080355)

Objective. To determine serum concentrations of: pentraxin 3 (PTX3) and its clinical associations in patients with systemic sclerosis (SSc). Methods. Serum PTX3 levels from 45 patients with diffuse cutaneous SSc (dSSc), 46 with limited cutaneous SSC (ISSc), and 20 healthy controls were examined by ELISA. PTX3 expression in the sclerotic skin from SSc patients was evaluated immunohistochemically. Normal and SSc fibroblasts were Cultured and PTX3 levels in the culture medium were also examined by ELISA. Results. Serum PTX3 levels were elevated in patients with SSc relative to controls. PTX3 levels in dSSc patients were significantly higher than in controls and ISSc patients. PTX3 expression in the sclerotic skin from SSc patients was more intense relative to normal skin. Elevation of serum PTX3 levels was associated with more frequent presence of pulmonary fibrosis, cardiac disease, and pitting scar/ulcer and increased serum immunoglobulin levels and erythrocyte sedimentation rates. PTX3 levels correlated positively with modified Rodnan total skin thickness score, and negatively with percentage vital capacity and percentage DLCO in patients with SSc. PTX3 levels also correlated positively with serum levels of 8-isoprostane, a marker of oxidative stress, and hyaluronan, recently identified as ail endogenous ligand for Toll-like receptors. PTX3 production from cultured SSc fibroblasts was increased by stimulation with hyaluronan. Conclusion. These results suggest that elevated serum PTX3 levels are associated with the disease severity of SSC. (First Release March 1 2009; J Rheumatol 2009;36:976-83; doi: 10.3899/jrheum.080343)

創傷治癒過程において、炎症期に浸潤してくる好中球、マクロファージなどの免疫細胞は、異物の除去や感染防御作用に加えて、さまざまなサイトカインや細胞成長因子を産生することで創傷治癒を促進させる。これまで創傷治癒過程におけるB細胞の役割については注目されてこなかったが、マウスモデルでの解析では、B細胞もサイトカインや細胞成長因子を産生することで創傷治癒に関与していることが示唆される。今後さらに研究が進み、B細胞がどのように創傷治癒過程を制御するか詳しく解明していくことで、創傷治癒を促進しうる新しい機序、難治性潰瘍に対する新たな治療が開発されることが期待される。(著者抄録)

The high mobility group box 1 protein (HMGB-1)/advanced glycation end products (RAGE) system is recently shown to play an important part in immune/inflammatory disorders. However, the association of this system in systemic sclerosis (SSc) remains unknown. To determine clinical association of serum levels of HMGB-1 and soluble RAGE (sRAGE) in patients with SSc, sera from 70 patients with SSc and 25 healthy controls were examined by enzyme-linked immunosorbent assay. Sera from tight-skin mice and bleomycin-induced scleroderma mice, animal models for SSc, were also examined. Skin HMGB-1 and RAGE expression was assessed by immunohistochemistry. Serum HMGB-1 and sRAGE levels in SSc were higher than those in controls. Similarly, HMGB-1 and sRAGE levels in animal SSc models were higher than those in control mice. SSc patients with elevated HMGB-1 and sRAGE levels had more frequent involvement of several organs and immunological abnormalities compared to those with normal levels. Furthermore, HMGB-1 and sRAGE levels correlated positively with modified Rodnan total skin thickness score and negatively with pulmonary function test. HMGB-1 and sRAGE expression in the sclerotic skin was more intense than normal skin. These results suggest that elevated serum HMGB-1 and sRAGE levels are associated with the disease severity and immunological abnormalities in SSc.

創傷治癒過程において,炎症期に浸潤してくる好中球,マクロファージなどの免疫細胞は様々なサイトカインや細胞増殖因子を産生することで創傷治癒を促進させる。B細胞シグナル伝達分子であるCD19を欠損したマウスにおける創傷治癒過程の解析により,B細胞もサイトカインや細胞増殖因子を産生することで創傷治癒に関与していることが示された。このCD19ノックアウトマウスにおける創傷治癒遅延はbasic fibroblast growth factorの投与により正常化されたことから,basic fibroblast growth factorが創傷治癒に重要かつ強力な作用を有していることが明らかにされた。(著者抄録)

73歳女性。患者は全身のそう痒を伴う浮腫性紅斑を主訴とした。受診時、体幹、四肢に不整形の浮腫性紅色斑が多発し、プレドニゾロン投与を行うも軽快せず、全身に水疱を形成していた。臨床検査では血清抗BP180抗体、抗BP230抗体が陽性を示し、病理組織学的に好酸球浸潤を伴う表皮下水疱が認められた一方、蛍光抗体直接法では表皮真皮境界部にIgG、C3の線状沈着がみられた。以上より、本症例は水疱性類天疱瘡と診断され、PSL投与を開始した結果、一時的に軽快を認めたものの、漸減に伴い再燃し、そのため、二重膜濾過血漿交換を計5回施行し、軽快が得られた。尚、経過中IgG型抗BP180抗体、IgE型抗BP180抗体のELISA値の測定を行ったところ、それぞれ病勢と相関が示された。

54歳男。患者は7年前に右肘部の腫瘤に気づいた。今回、半年前からこの腫瘤が急速に増大したため受診となったが、右肘部には弾性硬でやや紅色がかり半球状に隆起した105×102×60mmの巨大腫瘤が認められた。また、腫瘍表面は一部潰瘍化し、悪臭を伴っていた。一方、病理組織学的所見では主に好酸基性に染色されるbasaloid cellと好酸性に染色されるshadow cellで構成される不整形な腫瘍巣が深部に向かい浸潤性に増殖していた。そして腫瘍の大部分はbasaloid cellが占めており、同cellには異型性がみられ、Basaloid cellとsquamoid cell間の移行帯は欠如していた。以上より、本症例はpilomatrix carcinomaと診断され、画像所見では明らかなリンパ節、遠隔臓器への転移は認められなかったが、腫瘍の筋層への浸潤が疑われ、右上肢温存は困難と判断された。そこで、右上肢切断術を施行し、術後はペプロマイシンによる化学療法を行なった結果、術後8ヵ月経過で再発および転移は認められていない。

Systemic sclerosis (SSc) is characterized by immunological abnormalities, especially the production of autoantibodies against various cellular components. Treatment with histone deacetylase (HDAC) inhibitors prevents collagen accumulation in a mouse SSc model. Additionally, autoantibody against HDAC-3 is produced in colon cancer patients, while HDAC-1 and HDAC-2 do not elicit autoantibody response. To determine the presence and levels of antibodies (Abs) against HDAC-3 in SSc. Anti-HDAC-3 Ab was examined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting using human recombinant HDAC-3. The HDAC-3 activity was evaluated by ELISA using the fluorimetric HDAC lysyl substrate that comprises an acetylated lysine side chain. Contrary to our hypothesis that autoimmune background in SSc induced the production of autoantibody against HDACs, IgG and IgM anti-HDAC-3 Ab levels in SSc patients were significantly lower than in normal controls (p0.0005 and 0.001, respectively). Furthermore, decreased levels of IgG anti-HDAC-3 Ab were specific to SSc, since IgG anti-HDAC-3 Ab levels in patients with dermatomyositis (DM) and those with systemic lupus erythematosus (SLE) were similar and slightly increased relative to normal controls, respectively. Immunoblotting analysis showed that anti-HDAC-3 Ab was detected in normal controls and patients with DM or SLE, while it was absent in SSc patients. The HDAC-3 activity was significantly inhibited by IgG isolated from sera of normal controls, whereas such inhibitory effect was not observed by IgG isolated from sera of SSc patients. These results indicate the lack of anti-HDAC-3 autoantibody in SSc patients, which is produced in healthy individuals as well as DM and SLE patients, suggesting that this autoantibody might function as protective Ab.

Objective. To determine the serum concentrations and clinical association of polymorphonuclear neutrophilic leukocyte (PMN) elastase in patients with systemic sclerosis (SSc). Methods. Serum PMN elastase levels from 21 patients with limited Cutaneous SSc (ISSc) and 32 with diffuse Cutaneous SSc (dSSc) were examined by ELISA. Results. Serum PMN elastase levels were elevated in patients with SSc, especially dSSc, compared to healthy controls. SSc patients with elevated sertum PMN elastase levels had more frequent presence of pulmonary fibrosis, arthritis, contracture of phalanges, and diffuse pigmentation. Anticentromere antibody was detected less frequently in SSc patients with elevated Serum PMN elastase levels than in controls. Consistently, serum PMN elastase levels also correlated positively with serum levels of KL-6 and surfactant protein-D, serological markers for Pulmonary fibrosis. Serum PMN elastase levels were also associated with levels of serum 8-isoprostane, an oxidative stress marker in SSc. Conclusion. Serum PMN elastase levels were elevated in patients with SSc, and it was more prominent in patients with pulmonary fibrosis, Suggesting that serum PMN elastase is a novel serological marker for SSc-related pulmonary fibrosis. (First Release Oct 15 2009: J Rheumatol 2009; 36:99-105 doi: 10.3899/jrheum.080269)

高齢者においても皮膚悪性腫瘍は手術治療が原則となるが、多種多様な基礎疾患、術中合併症、術後の安静に伴う併発症などに対する配慮が必要であり、単純縫縮が困難な大きさの病変の場合には、治療に苦慮する症例もある。(1)局所麻酔による手術が可能で、手術時間はできるだけ短時間(2)手術侵襲が少なく、病理検査もできる(3)術後の安静期間が短く、早期離床できる(4)手術は1回で終了し修正、追加手災を必要としない(5)術後の合併症を生じにくいといった観点から、皮膚悪性腫瘍切除後の皮膚欠損部にThiersch植皮術(極薄分離植皮術)を多用しており、長期的な経過観察でも機能的、整容的予後で特に問題は経験していない。(著者抄録)

B細胞シグナル伝達分子であるCD19の創傷治癒機序について、CD19欠損マウス(KOM)と過剰発現マウス(TGM)を用いて検討した。野生型マウスと比較して、KOMでは創傷治癒遅延が、TGMでは促進がみられた。創傷部におけるサイトカインおよび増殖因子の発現量は、KOMではbasic Fibroblast growth factor(FGF)、acidic FGF、IL-6、IL-10、platelet-derived growth factor(PDGF)、transforming growth factor(TGF)-β1が減少し、TGMではacidic FGF、PDGF、TGF-β1が上昇していた。B細胞を内因性toll-like receptor(TLR)リガンドであるヒアルロン酸で刺激したところ、IL-6、IL-10、TGF-β1の発現はCD19に依存して亢進し、その発現はTLR4のシグナルを介していた。創傷部位で増加するヒアルロン酸により浸潤したB細胞は、TLR4を介して刺激され、様々なサイトカインや増殖因子を分泌して治癒を促進すると考えられた。

65歳男。患者は関節リウマチと診断されてステロイド剤から免疫抑制剤の内服を開始した。しかし、関節症状が悪化し、CRPも著明に上昇したため免疫抑制剤を増量したところ、四肢に皮疹が出現、更に高熱、乾性咳、下痢が出現した。内科受診となり、胸部X線および喀痰塗抹検査で肺結核と診断され、皮疹は両下肢中心にそう痒を伴った4〜5mm大の紅色丘疹が孤立性に多発、中央には黒色壊死を伴っていた。一方、病理組織学的所見では真皮中層から深層にかけて巨細胞が混ざる類上皮細胞肉腫がみられ、その周囲にはリンパ球、好中球を中心とした炎症細胞浸潤が認められた。皮膚組織に対して培養、PCR法を用いて結核菌の検索を行ったものの陰性であったが、入院後の精査では尿、血液、骨髄液から結核菌が検出された。以上より、本症例は肺結核に伴った丘疹壊疽性結核疹と確定診断され、イソニアジド等の4剤併用療法を開始した結果、約3ヵ月後、肺病変の改善に伴って皮疹も萎縮性瘢痕で略治した。

L-selectinノックアウトマウス(A)、ICAM-1ノックアウトマウス(B)、これらの野性型マウス(C)を用い、2,4-dinitrofluorobenzene(DNFB)誘発接触皮膚炎に対するエバスチンの効果について検討した。DNFBを耳介に塗布して浮腫を誘発し、誘発24時間前、誘発24、48時間後に耳介中央部の厚みを計測した。また、誘発24時間前、誘発時、誘発24時間後にエバスチンを経口投与し、PBS経口投与群と比較した。その結果、C群ではエバスチン投与群はPBS投与群と比較して有意な浮腫抑制を認め、誘発48時間後の組織学的所見は、エバスチン投与群の方が浮腫、白血球浸潤が減少していた。また、A群、B群はC群と比較してDNFB誘発48時間後に腫脹は有意な減少を認めた。エバスチン投与により、B群、C群は有意に浮腫反応、単核球浸潤抑制効果を認めたが、A群は有意な抑制効果を認めなかった。以上より、エバスチンはin vivoにおけるL-selectinへの発現や機能抑制に関与していると考えられた。