A Functional Polymorphism in B and T Lymphocyte Attenuator Is Associated with Susceptibility to Rheumatoid Arthritis

Inhibitory coreceptors are thought to play important roles in maintaining immunological homeostasis, and a defect in the negative signals from inhibitory coreceptors may lead to the development of autoimmune diseases. We have recently identified B and T lymphocyte attenuator (BTLA), a new inhibitory coreceptor expressed on immune cells, and we suggest that BTLA may be involved in the development of autoimmune diseases using BTLA-deficient mice. However, the role of BTLA in the pathogenesis of autoimmune diseases in humans remains unknown. We, therefore, examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) by conducting a case-control genetic association study. We found that 590C single-nucleotide polymorphism (SNP) of BTLA gene was significantly associated with susceptibility to RA, but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on concanavalin A- and anti-CD3 Ab-induced IL-2 production in Jurkat T cells. These results suggest that BTLA is an RA-susceptibility gene and is involved in the protection from autoimmunity in humans

ドッキョウ イカ ダイガク ビョウイン コキュウキ・アレルギー ナイカ ニオケル HIVカンセン カンジャ ノ カイセキ : トクニ ニューモシスチス ハイエン ノ ガッペイ レイ ニ ツイテ

獨協医科大学病院呼吸器・アレルギー内科を受診したHIV感染者を解析し,わが国および栃木県のHIV 感染者との比較検討を行った.対象は,2002年7月より2009年6月までの間,当科に受診歴のある34名(男27名,女7名,日本人29名,外国人5名),平均年齢は44.2歳(29歳〜67歳).男性の感染理由は,異性間(風俗,不特定)40.7%,同性間37.0%,女性はパートナーからの感染が57.1 %であった.64.7%がAIDS 発症によりHIV感染が判明し,HIV感染判明時の精査では79.4%がAIDSを発症しており,全症例の55.9%にニューモシスチス肺炎の合併を認めた.治療開始が推奨されているCD4陽性細胞低値(350/m l以下)は,97.1%の症例に認めた.以上の結果より,感染理由や年齢層については,全国の平均と同様な傾向を認めた.全国的には,HIV感染判明者の約7割がAIDS 発病前のキャリアの状態でHIV 感染が判明し,栃木県でも同様の傾向である.しかし,当科では大多数がAIDS 発症後およびAIDS 発症直前の低免疫状態でHIV 感染が判明しており,早期発見および早期介入が課題と考えられた.To be clear the clinical characteristics in Tochigi, we analyzedpatients with HIV infection in our department. Patientswith HIV infection between July 2002 and June 2009were 34 subjects (Man:Woman=27:7, Japanese:Foreigner=29:5), and mean age was 44.2 years old. In reasonof HIV infection for men, men who were infected by sexualintercourse with indefinite women were 40.7 % and menwho were infected by sexual intercourse with men were37.0 %. Women who were infected by their partners were57.1 %. 64.7 % of patients were recognized HIV infection byshowing AIDS. 79.4% of patients already had complicationsindicating AIDS, when they came to our hospital, and 55.9% of patients had pneumocystis jiroveci pneumonia. In 97.1% of patients, the number of CD4 positive cells were under350/m l. In conclusion, around 70 % of patients were recognizedHIV infection before they become AIDS in Japan. But,a large majority of patients in our department were withbecoming AIDS or just before AIDS. We need to developthe system of early intervention for HIV infection

Predominance of Abdominal Visceral Adipose Tissue Reflects the Presence of Aortic Valve Calcification

Background. Aortic valve calcification (AVC) is a common feature of aging and is related to coronary artery disease. Although abdominal visceral adipose tissue (VAT) plays fundamental roles in coronary artery disease, the relationship between abdominal VAT and AVC is not fully understood. Methods. We investigated 259 patients who underwent cardiac and abdominal computed tomography (CT). AVC was defined as calcified lesion on the aortic valve by CT. %abdominal VAT was calculated as abdominal VAT area/total adipose tissue area. Results. AVC was detected in 75 patients, and these patients showed higher %abdominal VAT (44% versus 38%, < 0.05) compared to those without AVC. When the cutoff value of %abdominal VAT was set at 40.9%, the area under the curve to diagnose AVC was 0.626. Multivariable logistic regression analysis showed that age (OR 1.120, 95% CI 1.078-1.168, < 0.01), diabetes (OR 2.587, 95% CI 1.323-5.130, < 0.01), and %abdominal VAT (OR 1.032, 95% CI 1.003-1.065, < 0.05) were independent risk factors for AVC. The net reclassification improvement value for detecting AVC was increased when %abdominal VAT was added to the model: 0.5093 (95% CI 0.2489-0.7697, < 0.01). Conclusion. We determined that predominance of VAT is associated with AVC

Activation-induced accumulation of B and T lymphocyte attenuator at the immunological synapse in CD4+ T cells

BTLA, a recently cloned coreceptor expressed on lymphocytes, negatively regulates cell activation by recruiting SHP-1/SHP-2. However, the mechanisms that regulate the intracellular localization of BTLA and its trafficking to the cell surface in T cells are still unknown. To determine the mechanisms that regulate the expression of BTLA on the surface of T cells, we examined the subcellular localization of BTLA in mouse T cells in a steady state, as well as upon activation by using a confocal laser-scanning microscopy. We found that BTLA was localized mainly in the Golgi apparatus and secretory lysosomes in resting CD4+ T cells. We also found that intracellular BTLA was translocated to the cell surface and accumulated at the immunological synapse upon TCR stimulation. Furthermore, we found that the BTLA-HVEM interaction was required for the association of BTLA with lipid rafts. These results indicate that the surface expression of BTLA and its accumulation at the immunological synapse are tightly regulated by TCR and HVEM stimulation to deliver efficient inhibitory signals in the regulation of CD4+ T cell activation

Epicardial Adipose Tissue Reflects the Presence of Coronary Artery Disease: Comparison with Abdominal Visceral Adipose Tissue

Accumulation of visceral adipose tissue is associated with a risk of coronary artery disease (CAD). The aim of this study was to examine whether different types of adipose tissue depot may play differential roles in the progression of CAD. Consecutive 174 patients who underwent both computed tomography (CT) and echocardiography were analyzed. Cardiac and abdominal CT scans were performed to measure epicardial and abdominal visceral adipose tissue (EAT and abdominal VAT, resp.). Out of 174 patients, 109 and 113 patients, respectively, presented coronary calcification (CC) and coronary atheromatous plaque (CP). The EAT and abdominal VAT areas were larger in patients with CP compared to those without it. Interestingly, the EAT area was larger in patients with CC compared to those without CC, whereas no difference was observed in the abdominal VAT area between patients with CC and those without. Multivariable logistic regression analysis revealed that the presence of echocardiographic EAT was an independent predictor of CP and CC, but the abdominal VAT area was not. These results suggest that EAT and abdominal VAT may play differential pathological roles in CAD. Given the importance of CC and CP, we should consider the precise assessment of CAD when echocardiographic EAT is detected