Objective-There are few data available on possible independent association between uric acid and carotid atherosclerosis.Here we first sought to investigate association between uric acid levels and metabolic syndrome in Japanese; second, we assessed whether there is an independent association of uric acid with prevalence of carotid atherosclerosis in individuals subdivided according to gender and metabolic syndrome status. Methods and Results-Cross-sectional data from 8144 individuals who underwent general health screening were analyzed.After adjusting for age, total cholesterol, and smoking status, the odds ratios (95% CI) of sex-specific quartiles of serum uric acid for metabolic syndrome were 1.0, 1.06 (0.60 to 1.87), 2.18 (1.30 to 3.64), and 4.17 (2.56 to 6.79) in women, and 1.0, 0.92 (0.74 to 1.14), 1.52 (1.25 to 1.65), and 1.97 (1.61 to 2.40) in men. After adjusting for age, serum levels, total cholesterol, and smoking status, prevalence of carotid plaque was higher in subjects in the second, third, and fourth quartiles of uric acid level with odds ratios (95% CI) of 1.24 (1.01 to 1.52), 1.37 (1.11 to 1.68), and 1.31 (1.05 to 1.63), respectively, in men without metabolic syndrome but not in men with metabolic syndrome or in women with or without metabolic syndrome. Conclusion-The prevalence of metabolic syndrome showed a graded increase according to serum uric acid values in both genders. In men who did not have metabolic syndrome, uric acid was found to be an independent risk factor for incidence of carotid plaque.

Antiviral cell–mediated immunity is initiated by the dendritic cell (DC) network in lymph nodes (LNs). Plasmacytoid DCs (pDCs) are known to migrate to inflamed LNs and produce interferon (IFN)-α, but their other roles in antiviral T cell immunity are unclear. We report that LN-recruited pDCs are activated to create local immune fields that generate antiviral cytotoxic T lymphocytes (CTLs) in association with LNDCs, in a model of cutaneous herpes simplex virus (HSV) infection. Although pDCs alone failed to induce CTLs, in vivo depletion of pDCs impaired CTL-mediated virus eradication. LNDCs from pDC-depleted mice showed impaired cluster formation with T cells and antigen presentation to prime CTLs. Transferring circulating pDC precursors from wild-type, but not CXCR3-deficient, mice to pDC-depleted mice restored CTL induction by impaired LNDCs. In vitro co-culture experiments revealed that pDCs provided help signals that recovered impaired LNDCs in a CD2- and CD40L-dependent manner. pDC-derived IFN-α further stimulated the recovered LNDCs to induce CTLs. Therefore, the help provided by pDCs for LNDCs in primary immune responses seems to be pivotal to optimally inducing anti-HSV CTLs.

Peyer’s patch (PP) dendritic cells (DCs) have been shown to exhibit a distinct capacity to induce cytokine secretion from CD4+ T cells compared with DCs in other lymphoid organs such as the spleen (SP). In this study, we investigated whether PP DCs are functionally different from DCs in the SP in their ability to induce Ab production from B cells. Compared with SP DCs, freshly isolated PP DCs induced higher levels of IgA secretion from naive B cells in DC-T cell-B cell coculture system in vitro. The IgA production induced by PP DCs was attenuated by neutralization of IL-6. In addition, the induction of IgA secretion by SP DCs, but not PP DCs, was further enhanced by the addition of exogenous IL-6. Finally, we demonstrated that only PP CD11b+ DC subset secreted higher levels of IL-6 compared with other DC subsets in the PP and all SP DC populations, and that PP CD11b+ DC induced naive B cells to produce higher levels of IgA compared with SP CD11b+ DC. These results suggest a unique role of PP CD11b+ DCs in enhancing IgA production from B cells via secretion of IL-6.

SummaryMetabolic complications associated with obesity are becoming more common among Japanese subjects. However, visceral fat accumulation is not always apparent by measuring body mass index (BMI) or waist circumference in Asian populations because of the physiological characteristics particular to those ethnicities. Excess visceral fat accumulation raises the odds ratio for developing cardiovascular disease. Thus, high-throughput determination of the amount of abdominal adipose tissue is necessary. We hypothesized that accumulating visceral fat alters the peripheral amino acid profile and that a multivariate logistic regression model of plasma free amino acids can distinguish visceral obesity. A total of 1449 Japanese subjects (985 males and 464 females) who had undergone a comprehensive health screening were enrolled in this study. The visceral fat area was determined using computed tomography imaging, and a plasma free amino acid index to identify high visceral fat areas (Ն100 cm 2 ) was developed. The sensitivity and specificity values of the generated amino acid index were 80% and 65%, respectively. In particular, the sensitivity of the generated index to identify subjects with non-apparent visceral obesity (BMI < 25 kg m -2 ; visceral fat area Ն 100 cm 2 ) was much greater than that of the waist circumference (73% vs. 46%, respectively). This index's high sensitivity and specificity may be the result of specific alterations in the patients' amino acid profiles, which were specifically correlated with the visceral fat areas and not with subcutaneous fat areas. This profile can be used as a predictor of elevated visceral obesity and a risk assessment tool for metabolic complications in Asian populations.Keywords: CT scan, high-throughput risk screening, non-apparent visceral obesity, plasma amino acid. What is already known about this subject• Asians with metabolic complications associated with obesity, a low body mass index and a low waist circumference have a greater proportion of visceral adipose tissue for a given amount of total body fat compared with Europeans.• Apparent obese humans and obese animal models show an elevation of branched-chain amino acid levels in plasma.• A multivariate logistic regression model of plasma free amino acids has been used to screen for several types of cancers in clinical settings. What this study adds• A specific formula incorporating six amino acid values (Ala, Gly, Glu, Trp, Tyr and branched-chain amino acid) was developed for discrimination of subjects with high visceral fat area by multivariate logistic regression analyses.• The generated amino acid formula was strongly correlated with visceral fat area in both apparent and non-apparent obese subjects.• Measuring plasma free amino acids can be used to distinguish the non-apparent visceral obesity in clinical settings in Asian populations.clinical obesity

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Depletion of CD4þ cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4 þ cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti-CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25 þ Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8 þ cell depletion. CD4 þ cell depletion led to the proliferation of tumor-specific CD8 þ T cells in the draining lymph node and increased infiltration of PD-1into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies.

Background-Recent experimental and epidemiological findings suggest that some infectious agents play a role in the development and promotion of atherosclerosis. We have investigated the possible association between hepatitis B virus surface antigen (HBsAg) positivity and carotid arteriosclerosis. Methods and Results-In this cross-sectional cohort study, we analyzed data from subjects undergoing general health-screening tests, including both high-resolution B-mode carotid ultrasound and assessment of HBsAg status, between 1994 and 2001 at our institute. Of the 4686 study subjects (3137 men and 1549 women; age 22 to 88 years), 1294 (28%) had carotid artery plaque and 40 (0.9%) were positive for HBsAg, indicating they were hepatitis B virus carriers. No HBsAg-positive subjects were positive either for antibodies against the hepatitis C virus (HCV) or for HCV core proteins. Univariate analysis revealed HBsAg positivity was associated with carotid plaque with an odds ratio of 1.58 (95% CI, 1.14 to 2.19, PϽ0.05). When other confounding risk factors for atherosclerosis were included as covariates in the statistical analysis, HBsAg positivity was still positively associated with carotid plaque with an odds ratio of 1.57 (95% CI, 1.10 to 2.24, PϽ0.05). Conclusions-These findings suggest a possible role of chronic hepatitis B infection in the pathogenesis of carotid arteriosclerosis.

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