Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.Cluster of differentiation 1 (CD1) proteins are a family of MHC class I-like glycoproteins that present lipid antigens to T cells. CD1 restricted T cells are abundant in humans and play important roles in host defense and immune regulation. Human CD1 proteins comprise five CD1 isoforms, CD1a, CD1b, CD1c, CD1d, and CD1e, which exhibit different intracellular trafficking behaviors and ligand binding preferences (1). Structurally, the main differences between these CD1 isoforms lie in the architecture of their lipophilic ligand binding grooves. Whereas all CD1 isoforms share a highly conserved A′ channel (or pocket) for binding C18–C26 acyl chains, specialization is provided by further connecting channels (2–7). In CD1a, the A′ channel is “fused” to a wide and shallow F′ channel, enabling binding of lipopeptides such as mycobacterial didehydroxymycobactin (DDM) (8). CD1b features a unique T′ tunnel that connects A′ and F′, thereby forming a “superchannel” for accommodating very long acyl chains (e.g., mycobacterial mycolates) (2, 4). CD1d, the only isoform also conserved in rodents, exhibits a two-branched ligand binding groove with two linear channels A′ and F′ connected near the main portal into the groove, known as the F′ portal. A similar two-branched arrangement of A′ and F′ is seen in CD1e, the only CD1 isoform not expressed on the cell surface. Compared with CD1d, CD1a, and CD1b, the portal into the groove in CD1e is widely exposed, consistent with its known role in lipid transfer processes inside lysosomes (6).CD1c presents foreign- (9, 10) as well as self-lipid antigens to T cells (11). Two recent crystal structures of human CD1c revealed a two-branched design similar to that of CD1d and CD1e, with two channels A′ and F′ connecting near the groove portal. In these structures, a mycobacterial phosphomycoketide (PM) or mannosyl-β1-phosphomycoketide (MPM) occupied the A′ channel, whereas an undefined short ligand was present in the F′ channel (7, 12). The spatial arrangement of these ligands in the CD1c groove was very similar to and virtually overlapping in 3D comparisons with that of alpha-galactosylceramide (αGC) in human CD1d (Fig. S1 A and B). Because CD1c and CD1d are known to traffic to the same intracellular compartments for antigen sampling (13), these CD1c-PM and CD1c-MPM structures did not readily explain how CD1c and CD1d could functionally differentiate. Furthermore, the F′ channel in both CD1c-PM and CD1c-MPM was widely open to solvent, which was strikingly different from known structures of CD1a, CD1b, and CD1d and reminiscent of CD1e (7, 12). Based on these facts we hypothesized that human CD1c might undergo substantial conformational transformations in the F′ channel region upon binding of more optimal ligands, with relevance for T-cell receptor binding.Open in a separate windowFig. S1.Published CD1d-αGC and CD1c-MPM structures show a similar arrangement of their bound ligands in both the A′ and F′ channel. (A) Comparison of the configurations of bound ligands in CD1d-αGC (PDB ID code 1ZT4), CD1c-MPM (PDB ID code 3OV6), and CD1c-SL (PDB ID code 5C9J). (B) Ligands bound to CD1d (PDB ID code 1ZT4) (αGC; shown in yellow) and CD1c (PDB ID code 3OV6) (MPM; shown in blue, and spacer lipid shown in cyan) are superimposed and shown in two different orientations.     

Alcohol drinking in young adults: the predictive value of personality when peers come around

This study examined whether personality traits and peer drinking affect alcohol consumption in young adults. Data were analyzed from a study that was conducted in a 'bar laboratory' in which ad-lib drinking of peer groups was observed. The findings indicate that extroversion is moderately associated with self-reported daily drinking, while low emotional stability is modestly associated with alcohol-related problems. With regard to drinking in the observational drinking setting, personality is not associated with young adults' actual alcohol consumption. Further, peer drinking levels were strongly related to young adults' drinking. Besides, agreeableness interacted with the effects of peer drinking on young adults' drinking in such a way that agreeable individuals adapted their actual alcohol consumption more easily than others when socializing in a high- or a low-drinking peer group. We concluded that drinking in a peer context, irrespective of personality, played a major role in forming young adults' drinking. However, personality (i.e. agreeableness) definitely played a role to the extent of the individuals' adaptation to peer drinking norms.     

Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma

Mantle cell lymphoma (MCL) is believed to originate from a naive B cell. However, we recently demonstrated that a subset of MCL displayed mutated V(H) genes. We also reported restricted use of certain V(H) genes. To assess the prognostic impact of these new findings, we performed V(H) gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%) patients had unmutated V(H) genes. Because the mutation rate was low in the mutated group (2.2%-6.7%), further investigation of the germline V(H) gene in T cells from 5 patients with mutated V(H) genes was carried out; results showed that the unrearranged V(H) gene was identical to the published sequence. These data confirm that the base pair substitutions within the rearranged V(H) genes represent hypermutations, and indicate germinal center exposure. However, V(H) gene mutation status did not correlate with prognosis because there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently used V(H) genes were V(H)3-21 (21 patients) and V(H)4-34 (19 patients). A novel finding was that V(H)3-21(+) MCL almost exclusively expressed lambda light chains and displayed highly restricted use of the V(lambda)3-19 gene. V(H)3-21(+) patients had longer median survival than the remaining patients (53 vs 34 months; P =.03), but they tended to be younger at diagnosis. The combined use of V(H)3-21/V(lambda)3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that V(H)3-21(+) patients constitute a new MCL entity.     

Body weight, plasma insulin, and coronary events with gemfibrozil in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT)

BackgroundThe Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that gemfibrozil significantly reduced major coronary events in men with known coronary heart disease (CHD). To better understand why therapy was especially effective with obesity, diabetes, and hyperinsulinemia, changes in body weight and plasma insulin were determined after 1 year of gemfibrozil or placebo therapy and related to changes in lipids and CHD events.ResultsWith gemfibrozil significantly more subjects lost weight (51.7% versus 38.6%, P < 0.0001) and significantly fewer subjects gained weight (42.5% versus 54.0%, P < 0.0001) than with placebo. Both a greater loss and smaller gain in weight with gemfibrozil were age-related and significant in subjects ≥66 years (median age), but not in younger subjects. Weight change was paralleled by changes in insulin. With gemfibrozil, CHD events were significantly reduced with weight loss (hazard ratio [HR], 0.61; 95% CI, 0.44–0.84; P = 0.002) and, particularly, with diabetes or hyperinsulinemia (HR, 0.53; 95% CI, 0.34–0.83; P = 0.006). In contrast, CHD events were not significantly reduced without weight loss (HR, 0.83; 95% CI, 0.62–1.12; P = 0.22).ConclusionsIn VA-HIT, gemfibrozil resulted in weight loss associated with reductions in insulin. With weight loss gemfibrozil produced a significant reduction in CHD events that did not occur in the absence of weight loss.     

Muscle MRI in patients with long-chain fatty acid oxidation disorders

Introduction

Muscle magnetic resonance imaging (MRI) is a useful tool for visualizing abnormalities in neuromuscular disorders. The value of muscle MRI has not been studied in long-chain fatty acid oxidation (lcFAO) disorders. LcFAO disorders may present with metabolic myopathy including episodic rhabdomyolysis.

Objective

To investigate whether lcFAO disorders are associated with muscle MRI abnormalities.

Methods

Lower body MRI was performed in 20 patients with lcFAO disorders, i.e. three carnitine palmitoyltransferase 2 deficiency (CPT2D), 12 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), three mitochondrial trifunctional protein deficiency (MTPD) and two isolated long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD).

Results

At the time of MRI, four patients had muscle weakness, 14 had muscle pain and 13 were exercise intolerant. Median creatine kinase (CK) level of patients at the day of MRI was 398 U/L (range 35-12,483). T1W and STIR signal intensity (SI) were markedly increased in MTPD patients from girdle to lower leg. VLCADD patients showed predominantly proximal T1W SI changes, whereas LCHADD patients mostly showed distal T1W SI changes. Prominent STIR weighted signal intensity increases of almost all muscle groups were observed in patients with VLCADD and LCHADD with very high CK (>11.000) levels.

Conclusions and relevance

lcFAO disorders are associated with specific patterns of increased T1W and STIR signal intensity. These patterns may reflect lipid accumulation and inflammation secondary to lcFAO defects and progressive muscle damage. Future studies are needed to investigate whether muscle MRI might be a useful tool to monitor disease course and to study pathogenesis of lcFAO related myopathy.     

Circunferência do Pescoço e Risco Cardiovascular em 10 Anos na Linha de Base do ELSA-Brasil: Diferenciais por Sexo

Background:Neck circumference (NC), an indirect measure of upper-body subcutaneous adipose tissue, has been pointed out as an independent predictor of cardiometabolic diseases.Objectives:To assess the association between NC and 10-year cardiovascular risk in men and in women.Methods:Cross-sectional analysis of 13,920 participants of the (baseline) Longitudinal Study of Adult Health (ELSA-Brasil). The association between NC (used as continuous variable and grouped into quartiles) and the 10-year cardiovascular risk was estimated by the Framingham Global Risk Score and analyzed by generalized linear models after adjustments for sociodemographic characteristics, health behaviors, body mass index and waist circumference. The significance level adopted was 5%.Results:Mean NC was 39.5 cm (SD± 3.6) in men and 34.0 cm (SD±2.9) in women. After adjustments, a one-centimeter increase in NC was associated with an increment of 3% (95%CI1.02-1.03) and 5% (95% 1.04-1.05) in the arithmetic mean of the 10-year CVD risk in men and women, respectively. Men and women in the last quartile showed an increment of 18% (95%CI 1.13-1.24) and 35% (95%CI 1.28-1.43), respectively in the arithmetic mean of the 10-year CVD risk, after adjustments.Conclusions:We found a positive, independent association between NC and the 10-year cardiovascular disease risk. NC may contribute to the prediction of cardiovascular risk, over and above traditional anthropometric measures.     

Evaluation of two 13-loci STR multiplex system regarding identification and origin discrimination of Brazilian Cannabis sativa samples

International Journal of Legal Medicine - According to the Brazilian Federal Police (BFP), the Brazilian Cannabis sativa illicit market is mainly supplied by drugs originated from Paraguay and...     

Geographic disparity: the dilemma of lower socioeconomic status,multiple listing,and death on the liver transplant waiting list

Due to the current regionally based allocation system, some patients list for and are transplanted away from home in regions with shorter waits and higher transplant rates. Of 147 included patients, 120 died waiting and 27 received transplants at outside centers during the study (32.5 months). Those transplanted elsewhere had higher median incomes than patients dying on the waitlist ($84 946 vs. $55 250, p = 0.0001). Those with median incomes <$60 244 were more likely to die than those with incomes >$60 244 (94% vs. 70%, RR: 1.35, 95% CI: 1.14–1.59). Patients with Medicaid were more likely to die waiting than those with other insurance (100% vs. 77%, RR: 1.30, 95% CI: 1.18–1.44). Our analysis demonstrates that those who died waiting were more likely to have lower incomes and Medicaid compared with those transplanted elsewhere. Even when we controlled for Medicaid status, patients who died waiting had lower incomes compared with those transplanted elsewhere. Increased organ sharing over geographically broader regions, as recommended by the Institute of Medicine in 1999, may reduce incentives for patients to travel to receive a liver and reduce inequities. Current efforts to address this disparity continue to fall short of the Institute of Medicine recommendations, United States Department of Health and Human Services regulations and the Final Rule.