HLA-G and the MHC Cusp Theory.

Human leukocyte antigens (HLA) are significant genetic risk factors in a long list of diseases. However, the mechanisms underlying these associations remain elusive in many cases. The best-characterized function of classical major histocompatibility complex (MHC) antigens is to allow safe presentation of antigenic peptides via a self/non-self-discrimination process. Therefore, most hypotheses to date have posited that the observed associations between certain HLA molecules and human diseases involve antigen presentation (AP). However, these hypotheses often represent inconsistencies with current knowledge. To offer answers to the inconsistencies, a decade ago we have invoked the MHC Cusp theory, postulating that in addition to its main role in AP, the MHC codes for allele-specific molecules that act as ligands in a conformationally-conserved cusp-like fold, which upon interaction with cognate receptors can trigger MHC-associated diseases. In the ensuing years, we have provided empirical evidence that substantiates the theory in several HLA-Class II-associated autoimmune diseases. Notably, in a recent study we have demonstrated that HLA-DRB1 alleles known to protect against several autoimmune diseases encode a protective epitope at the cusp region, which activates anti-inflammatory signaling leading to transcriptional and functional modulatory effects. Relevant to the topic of this session, cusp ligands demonstrate several similarities to the functional effects of HLA-G. The overall goal of this opinion article is to delineate the parallels and distinctive features of the MHC Cusp theory with structural and functional aspects of HLA-G molecules.

HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization.

Associations between particular human leukocyte antigen (HLA) alleles and susceptibility to-or protection from-autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit, but it is unclear whether HLA molecules might also have non-AP, disease-modulating effects. Here we demonstrate differential macrophage activation by HLA-DRB1 alleles known to associate with autoimmune disease risk or protection with resultant polarization of pro-inflammatory ("M1") versus anti-inflammatory ("M2") macrophages, respectively. RNA-sequencing analyses of in vitro-polarized macrophages in the presence of AP-incompetent short synthetic peptides corresponding to the third allelic hypervariable regions coded by those two HLA-DRB1 alleles showed reciprocal activation of pro- versus anti-inflammatory transcriptomes, with implication of corresponding gene ontologies and upstream regulators. These results identify a previously unrecognized mechanism of differential immune modulation by short HLA-DRB1-coded allelic epitopes independent of AP, and could shed new light on the mechanistic basis of HLA-disease association.

Trace Elements Associated with Systemic Lupus Erythematosus and Insulin Resistance.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease of multifactorial origin. Studies have shown that trace elements such as zinc and copper may help maintain optimum function of the immune system and metabolism, while toxic metals such as lead may increase systemic autoimmunity. The current study aimed to assess the relationship between serum concentration of lithium (Li), vanadium (V), copper (Cu), zinc (Zn), molybdenum (Mo), cadmium (Cd), and lead (Pb) and SLE diagnosis, disease activity measured by SLE disease activity index (SLEDAI) and insulin resistance (IR). This case-control, cross-sectional study included 225 patients, 120 healthy controls, and 105 SLE patients. Serum concentration of Li, V, Cu, Zn, Mo, Cd, and Pb was measured. Serum concentrations of V (p < 0.001), Zn (p < 0.001), and Pb (p < 0.001) were lower and Mo (p < 0.001) and Li (p < 0.001) were higher in patients with SLE compared to healthy controls. SLE diagnosis was associated with higher serum Li (p < 0.001) concentration and lower V (p < 0.001), Zn (p = 0.003), and Pb (p = 0.020). Toxic metals and trace elements were not associated with disease activity. Levels of Cd were higher in patients with IR (p = 0.042). There was no significant association between IR and the other metals. The results indicate that SLE patients have different profiles of trace elements and toxic metals compared to healthy controls. While some toxic metals and trace elements were found to be associated with SLE diagnosis, they had no effect on disease activity and IR.

Cranberry juice decreases disease activity in women with rheumatoid arthritis.

OBJECTIVES: Studies have shown that cranberry (Vaccinium macrocarpon) has antiinflammatory and antioxidant effects; however, to our knowledge, the effects of cranberry juice consumption have not been studied in patients with rheumatoid arthritis (RA). The aim of this study was to verify the effect of cranberry juice consumption on several inflammatory biomarkers and on the disease activity of patients with RA. METHODS: A prospective study was conducted with 41 women diagnosed with RA. The disease activity measured by Disease Activity Score 28 (DAS28) and anticyclic citrullinated peptide (anti-CCP) antibodies, and several inflammatory and biochemical biomarkers were analyzed. The control group (n = 18) maintained their usual diet. The cranberry group (n = 23) consumed 500 mL/d of low-calorie cranberry juice. RESULTS: Regarding the baseline values, the cranberry group presented a decrease in the values of DAS28 (P = 0.048) and anti-CCP (P = 0.034) after 90 d of treatment, whereas changes in inflammatory biomarkers were not found. CONCLUSION: The present study indicated that cranberry juice decreases disease activity and therefore has beneficial effects for RA patients, although larger and long-term studies are needed to definitively probe this effect and to clarify the mechanisms involved.

Metabolic syndrome components are associated with oxidative stress in overweight and obese patients.

OBJECTIVE: The aim of this study is to evaluate the influence of the body mass index (BMI) and the metabolic syndrome (MetS) parameters on oxidative and nitrosative stress in overweight and obese subjects. SUBJECTS AND METHODS: Individuals were divided into three groups: the control group (G1, n = 131) with a BMI between 20 and 24.9 kg/m2, the overweight group (G2, n = 120) with a BMI between 25 and 29.9 kg/m2 and the obese group (G3, n = 79) with a BMI ≥ 30 kg/m2. RESULTS: G3 presented higher advanced oxidation protein products (AOPPs) in relation to G1 and G2 (p = 0.001 and p = 0.011, respectively) whereas G2 and G3 had lower levels of nitric oxide (NO) (p = 0.009 and p = 0.048, respectively) compared to G1. Adjusted for the presence of MetS to evaluate its influence, the levels of AOPPs did not differ between the groups, whereas NO remained significantly lower. Data adjusted by the BMI showed that subjects with higher triacylglycerol levels had higher AOPPs (p = 0.001) and decreased total radical-trapping antioxidant parameter/uric Acid (p = 0.036). Subjects with lower high-density lipoprotein (HDL) levels and patients with higher blood pressure showed increased AOPPs (p = 0.001 and p = 0.034, respectively) and lower NO levels (p = 0.017 and p = 0.043, respectively). Subjects who presented insulin resistance had higher AOPPs (p = 0.024). CONCLUSIONS: Nitrosative stress was related to BMI, and protein oxidation and nitrosative stress were related to metabolic changes and hypertension. MetS components were essential participants in oxidative and nitrosative stress in overweight and obese subjects.

Metabolic syndrome components are associated with oxidative stress in overweight and obese patients

ABSTRACT Objective: The aim of this study is to evaluate the influence of the body mass index (BMI) and the metabolic syndrome (MetS) parameters on oxidative and nitrosative stress in overweight and obese subjects. Subjects and methods: Individuals were divided into three groups: the control group (G1, n = 131) with a BMI between 20 and 24.9 kg/m2, the overweight group (G2, n = 120) with a BMI between 25 and 29.9 kg/m2 and the obese group (G3, n = 79) with a BMI ≥ 30 kg/m2. Results: G3 presented higher advanced oxidation protein products (AOPPs) in relation to G1 and G2 (p = 0.001 and p = 0.011, respectively) whereas G2 and G3 had lower levels of nitric oxide (NO) (p = 0.009 and p = 0.048, respectively) compared to G1. Adjusted for the presence of MetS to evaluate its influence, the levels of AOPPs did not differ between the groups, whereas NO remained significantly lower. Data adjusted by the BMI showed that subjects with higher triacylglycerol levels had higher AOPPs (p = 0.001) and decreased total radical-trapping antioxidant parameter/uric Acid (p = 0.036). Subjects with lower high-density lipoprotein (HDL) levels and patients with higher blood pressure showed increased AOPPs (p = 0.001 and p = 0.034, respectively) and lower NO levels (p = 0.017 and p = 0.043, respectively). Subjects who presented insulin resistance had higher AOPPs (p = 0.024). Conclusions: Nitrosative stress was related to BMI, and protein oxidation and nitrosative stress were related to metabolic changes and hypertension. MetS components were essential participants in oxidative and nitrosative stress in overweight and obese subjects.

Metabolic syndrome and the decreased levels of uric acid by leflunomide favor redox imbalance in patients with rheumatoid arthritis.

Oxidative stress plays a role in the pathophysiology of rheumatoid arthritis (RA). The aim of the present study was to verify the influence of metabolic syndrome (MetS) and disease-modifying antirheumatic drugs on nitrosative and oxidative biomarkers in patients with RA. A total of 177 patients with RA and 150 healthy volunteers participated in this study, which measured lipid hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), carbonyl protein, total radical-trapping antioxidant parameter (TRAP), uric acid (UA), and C-reactive protein (CRP). NOx and the NOx/TRAP ratio were significantly increased in RA, while no significant differences in lipid hydroperoxides, AOPP, UA, and TRAP levels were found between both groups. Treatment with leflunomide was associated with increased levels of carbonyl protein, and lowered levels in TRAP and UA, while the NOx/TRAP ratio further increased. NOx and the NOx/TRAP ratio were significantly higher in women than in men, while TRAP and UA were significantly lower in women. MetS was accompanied by increased AOPP and UA levels. RA was best predicted by increased NOx/TRAP ratio, CRP, and BMI. In conclusion, our data demonstrated that NOx and NOx/TRAP are strongly associated with RA physiopathology. Our findings suggest that inhibition of iNOS may become an interesting therapeutic approach for the treatment of RA. In addition, the presence of MetS and a decrease in levels of UA by leflunomide favor redox imbalance in RA patients. More studies are needed to evaluate the impact of antioxidant capacity reduction on RA progression.

Increased lipid and protein oxidation and lowered anti-oxidant defenses in systemic lupus erythematosus are associated with severity of illness, autoimmunity, increased adhesion molecules, and Th1 and Th17 immune shift.

This study investigated nitro-oxidative stress in patients with systemic lupus erythematosus (SLE) in association with disease activity, immune-inflammatory biomarkers, and adhesion molecules. Two-hundred-four patients with SLE and 256 healthy volunteers were enrolled in this case-control study, which measured nitro-oxidative stress biomarkers, including lipid peroxides (LOOH), advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), sulfhydryl (-SH) groups, products of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) oxidative degradation, and total radical-trapping anti-oxidant parameter (TRAP). Also measured were anti-nuclear antibodies (ANAs), antibodies against double-stranded DNA (dsDNA), plasma levels of diverse cytokines, C-reactive protein, and adhesion molecules. LOOH (p < 0.001) and AOPP (p < 0.001) were significantly higher, while TRAP was significantly lower (p < 0.001) in SLE patients than in controls. AOPP and LOOH were significantly and positively associated with SLE disease activity index (SLEDAI) scores, anti-nuclear antibodies, and antibodies against double-stranded DNA (anti-dsDNA) levels, while TRAP was significantly and inversely correlated with SLEDAI, ANA, and dsDNA antibody levels. There were significant positive associations between AOPP and LOOH and immune-inflammatory markers, indicating T helper (Th)-17 and Th1 bias and Th1 + Th17/Th2 ratio (p = 0.002 and p = 0.001, respectively). AOPP and LOOH (positively) and TRAP (inversely) were associated with adhesion molecule expression. A model predicting SLE was computed showing that, using LOOH, AOPP, NOx, adhesion molecules, and body mass index, 94.2% of the patients were correctly classified with a specificity of 91.5%. Increased nitro-oxidative stress takes part in the (auto)immune pathophysiology of SLE and modulates severity of illness and adhesion molecule expression.

The impact of cranberry (Vaccinium macrocarpon) and cranberry products on each component of the metabolic syndrome: a review

BACKGROUND: Some studies have shown that cranberry (Vaccinium macrocarpon) has beneficial effects on the components of the metabolic syndrome (MetS), a condition characterized by a cluster of cardiovascular risk factors suchas central obesity, hypertension, impaired glucose homeostasis, elevated triglycerides, and decreased HDL cholesterol levels. Cranberry is very rich in polyphenols, which may significantly reduce cardiovascular disease (CVD) risk. Main body of the ABSTRACT: Nutritional intervention studies have indicated that the intake of cranberries and cranberry products may have the following impact on metabolic health: (1) attenuate markers of obesity such as body weight, body mass index, and waist circumference; (2) reduce systolic and diastolic pressures; (3) decrease plasma concentrations of triglycerides and oxidized LDL-cholesterol, as well as increase HDL cholesterol; and (4) promote glucose homeostasis. In addition, nutritional intervention with cranberries could confer antioxidant and anti-inflammatory properties and the ability to reduce biomarkers of atherosclerosis associated with the MetS, such as homocysteine. Short CONCLUSION: Although there has been promising results, particularly related to lipid profile and blood pressure, further research is needed to support the recommendation of cranberry intake as a nutritional intervention for the treatment of MetS

Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles.

The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case-control study. Plasma cytokines levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1ß, IL- 4, IL-6, IL-10, IL-12 and IL-17 were measured and cytokines profiles were computed. IL-6, IL-12, IL-17, IFN-γ and IL-10 levels were significantly higher in SLE, while IL-4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFα+IL-6+IL-1ß). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL-10 (positively associated) and IL-4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL-10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL-17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL-4 and IFNγ values. 25-OH vitamin D was inversely associated with IFN-γ levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL-4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines.

Profile of oxidative stress markers is dependent on vitamin D levels in patients with chronic hepatitis C.

OBJECTIVES: Although vitamin D deficiency can change liver injury progression in patients with hepatitis C virus (HCV), the main molecular mechanisms involved are largely unknown. The first aim of this study was to evaluate the association between oxidative stress and hypovitaminosis D in patients with HCV. The second aim was to verify whether oxidative stress is involved in the molecular mechanisms related to liver injury. METHODS: The study included 147 participants: 89 controls and 58 patients with HCV (vitamin D < 30, n = 32; vitamin D > 30, n = 26). RESULTS: Patients with HCV and hypovitaminosis D presented significantly higher aminotransferase-to-platelet ratio index (APRI; P = 0.0464) and viral load (P = 0.0426) levels than patients with HCV without hypovitaminosis D. Regarding oxidative stress, HCV patients with hypovitaminosis D had higher advanced oxidation protein products (P = 0.0409), nitric oxide metabolites (P = 0.0206) levels, and oxidative stress index (P = 0.0196), whereas total radical-trapping antioxidant parameter (P = 0.0446) levels were significantly lower than HCV patients without hypovitaminosis D. Vitamin D in patients with HCV showed inverse correlations with levels of iron (r = -0.407, P = 0.0285), ferritin (r = -0.383, P = 0.0444), APRI (r = -0.453, P = 0.0154) and plasma lipid hydroperoxides levels (r = -0.426, P = 0.0189). CONCLUSION: Vitamin D insufficiency contributes to the inflammatory process and oxidative stress imbalance in patients with HCV. The profile of oxidative stress markers in these patients depends on vitamin D levels, which probably change intracellular signalling pathways and increase inflammation and liver injury.

Metabolic syndrome increases oxidative stress but does not influence disability and short-time outcome in acute ischemic stroke patients.

Oxidative stress has been implicated in the pathophysiology of cardiovascular disease and MetS and it may be one of molecular mechanisms involved in stroke. The aims of the present study were to verify differences in oxidative stress markers in acute ischemic stroke patients with and without MetS and to verify whether MetS influences disability and short time outcome of the patients. 148 patients with acute ischemic stroke were divided in two groups: with MetS (n = 92) and without MetS (n = 56). The modified Rankin Scale (mRS) was used for measuring the functional disability after 3-month follow-up. The study assessed the metabolic profile and oxidative stress markers. Stroke patients with MetS had higher levels of lipid hydroperoxides (p < 0.0001) and advanced oxidation protein products (AOPP, p = 0.0302) than those without MetS. Hydroperoxides were directly and independently associated with MetS (OR: 1.000, 95 % IC = 1.000-1.000, p = 0.005). Linear regression demonstrated that AOPP levels (R(2) = 0.281, p < 0.0001) and oxidative stress index (OSI, R(2) = 0.223, p < 0.0001) were directly associated with triglycerides levels and hydroperoxides levels was also directly associated with glucose levels (R(2) = 0.080, p = 0.013. The mRS and short-come outcome did not differ after 3 months in both groups. In conclusion, an increase in oxidative stress markers was shown in acute ischemic stroke patients with MetS and this elevation seems to be involved mainly with changes in lipid profile, but the presence of MetS did not influence short-time disability and survival of the acute ischemic stroke patients.

Fish oil N-3 fatty acids increase adiponectin and decrease leptin levels in patients with systemic lupus erythematosus.

Cardiovascular disease (CVD) has emerged as an important cause of death in patients with systemic lupus erythematosus (SLE). Reduced adiponectin and elevated leptin levels may contribute to CVD in SLE patients. The purpose of this study was to verify the effects of fish oil (FO) on adiponectin and leptin in patients with SLE. Biochemical and disease activity analysis were performed. Patients with SLE were divided in two groups: patients who used fish oil for four months and patients who did not use fish oil. Patients with SLE who used FO had a significant decrease in SLE disease activity index (SLEDAI) score (p ˂ 0.023) in relation to baseline. SLE patients who used fish oil had increased adiponectin levels (p ˂ 0.026) and decreased leptin levels (p ˂ 0.024) compared to baseline values, whereas there were no differences in adiponectin and leptin levels in patients with SLE who did not use fish oil. In conclusion, the findings of increased serum adiponectin an decreased leptin levels after 120 days in the fish oil group, reinforce the importance of evaluating prospective studies of fish and fish oil fish ingestion on these adipokines in an attempt to decrease cardiovascular risk factors in patients with SLE.