Rafael Gonzalez

Monocytes and T lymphocytes in HIV-1-positive patients express HLA-G molecule.

Objective To study the expression of HLA-G on peripheral blood mononuclear cells (PBMC) from HIV-1-infected individuals in order to determine whether this molecule is induced as a consequence of HIV-1 infection. Design A total of 23 HIV-positive individuals in different stages of the disease were studied. Methods Flow cytometric analysis and Western blot were used to measure HLA-G expression on PBMC obtained from HIV-positive and control individuals. Results Most of the monocytes obtained from HIV-1-infected individuals express HLA-G, whereas only a very low proportion of monocytes from healthy individuals express this molecule. When T lymphocytes from HIV-1 infections were studied, it was found that 30% of them express HLA-G, whereas only 1% were HLA-G-positive in healthy individuals. HLA-G expression was also confirmed by Western blot using specific anti-HLA-G monoclonal antibodies. Conclusion The synthesis of HLA-G is increased in monocytes and certain T lymphocytes from HIV-1-infected individuals.

Emerging topics and new perspectives on HLA-G

Following the Fifth International Conference on non-classical HLA-G antigens (HLA-G), held in Paris in July 2009, we selected some topics which focus on emerging aspects in the setting of HLA-G functions. In particular, HLA-G molecules could play a role in: (1) various inflammatory disorders, such as multiple sclerosis, intracerebral hemorrhage, gastrointestinal, skin and rheumatic diseases, and asthma, where they may act as immunoregulatory factors; (2) the mechanisms to escape immune surveillance utilized by several viruses, such as human cytomegalovirus, herpes simplex virus type 1, rabies virus, hepatitis C virus, influenza virus type A and human immunodeficiency virus 1 (HIV-1); and (3) cytokine/chemokine network and stem cell transplantation, since they seem to modulate cell migration by the downregulation of chemokine receptor expression and mesenchymal stem cell activity blocking of effector cell functions and the generation of regulatory T cells. However, the immunomodulatory circuits mediated by HLA-G proteins still remain to be clarified.

Characterization of gliadin-specific Th17 cells from the mucosa of celiac disease patients.

OBJECTIVES:Celiac disease (CD) is a disorder characterized by a deregulated immune response to ingested wheat gluten and related cereal proteins in susceptible individuals. It has been considered that the onset of CD is mediated by a skewed Th1 response. However, the participation of Th17 cells in the pathogenesis of the disease, a key cell population in other autoimmune disorders, has not been studied in detail. We have investigated the presence of Th17 cells in the mucosa of active CD patients and their functional implications in the pathogenesis of the disease.METHODS:T cells obtained from duodenum biopsies from 15 untreated patients and 11 control individuals were characterized by flow cytometry, immunoassays, and real-time PCR.RESULTS:We found gliadin-specific CD4+ interleukin (IL)-17A-producing T cells in the mucosa of CD patients with a phenotype consisting of TCR (T-cell receptor)αβ+ CD45RO+ CD161+ CCR6+ (C–C chemokine receptor type 6) and IL-23R+. Functional analysis showed that Th17 cells from CD patients are different from those of control individuals in terms of cytokines production. Th17 cells from CD patients, but not from controls, simultaneously express transforming growth factor-β (TGFβ). Th17 CD cells also produce interferon-γ (IFNγ), IL-21, and IL-22. The analysis of the transcription factors revealed a high expression of interferon regulatory factor-4 as a feature of gliadin-specific cells from CD patients with respect to controls.CONCLUSIONS:Gliadin-specific Th17 cells are present in the mucosa of CD patients having a dual role in the pathogenesis of the disease as they produce proinflammatory cytokines (such as IL-17, IFNγ, IL-21), mucosa-protective IL-22, and regulatory TGFβ, which actively modulates IL-17A production by T cells in the celiac mucosa.

Co-morbid psychiatric disorders among incarcerated ADHD populations: a meta-analysis

Background Rates of psychiatric disorders are highly prevalent among prison inmates, and recent evidence confirms over-representation of youths and adults with attention deficit hyperactivity disorder (ADHD). The risk for psychiatric co-morbidity may be greater among offenders with ADHD. We undertook a systematic review and meta-analysis of reported rates of co-existing psychiatric morbidity with ADHD in prison samples. Method Studies published from 1980 to 2015 were identified using five bibliographic indexes, review articles and reference lists. Included studies had a defined ADHD group and provided additional prevalence on at least one of the following: conduct disorder, substance use disorder, mood disorder, anxiety disorder, or personality disorder. We performed meta-analytical estimates of the prevalence of each co-morbid disorder within ADHD, and estimated the risk for co-existing disorders among prisoners with ADHD by pooling odds ratios (OR) with 95% confidence intervals. Results Eighteen studies with data for 1615 with ADHD and 3128 without ADHD were included. The risk (OR) of all psychiatric morbidity is increased among adult inmates with ADHD. Associations in youths with ADHD were restricted to mood disorder (OR 1.89, 95% confidence interval 1.09–3.28). Conclusions This study quantifies the extent of co-morbidity presented by offenders with ADHD, especially adults. The differences between risk estimates for youths and adults indicate an incremental effect in both frequency and severity for the development of further co-morbid pathology through adulthood. The findings have implications for clinical intervention and for criminal justice policy.

Natural Killer KIR3DS1 Is Closely Associated with HCV Viral Clearance and Sustained Virological Response in HIV/HCV Patients

Aim To evaluate the influence of the presence of the killer cell immunoglobulin-like receptor (KIR) 3DS1 on HCV treatment response in HIV/HCV genotype 1 co-infected patients Methods HIV/HCV co-infected patients were included. KIR3DS1, their specific HLA-B ligands and IL28B gene were genotyped. Reductions of plasma HCV RNA levels between baseline and week 1, week 2 and week 4 were analyzed for IL28B genotype and KIR3DS1 (HLA Bw4 or Bw6). Rapid and sustained virological response (RVR and SVR) rates were also analyzed. Results Sixty HIV/HCV genotype 1 co-infected patients were included. Patients with KIR3DS1 and Bw4 had higher rates of HCV viral decline than those who were not carriers of KIR3DS1 (week1: p = 0.01; week2: p = 0.038; week 4: p = 0.03). Patients carrying KIR3DS1/Bw4 had higher rates of RVR and SVR than those who did not carry KIR3DS1 (RVR: 46.15% versus 17.02%, p = 0.012; SVR: 63.6% versus 13 26.5%, p = 0.031). With respect to patients carrying the IL28B-CC genotype, those with KIR3DS1/Bw4 had greater rates of HCV viral clearance (week1: p<0.001; week2: p = 0.01; week 4: p = 0.02), RVR (p = 0.015) and SVR (p = 0.029) than those not carrying KIR3DS1. Conclusion Our results show that the KIR3DS1 genotype has a positive effect on HCV viral clearance during the first weeks of Peg-IFN/RBV treatment in HCV/HCV co-infected patients bearing genotype 1, and higher RVR and SVR rates.

Adult Attention Deficit Hyperactivity Disorder and Violence in the Population of England: Does Comorbidity Matter?

Background It is unclear whether the association between Attention Deficit/Hyperactivity Disorder (ADHD) and violence is explained by ADHD symptoms or co-existing psychopathology. We investigated associations of ADHD and its symptom domains of hyperactivity and inattention, among individuals reporting violence in the UK population. Methods We report data from the Adult Psychiatric Morbidity Survey (2007), a representative sample of the household population of England. A randomly selected sample of 7,369 completed the Adult Self-Report Scale for ADHD and the self-reported violence module, including repetition, injury, minor violence, victims and location of incidents. All models were weighted to account for non-response and carefully adjusted for demography and clinical predictors of violence: antisocial personality, substance misuse and anxiety disorders. Results ADHD was moderately associated with violence after adjustments (OR 1.75, p = .01). Hyperactivity, but not inattention was associated with several indicators of violence in the domestic context (OR 1.16, p = .03). Mild and moderate ADHD symptoms were significantly associated with violence repetition, but not severe ADHD where the association was explained by co-existing disorders. Stratified analyses further indicated that most violence reports are associated with co-occurring psychopathology. Conclusions The direct effect of ADHD on violence is only moderate at the population level, driven by hyperactivity, and involving intimate partners and close persons. Because violence associated with severe ADHD is explained by co-existing psychopathology, interventions should primarily target co-existing disorders.

Childhood ADHD Symptoms Are Associated With Lifetime and Current Illicit Substance-Use Disorders and In-Site Health Risk Behaviors in a Representative Sample of Latino Prison Inmates

Objective: This study aimed to explore retrospective childhood ADHD symptomatology, psychiatric comorbidity, rates of substance-use disorders (SUD), as well as their association with high-risk health behaviors in prison and adverse health outcomes. Method: A randomly selected representative sample of inmates in the Puerto Rico correctional system (N = 1,179) was assessed with the Spanish-language Wender Utah Rating Scale (WURS); the Composite International Diagnostic Interview (CIDI) modules for lifetime/current major depression disorder (MDD), generalized anxiety disorder (GAD), and SUD; the Davidson Trauma Scale (DTS; posttraumatic stress disorder [PTSD]); and self-reports of in-site high-risk behaviors. Results: Wald χ2 tests revealed significant associations of ADHD with MDD and PTSD, as well as increased risk for overdosing and intravenous drug use in prison. A logistic regression model adjusted for mood and anxiety comorbidity predicted lifetime SUD diagnosis (odds ratio = 2.38; 95% confidence interval = [1.15, 4.94]). Conclusion: Our results provide further evidence on the association of drug dependence and ADHD symptoms, and their overrepresentation among prison inmates.

CD8+HLA-G+ Regulatory T Cells Are Expanded in HIV-1-Infected Patients

It has been recently reported that CD8(+) T cells from healthy human peripheral blood express the tolerogenic HLA-G molecule originally described in trophoblasts. The majority of these CD8(+)HLA-G(+) cells exhibit a naïve phenotype and are FoxP3 negative, and they have been classified as a novel subset of regulatory T cells based on their potent suppressive function. We have investigated if this new cell population is expanded during HIV-1 infection. The results presented here show an increase in the percentage of CD8(+)HLA-G(+) cells within the total CD8 T-cell population in HIV-1(+) patients. As in healthy controls, these CD8(+)HLA-G(+) are mostly naïve T cells. However, we have also observed that only in HIV-1-infected patients are there effector and effector memory cells that express HLA-G.

Levels of HBV-DNA and HBsAg after acute liver allograft rejection treatment by corticoids and OKT3.

The aim of this work was to analyze whether the treatment of acute rejection of orthotopic liver transplants (OLT), either with corticoids or OKT3, has any effect on the levels of hepatitis B virus (HBV)‐DNA and HBsAg in individuals which were originally affected by cirrhosis or fulminant hepatic failure as a result of B virus. 
We have found that HBV‐DNA is present in macrophages, B cells and both CD4+ and CD8+ T cells after OLT in all cases studied. Interestingly, the levels of HBV‐DNA and HBsAg in the serum analyzed were increased extremely rapidly in the patients treated with OKT3 in an acute rejection episode. However, the serum levels of HBV‐DNA and HBsAg found were lower when the patients were treated with steroids, and were not found in non‐treated patients. As the serum levels of HBV‐DNA increase, the process of liver reinfection could be accelerated; therefore, these results may help to understand how OKT3 and corticoids immunosuppressive therapy may accelerate the reinfection of OLT by HBV. 
In conclusion, our results suggest that special care must be taken in the use of OKT3 in the treatment of acute liver rejection episodes in chronic or fulminant HBV transplanted patients.

LDLr genotype modifies the impact of IL28B on HCV viral kinetics after the first weeks of treatment with PEG-IFN/RBV in HIV/HCV patients.

Objective:To evaluate the effect of low-density lipoprotein receptor (LDLr) and IL28B genotypes on hepatitis C virus (HCV) viral kinetics in the first 4 weeks of treatment with pegylated-interferon (PEG-IFN)/ribavirin (RBV) in HIV patients co-infected with HCV genotype 1. Methods:HIV patients co-infected with HCV genotype 1 and naïve to PEG-IFN/RBV treatment were enrolled in a prospective study. HCV RNA viral loads were measured at baseline and at weeks 1, 2 and 4 after start of therapy. Differences in viral load decline were evaluated for IL28B (CC versus non-CC) and LDLr (CC versus non-CC) genotypes between baseline and weeks 1, 2 and 4. Additionally, the effect of LDLr genotype on HCV viral decline in IL28B CC genotype patients (CC/CC versus CC/non-CC) was analyzed. Results:Eighty-seven HIV/HCV genotype 1 co-infected patients were included in the study. Patients carrying the LDLr-CC or IL28B-CC genotypes showed greater HCV viral decline than those with IL28B non-CC or LDLr non-CC genotypes at every time-point analyzed. CC/CC patients had higher rapid virological response (RVR) rates than CC/non-CC patients (41.2 versus 13.3%; P < 0.001). Moreover, at all time points, the CC/CC pattern was associated with greater HCV viral decline than the CC/non-CC genotype (week 1: 1.18 ± 0.51 versus 0.31 ± 0.29, P = 0.041; week 2: 1.55 ± 0.81 versus 0.93 ± 0.73, P = 0.032; week 4: 2.23 ± 1.1 versus 1.5 ± 0.94, P = 0.039). Conclusion:The LDLr genotype impacts on viral kinetics during the first days of starting treatment with PEG-IFN/RBV in HIV/HCV genotype 1 co-infected patients, and modifies the impact of IL28B on HCV viral decay.