Increased levels of soluble HLA-G molecules in Tunisian patients with chronic hepatitis B infection.

Hepatitis B virus (HBV) infection is a global health problem. The mechanisms of immune tolerance in HBV infection are still unclear. The host immune response plays a critical role in determining the outcome of HBV infection. Human leucocyte antigen-G (HLA-G) is involved in immunotolerogenic process and infectious diseases. This study aimed to explore the implication of soluble HLA-G (sHLA-G) and its isoforms in HBV infection. Total sHLA-G (including shedding HLA-G1 and HLA-G5) was analysed by ELISA in 95 chronic HBV patients, 83 spontaneously resolvers and 100 healthy controls (HC). To explore the presence of sHLA-G dimers, we performed an immunoprecipitation and a Western blot analysis on positive samples for sHLA-G in ELISA. The serum levels of sHLA-G were significantly increased in patients with chronic HBV patients compared to spontaneously resolvers and HC (P<.0001). Interestingly, we found an increased level of sHLA-G1 in chronic HBV patients than in spontaneously resolvers and HC (P<.001). In addition, the expression of HLA-G5 seems to be higher in the sera of chronic HBV patients than spontaneously resolvers (P=.026). The analysis of HLA-G dimers showed the presence of homodimers in 93% of chronic HBV patients, 67% in spontaneously resolvers and 60% in HC. These results provide evidence that sHLA-G may have a crucial role in the outcome of HBV infection and could be proposed as a biomarker for infection outcome. Based on its tolerogenic function, HLA-G might be considered as a new promising immunotherapeutic approach to treat the chronic infection with HBV.

HLA-E polymorphism and soluble HLA-E plasma levels in chronic hepatitis B patients.

Chronic hepatitis B virus (HBV) infection occurs in association to a deregulation of immune system. Human leukocyte antigen E (HLA-E) is an immune-tolerant nonclassical HLA class I molecule that could be involved in HBV progression. To measure soluble (s) HLA-E in patients with chronic HBV hepatitis (CHB). We tested the potential association of HLA-E*01:01/01:03 A > G gene polymorphism to CHB. Our cohort consisted of 93 Tunisian CHB patients (stratified in CHB with high HBV DNA levels and CHB with low HBV DNA levels) and 245 healthy donors. Plasma sHLA-E was determined using enzyme-linked immunosorbent assay (ELISA). Genotyping was performed using polymerase chain reaction sequence-specific primer. No association between HLA-E*01:01/01:03 A > G polymorphism and HBV DNA levels in CHB patients was found. G/G genotype is less frequent in CHB patients without significance. sHLA-E is significantly enhanced in CHB patients compared with healthy controls (P = 0.0017). Stratification according to HBV DNA levels showed that CHB patients with low HBV DNA levels have higher sHLA-E levels compared with CHB patients with high HBV DNA levels. CHB patients with G/G genotype have enhanced sHLA-E levels compared with other genotypes (P = 0.037). This significant difference is maintained only for CHB women concerning G/G genotypes (P = 0.042). Finally, we reported enhanced sHLA-E in CHB patients with advanced stages of fibrosis (P = 0.032). We demonstrate, for the first time, the association of sHLA-E to CHB. Owing to the positive correlation of HLA-E*01:01/01:03 A > G polymorphism and the association of sHLA-E to advanced fibrosis stages, HLA-E could be a powerful predictor for CHB progression. Further investigations will be required to substantiate HLA-E role as a putative clinical biomarker of CHB.

Association of an HLA-G 14-bp Insertion/Deletion polymorphism with high HBV replication in chronic hepatitis.

Identification of an HLA-G 14-bp Insertion/Deletion (Ins/Del) polymorphism at the 3' untranslated region of HLA-G revealed its importance in HLA-G mRNA stability and HLA-G protein level variation. We evaluated the association between the HLA-G 14-bp Ins/Del polymorphism in patients with chronic Hepatitis B virus (HBV) infection in a case-control study. Genomic DNA was extracted from 263 patients with chronic HBV hepatitis and 246 control subjects and was examined for the HLA-G 14-bp Ins/Del polymorphism by PCR. The polymorphic variants were genotyped in chronic HBV seropositive cases stratified according to HBV DNA levels, fibrosis stages and in a control population. There was no statistical significant association between the 14-bp Ins/Del polymorphism and increased susceptibility to HBV infection neither for alleles (P = 0.09) nor for genotypes (P = 0.18). The stratification of HBV patients based on HBV DNA levels revealed an association between the 14-bp Ins/Del polymorphism and an enhanced HBV activity with high HBV DNA levels. In particular, the Ins allele was significantly associated with high HBV DNA levels (P = 0.0024, OR = 1.71, 95% CI 1.2-2.4). The genotype Ins/Ins was associated with a 2.5-fold (95% CI, 1.29-4.88) increased risk of susceptibility to high HBV replication compared with the Del/Del and Ins/Del genotypes. This susceptibility is linked to the presence of two Ins alleles. No association was observed between the 14-bp Ins/Del polymorphism and fibrosis stage of HBV infection. We observed an association between the 14-bp Ins/Del polymorphism and high HBV replication characterized by high HBV DNA levels in chronic HBV patients. These results suggest a potential prognostic value for disease outcome evaluation.

Nephropathy following Type 2 diabetes mellitus in Tunisian population / Nefropatía tras la diabetes mellitus tipo 2 en la población Tunesina

OBJECTIVE: The purpose was to compare the characteristics of Tunisians with Type 2 diabetes mellitus (Type 2 DM) and nephropathy with those without nephropathy. This study assessed whether or not phenotypic characteristics can predict nephropathy development in Type 2 DM. The prevalence of nephropathy in Tunisian Type 2 DM patients, and their relationship with clinical and biochemical factors as well as chronic complications of the disease were determined. METHODS: This was a cross-sectional study of patients with diabetes diagnosed between January 2008 and December 2010. Altogether, 73 Type 2 DM and 42 healthy volunteers from the Basic Health Group of Sousse, were targeted for the study. Clinical, biochemical data, as well as complications of diabetes were collected. Kidney malfunction was defined by glomerular filtration rate (GFR). RESULTS: Diabetic patients were older. Diabetic women were more likely to have higher body mass index than men (p = 0.004). Obesity was more in women than men (60/23%). Complications including hypertension and dyslipidaemia were co-associated in women. Urinary creatinine clearance in Type 2 DM patients without nephropathy was significantly lower than in healthy participants (p < 0.0001). Microalbuminuria and urinary creatinine clearance were associated only in women with Type 2 DM with nephropathy (R² = 0.95); 1.5% of Type 2 DM patients without nephropathy had GFR < 60 mL/min/1.73m² and 76% had a GFR between 60 and 89 mL/min/1.73m². Glomerular filtration rate difference between Type 2 DM patients with/without nephropathy, as well as between Type 2 DM patients with nephropathy/Type 2 DM without nephropathy, and with retinopathy was not significant. CONCLUSIONS: By analysing factors associated with nephropathy in Type 2 DM Tunisian patients, this study demonstrated their susceptibility to nephropathy. In addition, retinopathy is potentially associated with incipient nephropathy in Type 2 DM Tunisian patients.

OBJETIVO: El propósito fue comparar las características de los tunesinos con diabetes mellitus tipo 2 (DMT2) y nefropatía, con aquéllos que no padecen nefropatía. Este estudio evaluó la posibilidad de saber si las características fenotípicas pueden predecir el desarrollo de una nefropatía en pacientes de DMT2. Se determinó la prevalencia de la nefropatía en los pacientes tunesinos con DMT2, y su relación con factores clínicos y bioquímicos, así como las complicaciones crónicas de la enfermedad. MÉTODOS: Se realizó un estudio transversal de pacientes con diabetes diagnosticada entre enero de 2008 y diciembre de 2010. En total, 73 voluntarios con DMT2 y 42 saludables del Grupo Básico de Salud de Sousse, fueron escogidos para el estudio. Se recogieron los datos clínicos y bioquímicos, así como las complicaciones por diabetes. El grado de mal funcionamiento renal fue determinado por la tasa de filtrado glomerular (GFR). RESULTADOS: Los pacientes diabéticos tenían más edad. Las mujeres diabéticas presentaban una mayor probabilidad de tener un índice de masa corporal más alto que los hombres (p = 0.004). Hubo mayor obesidad en las mujeres que en los hombres (60/23%). Las complicaciones - incluyendo hipertensión y dislipidemia - estuvieron co-asociadas en las mujeres. La depuración de la creatinina urinaria en los pacientes de DMT2 sin nefropatía fue significativamente más baja (p < 0.0001) que en los participantes saludables. La microalbuminuria y la depuración de la creatinina urinaria estuvieron asociadas en las mujeres con DMT2 con nefropatía (R² = 0.95); 1.5% de los pacientes con DMT2 sin nefropatía, tuvo una tasa GFR < 60 mL/min/1.73m² y 76% tuvo una GFR entre 60 y 89 mL/min/1.73m². La diferencia de la tasa de filtrado glomerular entre los pacientes de DMT2 con/sin nefropatía, así como entre los pacientes de DMT2 con nefropatía/DMT2 sin nefropatía, y con retinopatía, no fue significativa. CONCLUSIONES: Analizando factores asociados con la nefropatía en pacientes tunesinos con DMT2, este estudio demostró que estos últimos son susceptibles a la nefropatía. Además, la retinopatía se halla potencialmente asociada con la nefropatía incipiente en los pacientes tunesinos que padecen DMT2.

Nephropathy following type 2 diabetes mellitus in Tunisian population.

OBJECTIVE: The purpose was to compare the characteristics of Tunisians with Type 2 diabetes mellitus (Type 2 DM) and nephropathy with those without nephropathy. This study assessed whether or not phenotypic characteristics can predict nephropathy development in Type 2 DM. The prevalence of nephropathy in Tunisian Type 2 DM patients, and their relationship with clinical and biochemical factors as well as chronic complications of the disease were determined. METHODS: This was a cross-sectional study of patients with diabetes diagnosed between January 2008 and December 2010. Altogether, 73 Type 2 DM and 42 healthy volunteers from the Basic Health Group of Sousse, were targeted for the study. Clinical, biochemical data, as well as complications of diabetes were collected. Kidney malfunction was defined by glomerular filtration rate (GFR). RESULTS: Diabetic patients were older Diabetic women were more likely to have higher body mass index than men (p = 0.004). Obesity was more in women than men (60/23%). Complications including hypertension and dyslipidaemia were co-associated in women. Urinary creatinine clearance in Type 2 DM patients without nephropathy was significantly lower than in healthy participants (p < 0.0001). Microalbuminuria and urinary creatinine clearance were associated only in women with Type 2 DM with nephropathy (R2 = 0.95); 1.5% of Type 2 DM patients without nephropathy had GFR < 60 mL/min/1.73m2 and 76% had a GFR between 60 and 89 mL/min/1.73m2. Glomerular filtration rate difference between Type 2 DM patients with/without nephropathy, as well as between Type 2 DM patients with nephropathy/Type 2 DM without nephropathy, and with retinopathy was not significant. CONCLUSIONS: By analysing factors associated with nephropathy in Type 2 DM Tunisian patients, this study demonstrated their susceptibility to nephropathy. In addition, retinopathy is potentially associated with incipient nephropathy in Type 2 DM Tunisian patients.

Golimumab and immunogenicity? 2010 and beyond.

Immunogenicity is a frequent adverse event observed with biological agents' therapy. Challenges of management in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis treated with golimumab, an anti-TNF-alpha blocker, include limited generation of antibodies like anti-nuclear, anti-golimumab, and anti-double stranded DNA antibodies. We conducted here a meta-analysis study in order to evaluate and compare the newly generated antibody levels after golimumab therapy. The examination of original clinical trials revealed that their levels were neither higher nor significant. Moreover, no evident associations between the induced-antibodies and lupus-like syndromes and/or infusion site reaction were reported. The reduced patients cohort and the absence of systematic newly generated antibodies follow-up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy, and/or predicting for their worse prognosis. Hence, further studies are required to ascertain the real impact of the induced antibodies after golimumab's therapy.

Dermatologic adverse events: golimumab, friend or foe?

Golimumab is a fully human anti-TNF-alpha blocker that has demonstrated its efficacy in the treatment of numerous kinds of diseases. Although it is generally safe and well tolerated, various adverse events have been reported. The present aim is to improve the understanding of dermatologic adverse events associated with golimumab following a search of various scientific databases. This systematic review and meta-analysis shows that golimumab is associated neither with severe injection-site reactions nor with injection-site erythema. We found no significant lupus-like syndromes, and no significant skin squamous cell carcinoma. We further suggest systematic dermatologic monitoring in clinical practice during golimumab therapy. Subsequent research should employ a larger cohort of patients to ensure clear and significant future conclusions.

Golimumab therapy of rheumatoid arthritis: an overview.

Golimumab is a new approved humanized antibody for the treatment of rheumatoid arthritis (RA). This antibody belonging to biologic agents is raised against the pro-inflammatory cytokine tumour necrosis factor-alpha playing an essential role in the initiation of RA. To date, Golimumab administration for patients with RA, as indicated by USA Food and Drug Administration, is subcutaneous combined with methotrexate (MTX). Here, we have reviewed current literature with a focus on characteristics of Golimumab and also have exposed the clinical trials either using MTX or not using MTX. We have also highlighted the incoming clinical trials on Golimumab and have proposed some indications for the future studies based on a setting of clinical data and post-marketing observational studies. These studies will advance rheumatologists' decisions in the beginning of RA therapeutic interventions to insure the best outcomes for patients with RA and to improve their quality of life.

Soluble HLA-G induces NF-kappaB activation in natural killer cells.

Human leukocyte antigen (HLA)-G is an immunomodulatory molecule discovered for the first time in the maternal-fetal interface. In cancer context, where high number of natural killer (NK) cells is described, the presence of HLA-G in its soluble form is thought to be essential for NK cells signaling. To evaluate intracellular signaling in NK cells upon HLA-G soluble forms stimulation, we investigate the role of soluble HLA-G (HLA-G5- and HLA-G1 shedding form) stimulation on classical nuclear factor (NF)-kappaB pathway activation. We reported that these two forms of soluble HLA-G could activate NF-kappaB in NK cells. NF-kappaB activation in NK cells does implicate neither phosphatidylinositol 3-kinase (PI3K) nor MEK (MAP kinase kinase) as demonstrated after specific inhibition experiments. We demonstrated elsewhere that NF-kappaB activation in NK cells is not implicated in cytotoxicity inhibition by HLA-G. Our findings may suggest the important role played by NF-kappaB activation after soluble HLA-G stimulation in other NK cells function.

Soluble HLA-G induces NF-kB activarion in natural killer cells

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Human leukocyte antigen (HLA)-G is an immunomodulatory molecule discovered for the first time in the maternal–fetal interface. In cancer context, where high number of natural killer (NK) cells is described, the presence of HLA-G in its soluble form is thought to be essential for NK cellssignaling. To evaluate intracellular signaling in NK cells upon HLA-G soluble forms stimulation, we investigate the role of soluble HLA-G (HLA-G5- and HLA-G1 shedding form) stimulation on classical nuclear factor (NF)–κB pathway activation. We reported that these two forms of soluble HLA-G could activate NF–κB in NK cells. NF–κB activation in NK cells does implicate neither phosphatidylinositol 3-kinase (PI3K) nor MEK (MAP kinase kinase) as demonstrated after specific inhibition experiments. We demonstrated elsewhere that NF–κB activation in NK cells is not implicated in cytotoxicity inhibition by HLA-G. Our findings may suggest the important role played by NF–κB activation after soluble HLA-G stimulation in other NK cells function (AU)

Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-kappaB inducers.

HLA-G is expressed by tumors, in which it contributes to the evasion of immunosurveillance. NF-kappaB appears to be a candidate for regulating HLA-G expression, since it is considered to be a hallmark of cancer. We investigated the role of NF-kappaB in modulating HLA-G expression in HLA-G-positive tumor cells, JEG-3 (choriocarcinoma), FON (melanoma), and M8-HLA-G1 (HLAG1-transfected melanoma). The treatment of tumor cells with two NF-kappaB inducers, tumor necrosis factor-alpha and phorbol 12-myristate 13-acetate, decreased HLA-G1 cell surface expression but increased intracytoplasmic HLA-G proteins. Reduction in HLA-G1 cell surface expression is driven by NF-kappaB and involves a proteolytic shedding process dependent on metalloproteinase activity. In contrast, an increase in intracytoplasmic HLA-G proteins involves post-transcriptional mechanisms that are independent of NF-kappaB. These results, and the fact that soluble HLA-G1 reduces the cytotoxicity of the NKL cell line, lead us to propose a novel regulatory pathway for HLA-G expression by tumor cells that may have particular relevance in tumor escape.