Gabriella Pár

Progesterone as an immunomodulatory molecule

Increased progesterone sensitivity of pregnancy lymphocytes is due to activation-induced appearance of progesterone binding sites in the lymphocytes. Following recognition of fetally derived antigens gamma/delta TCR+ cells develop progesterone receptors. Progesterone binding results in the synthesis of a mediator protein named the progesterone-induced blocking factor (PIBF). PIBF by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling NK activity exerts an anti-abortive effect.

Decrease in CD3-negative-CD8dim+ and Vδ2/Vγ9 TcR + peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection

BACKGROUND/AIMS As chronic hepatitis C virus (HCV) infection is associated with impaired natural killer (NK) cell cytotoxicity, we examined the phenotypes and perforin expression of peripheral blood lymphocytes, as well as the effect of interferon-alpha2b (IFN-alpha2b) therapy. METHODS Thirty-three patients had chronic hepatitis C, and of them 12 had been on IFN-alpha2b treatment. Eleven individuals had been treated earlier with IFN-alpha2b and completely cured, and eight were HCV carriers with persistently normal serum alanine aminotransferase. Three-colour flow cytometry was used to measure the percentage of CD3(+/-)CD8+, CD3+CD4+, gammadeltaTcR+, Vdelta2 TcR+, Vgamma9 TcR+, Vdelta1 TcR+, CD3-CD16+, CD3-CD56+, CD19+ and perforin-positive cells. NK cell activity was assessed by single cell cytotoxic and flow cytometric assay. RESULTS Patients with chronic hepatitis C showed an impaired NK cytotoxicity, decreased percentage of CD3-negative-CD8dim-positive (NK subtype) and Vgamma9/Vdelta2 TcR+ as well as perforin-positive T lymphocytes, compared to controls and to those who were cured from HCV infection. IFN-alpha2b increased NK cell cytotoxicity and the percentage of perforin-positive lymphocytes. CONCLUSIONS Our findings suggest that in chronic HCV infection a decreased percentage of CD3(-)CD8+, Vgamma9/Vdelta2 TcR+ and perforin-positive T cells and simultaneous decreased peripheral NK activity may contribute to the impaired cellular immune response and the chronicity of the disease.

The role of γ/δ T cells in progesterone-mediated immunomodulation during pregnancy: A review

PROBLEM: To determine if pregnancy is recognized by the immune system and if inadequate recognition of fetal antigens might result in failed pregnancy.

Progesterone and Non‐specific Immunologic Mechanisms in Pregnancy

PROBLEM: Progesterone‐dependent immunomodulation is one of the mechanisms that enables pregnancy to proceed to term. Immunologic effects of progesterone are mediated by a protein named the progesterone‐induced blocking factor (PIBF). Among other effects this protein inhibits natural killer (NK) activity and displays an anti‐abortive effect in mice. Recently we have shown that PIBF induces a Th2 shift in vitro. The present study was aimed at investigating the in vivo effect of PIBF on cytokine production, as well as the relationship between cytokine production, NK activity, and pregnancy loss.

Progesterone-Induced Blocking Factor Activates STAT6 via Binding to a Novel IL-4 Receptor

Progesterone-induced blocking factor (PIBF) induces Th2-dominant cytokine production. Western blotting and EMSA revealed phosphorylation as well as nuclear translocation of STAT6 and inhibition of STAT4 phosphorylation in PIBF-treated cells. The silencing of STAT6 by small interfering RNA reduced the cytokine effects. Because the activation of the STAT6 pathway depends on the ligation of IL-4R, we tested the involvement of IL-4R in PIBF-induced STAT6 activation. Although PIBF does not bind to IL-4R, the blocking of the latter with an Ab abolished PIBF-induced STAT6 activation, whereas the blocking of the IL-13R had no effect. PIBF activated suppressor of cytokine signaling-3 and inhibited IL-12-induced suppressor of cytokine signaling-1 activation. The blocking of IL-4R counteracted all the described effects, suggesting that the PIBF receptor interacts with IL-4R α-chain, allowing PIBF to activate the STAT6 pathway. PIBF did not phosphorylate Jak3, suggesting that the γ-chain is not needed for PIBF signaling. Confocal microscopic analysis revealed a colocalization and at 37°C a cocapping of the FITC PIBF-activated PIBF receptor and PE anti-IL-4R-labeled IL-4R. After the digestion of the cells with phosphatidylinositol-specific phospholipase C, the STAT6-activating effect of PIBF was lost, whereas that of IL-4 remained unaltered. These data suggest the existence of a novel type of IL-4R composed of the IL-4R α-chain and the GPI-anchored PIBF receptor.

Progesterone regulates IL12 expression in pregnancy lymphocytes by inhibiting phospholipase A2

Par G, Geli J, Kozma N, Varga P, Szekeres‐Bartho J. Progesterone regulates IL12 expression in pregnancy lymphocytes by inhibiting phospholipase A2. AJRI 2003; 49:1–5

Presence of Anti-Microbial Antibodies in Liver Cirrhosis – A Tell-Tale Sign of Compromised Immunity?

Background Bacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohns disease and considered to be caused by sustained exposure to gut microflora constituents. We hypothesized that anti-microbial antibodies are present in patients with liver cirrhosis and may be associated with the development of bacterial infections. Methodology/Principal Findings Sera of 676 patients with various chronic liver diseases (autoimmune diseases:266, viral hepatitis C:124, and liver cirrhosis of different etiology:286) and 100 controls were assayed for antibodies to Saccharomyces cerevisiae(ASCA) and to antigens derived from two intestinal bacterial isolates (one gram positive, one gram negative, neither is Escherichia coli). In patients with liver cirrhosis, we also prospectively recorded the development of severe episodes of bacterial infection. ASCA and anti-OMP Plus™ antibodies were present in 38.5% and 62.6% of patients with cirrhosis and in 16% and 20% of controls, respectively (p<0.001). Occurrence of these antibodies was more frequent in cases of advanced cirrhosis (according to Child-Pugh and MELD score; p<0.001) or in the presence of ascites (p<0.001). During the median follow-up of 425 days, 81 patients (28.3%) presented with severe bacterial infections. Anti-microbial antibody titers (p = 0.003), as well as multiple seroreactivity (p = 0.036), was associated with infectious events. In logistic regression analysis, the presence of ascites (OR:1.62, 95%CI:1.16–2.25), co-morbidities (OR:2.22, 95%CI:1.27–3.86), and ASCA positivity (OR:1.59, 95%CI:1.07–2.36) were independent risk factors for severe infections. A shorter time period until the first infection was associated with the presence of ASCA (p = 0.03) and multiple seropositivity (p = 0.037) by Kaplan-Meier analysis, and with Child-Pugh stage (p = 0.018, OR:1.85) and co-morbidities (p<0.001, OR:2.02) by Cox-regression analysis. Conclusions/Significance The present study suggests that systemic reactivity to microbial components reflects compromised mucosal immunity in patients with liver cirrhosis, further supporting the possible role of bacterial translocation in the formation of anti-microbial antibodies.

Impaired Reproduction of Histamine Deficient (histidine‐decarboxylase Knockout) Mice is Caused Predominantly by a Decreased Male Mating Behavior

PROBLEM: Histamine induces a Th2 shift. As successful allopregnancy is characterized by a peripheral Th2 dominance, we investigated the role of histamine in reproduction.

Low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet improves symptoms in adults suffering from irritable bowel syndrome (IBS) compared to standard IBS diet: A meta-analysis of clinical studies

Background Irritable bowel syndrome (IBS) and functional digestive tract disorders, e.g. functional bloating, carbohydrate maldigestion and intolerances, are very common disorders frequently causing significant symptoms that challenge health care systems. A low Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols (FODMAP) diet is one of the possible therapeutic approaches for decreasing abdominal symptoms and improving quality of life. Objectives We aimed to meta-analyze data on the therapeutic effect of a low-FODMAP diet on symptoms of IBS and quality of life and compare its effectiveness to a regular, standard IBS diet with high FODMAP content, using a common scoring system, the IBS Symptom Severity Score (IBS-SSS). Methods A systematic literature search was conducted in PubMed, EMBASE and the Cochrane Library as well as in the references in a recent meta-analysis. Adult patients diagnosed with IBS according to the Rome II, Rome III, Rome IV or NICE criteria were included in the analysis. Statistical methods Mean differences with 95% confidence intervals were calculated from studies that contained means, standard deviation (SD) or mean differences and SD of differences and p-values. A random effect model was used because of the heterogeneity (Q test (χ2) and I2 indicator). A p-value of less than 0.05 was chosen to indicate a significant difference. Results The literature search yielded 902 publications, but only 10 were eligible for our meta-analysis. Both regular and low-FODMAP diets proved to be effective in IBS, but post-diet IBS-SSS values were significantly lower (p = 0.002) in the low-FODMAP group. The low-FODMAP diet showed a correlation with the improvement of general symptoms (by IBS-SSS) in patients with IBS. Conclusions This meta-analysis provides high-grade evidence of an improved general symptom score among patients with irritable bowel syndrome who have maintained a low-FODMAP diet compared to those on a traditional IBS diet, therefore showing its superiority to regular IBS dietary therapy. These data suggest that a low-FODMAP diet with dietitian control can be a candidate for first-line therapeutic modality in IBS. Because of a lack of data, well-planned randomized controlled studies are needed to ascertain the correlation between improvement of separate key IBS symptoms and the effect of a low-FODMAP diet.

Mannose-binding lectin deficiency confers risk for bacterial infections in a large Hungarian cohort of patients with liver cirrhosis.

BACKGROUND & AIMS Mannose-binding lectin (MBL) is a serum lectin synthesized by the liver and involved in innate host defense. MBL deficiency increases the risk of various infectious diseases mostly in immune-deficient conditions. Bacterial infections are a significant cause of morbidity and mortality in liver cirrhosis due to the relative immuncompromised state. METHODS Sera of 929 patients with various chronic liver diseases [autoimmune liver diseases (ALD), 406; viral hepatitis C (HCV), 185; and liver cirrhosis (LC) with various etiologies, 338] and 296 healthy controls (HC) were assayed for MBL concentration. Furthermore, a follow-up, observational study was conducted to assess MBL level as a risk factor for clinically significant bacterial infections in cirrhotic patients. RESULTS MBL level and the prevalence of absolute MBL deficiency (<100 ng/ml) was not significantly different between patients and controls (ALD: 14.5%, HCV: 11.9%, LC: 10.7%, HC: 15.6%). In cirrhotic patients, the risk for infection was significantly higher among MBL deficient subjects as compared to non-deficient ones (50.0% vs. 31.8%, p=0.039). In a logistic regression analysis, MBL deficiency was an independent risk factor for infections (OR: 2.14 95% CI: 1.03-4.45, p=0.04) after adjusting for Child-Pugh score, co-morbidities, gender, and age. In a Kaplan-Meier analysis, MBL deficiency was associated with a shorter time to develop the first infectious complication (median days: 579 vs. 944, pBreslow=0.016, pLogRank=0.027) and was identified as an independent predictor in a multivariate Cox-regression analysis (p=0.003, OR: 2.33, 95% CI: 1.34-4.03). CONCLUSIONS MBL deficiency is associated with a higher probability and shorter time of developing infections in liver cirrhosis, further supporting the impact of the MBL molecule on the host defense.