Purinergic signaling modulates human visceral adipose inflammatory responses: implications in metabolically unhealthy obesity.

Obesity is accompanied by chronic inflammation of VAT, which promotes metabolic changes, and purinergic signaling has a key role in a wide range of inflammatory diseases. Therefore, we addressed whether fat inflammation could be differentially modulated by this signaling pathway in the MUO and in individuals who remain MHO. Our results show that the necrotized VAT of both groups released greater levels of ATP compared with lean donors. Interestingly, MUO tissue SVCs showed up-regulation and engagement of the purinergic P2X7R. The extracellular ATP concentration is regulated by an enzymatic process, in which CD39 converts ATP and ADP into AMP, and CD73 converts AMP into adenosine. In VAT, the CD73 ectoenzyme was widely distributed in immune and nonimmune cells, whereas CD39 expression was restricted to immune CD45PAN+ SVCs. Although the MUO group expressed the highest levels of both ectoenzymes, no difference in ATP hydrolysis capacity was found between the groups. As expected, MUO exhibited the highest NLRP3 inflammasome expression and IL-1ß production. MUO SVCs also displayed up-regulation of the A2AR, allowing extracellular adenosine to increase IL-1ß local secretion. Additionally, we demonstrate that metabolic parameters and BMI are positively correlated with purinergic components in VAT. These findings indicate that purinergic signaling is a novel mechanism involved in the chronic inflammation of VAT underlying the metabolic changes in obesity. Finally, our study reveals a proinflammatory role for adenosine in sustaining IL-1ß production in this tissue.

Mechanisms involved in the expansion of Tregs during pregnancy: role of IL-2/STAT5 signalling.

Several studies have reported that the fine-tuning of regulatory T cells (Tregs) is required for a successful pregnancy and for the control of autoimmune diseases. Here, we review the mechanisms that control the expansion of Tregs, based on insights obtained from the study of women suffering unsuccessful pregnancies and on recent data from patients with autoimmune diseases or with chronic viral infections such as HCV. In particular, we review the role of endocrine factors and IL-2/STAT5 signalling in the impaired expansion of Tregs.

IL-6 trans-signaling and the frequency of CD4+FOXP3+ cells in women with reproductive failure.

Pregnancy constitutes a major challenge to the maternal immune system, as it requires tolerance of paternal alloantigen. Maternal rejection of the fetus may develop when T regulatory (Treg) cells fail to control the balance between tolerance and immunity. Increasing evidence supports the role of IL-6 trans-signaling within T cells as a key pathway for blockade of the development of adaptive Treg cells. The present study investigated whether alteration of the components of the IL-6 trans-signaling might be a mechanism associated with modified immune responses in patients experiencing recurrent spontaneous abortion (RSA). In contrast with control women, sera from RSA women induced an enhanced mixed lymphocyte reaction (MLR) against paternal PBMCs, showing increased proliferation and lack of MLR-blocking factor activity. The sera from RSA women inhibited expansion of the FOXP3+ T cell population in TCR-activated PBMCs and showed an imbalance in levels of soluble components of the IL-6 trans-signaling pathway. In comparison with fertile women, those with RSA showed significantly increased levels of soluble IL-6 receptor and IL-6, and decreased levels of soluble gp130, the trans-signaling inhibitor. Finally we found that paternal alloimmunization acts to modulate serum levels of factors involved in the IL-6 trans-signaling pathway and increases the frequency of Treg cells. Consequently, women with reproductive failure show evidence of alteration in the IL-6 trans-signaling pathway which might be associated with abnormal performance of Treg cells in mediating feto-maternal tolerance.

KIR genes polymorphism in Argentinean Caucasoid and Amerindian populations.

In natural killer cells, killer immunoglobulin-like receptors (KIRs) loci code for either inhibitory or activating receptors, and according to the number of genes present in each individual, it is possible to identify a high rate of polymorphism in the populations. We performed KIR typing by polymerase chain reaction-sequence-specific oligonucleotide probing in 402 Argentinean Caucasoid and in two Amerindian populations (101 Wichis and 54 Chiriguanos) from the North of Argentina. KIR2DL4, KIR3DL2, KIR3DL3 and KIR3DP1 were always present, whereas the frequencies of KIR2DL1, KIR2DL3, KIR2DS4, KIR3DL1 and KIR2DP1 ranged between 84% and 96%. The frequencies of KIR2DS2, KIR2DL2, KIR2DL5, KIR2DS5, KIR2DS1 and KIR3DS1 ranged between 41% and 62%. The KIR2DS3 with a frequency of 29% in Argentinean Caucasoid population was present at a very low frequency in Amerindian populations. Haplotype segregation studies performed in 10 Wichi families showed the presence of only three haplotypes: A, B5 and B1. The Amerindian populations showed several similarities to Asian but not to Caucasoid populations with regard to the frequency of KIR2DS3, full-length KIR2DS4 gene and KIR2DL4 alleles.

Increased frequencies of activating natural killer receptors are associated with liver injury in individuals who do not eliminate hepatitis C virus.

This study was designed to investigate the role of killer immunoglobulin-like receptor (KIR) genes in the outcome of hepatitis C virus (HCV) infection. In patients who cleared the virus (HCV RNA-) we found a decrease of 2DL2 (P= 0.04), and 2DS2 (P= 0.014) accompanied by an increase of 2DS5 (P= 0.04). Those RNA+ patients with elevated levels of hepatic transaminases (HCV RNA+ elevated alanine aminotransferase) showed an increased frequency of 2DS3 (P= 0.018). Additionally, in cirrhotic patients we found an increased frequency of individuals having two copies of 3DS1 and HLA-Bw4 (P= 0.016). We conclude that higher natural killer cytotoxicity might be associated with a worse progression of the HCV infection.

KIR receptors and HLA-C in the maintenance of pregnancy.

The present study demonstrated that patients who have recurrent spontaneous abortions (RSA) presented a decreased number of killer immunoglobulin-like inhibitory receptors (KIR), in particular KIR2DL2. The KIR AA genotype was found increased in comparison with controls. Individuals AA will also be homozygous for 2DL3, which in contrast to 2DL2, show a weaker interaction with C1 ligands and therefore a weaker inhibition. The present study might support that in RSA patients, the balance between inhibitory and activating receptors present in natural killer cells is inclined toward an activating state that may contribute to pregnancy loss.