Phenotypic and functional characteristics of murine CD11c+ B cells which is suppressed by metformin.

Since the description of age-associated or autoimmune-associated B cells (ABCs), there has been a growing interest in the role of these cells in autoimmunity. ABCs are differently defined depending on the research group and are heterogenous subsets. Here, we sought to characterize ABCs in Sle1/2/3 triple congenic (TC) mice, which is a well accepted mouse model of lupus. Compared to follicular (FO) B cells, ABCs have many distinct functional properties, including antigen presentation. They express key costimulatory molecules for T cell activation and a distinct profile of cytokines. Moreover, they exhibit an increased capacity for antigen uptake. ABCs were also compared with germinal center (GC) B cells, which are antigen activated B cell population. There are several phenotypic similarities between ABCs and GC B cells, but GC B cells do not produce proinflammatory cytokines or take up antigen. While T cell proliferation and activation is induced by both FO B and ABCs in an antigen-dependent manner, ABCs induce stronger T cell receptor signaling in naïve CD4+ T cells and preferentially induce differentiation of T follicular helper (Tfh) cells. We found that ABCs exhibit a distinct transcriptomic profile which is focused on metabolism, cytokine signaling and antigen uptake and processing. ABCs exhibit an increase in both glycolysis and oxidative phosphorylation compared to FO B cells. Treatment of ABCs with metformin suppresses antigen presentation by decreasing antigen uptake, resulting in decreased Tfh differentiation. Taken together, these findings define a fundamental connection between metabolism and function within ABCs.

IL-17-producing follicular Th cells enhance plasma cell differentiation in lupus-prone mice.

Follicular Th (Tfh) cells are key CD4+ Th cells involved in regulating B cell differentiation in the germinal center. Mice with conditional KO (CKO) of B lymphocyte-induced maturation protein-1 (BLIMP-1) expression in CD11chi DCs (Prdm1 CKO) spontaneously develop a lupus-like disease. We found an increase in the number of Tfh cells in secondary lymphoid organs in lupus-prone Prdm1-CKO mice. B cells stimulated with Tfh cells become Ab-secreting cells (ASCs); there was an increase in ASC differentiation mediated by Tfh cells from Prdm1-CKO mice compared with Tfh cells from control mice. This was mainly due to the increased expression of molecules within the IL-23/IL-17 pathway in Tfh cells from Prdm1-CKO mice. There was an increased frequency of IL-17A+ Tfh cells in Prdm1-CKO mice. These Tfh cells secrete IL-17A and an increased amount of IL-21. Furthermore, neutralizing IL-17A and IL-21 reduced ASC differentiation induced by Tfh cells. Lastly, we found the expression of IL-1ß and IL-6 was increased in BLIMP-1-deficient DCs, which are key for Th17 induction. Altogether, the lack of BLIMP-1 expression in DCs induces not only an increased number of Tfh cells, but also functionally distinct Tfh cells that lead to increased ASC differentiation.

Brazilian cohort and genes encoding for drug-metabolizing enzymes and drug transporters.

Background & aim: Genetic variability in drug absorption, distribution, metabolism and excretion (ADME) genes contributes to the high heterogeneity of drug responses. The present study investigated polymorphisms of ADME genes frequencies and compared the findings with populations from other continents, available in the 1000 Genome Project (1 KGP) and the Exome Aggregation Consortium (ExAC) databases. Methodology & results: We conducted a study of 100 patients in Brazil and a total of 2003 SNPs were evaluated by targeted next-generation sequencing in 148 genes, including Phase I enzymes (n = 50), Phase II enzymes (n = 38) and drug transporters (n = 60). Overall, the distribution of minor allele frequency (MAF) suggests that the distribution of 2003 SNPs is similar between Brazilian cohort, 1 KGP and ExAC; however, we found moderate SNP allele-frequency divergence between Brazilian cohort and both 1000 KGP and ExAC. These differences were observed in several relevant genes including CYP3A4, NAT2 and SLCO1B1. Conclusion: We concluded that the Brazilian population needs clinical assessment of drug treatment based on individual genotype rather than ethnicity.

Intraoperative Surgical Portosystemic Shunt in Liver Transplantation: Systematic Review and Meta-Analysis.

BACKGROUND Expanded clinical and surgical techniques in liver transplantation can markedly improve patient and graft survival. The main purpose of this study was to evaluate the efficacy of intraoperative portocaval shunts in liver transplantation. MATERIAL AND METHODS Searches were conducted in Cochrane, MEDLINE, and EMBASE databases, and updated in January 2018. The following specific outcomes of interest were defined and evaluated separated using 2 different reviews and meta-analyses for 1) hemi-portocaval shunt (HPCS) and 2) temporary portocaval shunt (TPCS). Comparative studies were analyzed separately for both surgical portocaval shunt modalities. RESULTS Only 1 well-designed randomized controlled trial was found. Most studies were retrospective or prospective. Initially, we found 1479 articles. Of those selected, 853 were from PubMed/MEDLINE, 32 were from Cochrane and 594 were from EMBASE. Our meta-analysis included a total of 3232 patients for all the included studies. Results found that 41 patients with HPCS experienced increased 1-year patient survival (OR 16.33; P=0.02) and increased 1-year graft survival (OR 17.67; P=0.01). The TPCS analysis with 1633 patients found patients had significantly shorter intensive care unit length of stay (days) (P=0.006) and hospital length of stay (P=0.02) and had decreased primary nonfunction (PNF) (OR 0.30, P=0.02) and mortality rates (OR 0.52, P=0.01). CONCLUSIONS Intraoperative surgical portosystemic shunt in relation to liver transplantation with TPCS was able to prevent PNF, decrease hospital length of stay and unit care length of stay. Furthermore, in analyzing data for patients with HPCS, we observed increases in the 1-year graft and patient survival rates. More prospective randomized trials are needed to arrive at a more precise conclusion.

Translational medical research and liver transplantation: systematic review.

Translational medicine has become a priority, but there is still a big difference between the arrival of new treatments and investment. Basic science should not be neglected because the translation from basic research is not sustained in the absence of basic research. The purpose of this literature review was to analyze the translational medicine in the liver transplant field: liver ischemia-reperfusion injury (IRI), immunosuppression, clinical and surgical complications, small-for-size syndrome (SFSS), rejection, and ongoing innovations (liver machine, liver preservation, artificial livers, and regenerative medicine). We performed a systematic literature review that were updated in October 2016. The searches were performed in the Cochrane Central Register of Controlled Trials and Review, PubMed/Medline, Embase, and LILACS databases. All the selected studies on the management of translational medical research in liver transplantation (LT) were analyzed. Initially the search found 773 articles. Methodological viewing and analysis of the articles, followed by the application of scientific models, including translational medicine in the liver transplant field. In conclusions, this review demonstrates the application of scientific research with translation medical benefits regarding the LT. The literature has a great tendency, improvements and investments in the study of translational medicine in LT. Innovative studies and technologies from basic science help to clarify clinical doubts. Moreover, evidence increases the importance of scientific research in quality of clinical practice care.