Pro and anti-inflammatory diets as strong epigenetic factors in inflammatory bowel disease

Inflammatory bowel disease(IBD)is the consequence of a complex interplay between environmental factors,like dietary habits,that alter intestinal microbiota in response to luminal antigens in genetically susceptible individuals.Epigenetics represents an auspicious area for the discovery of how environmental factors influence the pathogenesis of inflammation,prognosis,and response to therapy.Consequently,it relates to gene expression control in response to environmental influences.The increasing number of patients with IBD globally is indicative of the negative effects of a food supply rich in trans and saturated fats,refined su-gars,starches and additives,as well as other environmental factors like seden-tarism and excess bodyweight,influencing the promotion of gene expression and increasing DNA hypomethylation in IBD.As many genetic variants are now associated with Crohn's disease(CD),new therapeutic strategies targeting modi-fiable environmental triggers,such as the implementation of an anti-inflammatory diet that involves the removal of potential food antigens,are of growing interest in the current literature.Diet,as a strong epigenetic factor in the pathogenesis of inflammatory disorders like IBD,provides novel insights into the pathophysio-logy of intestinal and extraintestinal inflammatory disorders.

Review: Pathogenesis of cholestatic liver diseases

Cholestatic liver diseases(CLD)begin to develop after an impairment of bile flow start to affect the biliary tree.Cholangiocytes actively participate in the liver response to injury and repair and the intensity of this reaction is a determinant factor for the development of CLD.Progressive cholangiopathies may ultimately lead to end-stage liver disease requiring at the end orthotopic liver transplantation.This narrative review will discuss cholangiocyte biology and pathogenesis mechanisms involved in four intrahepatic CLD:Primary biliary cholangitis,primary sclerosing cholangitis,cystic fibrosis involving the liver,and polycystic liver disease.

Mapping Toll-Like Receptor Signaling Pathway Genes of Zhikong Scallop(Chlamys farreri) with FISH

Toll-like receptor(TLR) signaling pathway plays a pivotal role in the innate immune system. Studies on TLR signaling pathway genes in Zhikong scallop(Chlamys farreri) have mainly focused on sequence analysis and expression profiling, no research has been carried out on their localization. The chromosomal position of TLR signaling pathway genes can be valuable for assemblying scallop genome and analysizing gene regulatory networks. In the present study, five key TLR signaling pathway genes(Cf TLR, Cf Myd88, Cf TRAF6, Cf NFκB, and Cf IκB) containing bacterial artificial chromosomes(BACs) were isolated and physically mapped through fluorescence in situ hybridization on five non-homologous chromosome pairs, showing a similar distribution to another five model species. The isolation and mapping of these key immune genes of C. farreri will aid to the research on innate immunity, assignment of interested genes to chromosomes, and integration of physical, linkage and cytogenetic maps of this species.

Prevalence of Human Leukocyte Antigen HLA-B*5701 in HIV-1 Infected Individuals in Brazil

This study was designed to establish the prevalence of HLA-B*5701 at HIV-1 infected individuals in Brazil. A total of 517 consecutive individuals were followed in this study from February 2009 through July 2011. The presence of HLA-B*5701 was determined by Nested-PCR with HLA-B*57 and HLA-B*5701 sequence-specific primers (PCR-SSP). The expression of HLA-B*57 was negative in the 385 (74.5%) and positive in the 103 (19.9%) of infected individuals. Among these, the expression of HLA-B5701 was positive in the 29 (5.6%) of individuals. No demographic or ethnic differences were found between HLA-B*57/HLA-B*5701 HIV-1 negative patients, with a prevalence of Caucasians (57.1%) individuals. During the period of study, 68 patients were submited to an abacavir contain- ing regimen. The HLA-B*5701 allele was observed in 7 (10.3%) patients, with a significant incidence of Hypersensitivity reactions at 4 of them (p < 0.001). Conclusions: Although Brazilian population consists of a mixture of individuals of Caucasian, African and Native American genetic background, prevalence of HLA-B*5701 in this population is similar to the one found in pure Caucasians.

Total IgA and IgA reactivity to antigen I/II epitopes in HLA-DRB1*04 positive subjects

Bacterial adherence to the acquired dental pellicle, important in dental caries (caries), is mediated by receptor-adhesins such as salivary agglutinin binding to Streptococcus mutans antigen I/II (I/II). Ten selected I/II epitopes were chosen to determine their reactivity to human salivary IgA. Previous studies suggested that a specific HLA biomarker group (HLA-DRB1*04) may have differential influence of immune responses to I/II. However, it was not known whether secretory IgA (SIgA) responses to the selected epitopes from HLA-DRB1*04 positive subjects were different compared to controls, or across other caries-related factors such as total IgA (TIgA). Thirty-two total subjects were matched according to HLA type, gender, ethnicity and age. HLA genotyping, oral bacterial, immunoglobulin and antibody analyses were performed. A large observed difference emerged with regard to the natural immune reservoir of TIgA in HLA-DRB1*04 positive subjects, specifically, a 27.6% reduction compared to controls. In contrast to all other epitopes studied, HLA-DRB1*04 positive subjects also exhibited reduced reactivity to I/II epitope 834-853. HLA-DRB1*04 positive subjects exhibited lower specific SIgA activity/TIgA to 834-853 and also a lower specific reactivity to 834-853/whole cell S. mutans UA159. Furthermore, HLA-DRB1*04 positive subjects exhibited lower responses to I/II in its entirety. The large observed difference in TIgA and the 834-853 reactivity pattern across multiple measures suggest potentially important connections pertaining to the link between HLA-DRB1*04 and caries.

TRAF1/C5 rs3761847 SNP Is Associated with Severe Pattern of Rheumatoid Arthritis in Greek Patients

The era of whole genome study analysis has introduced a profound research in the genetics of autoimmune diseases. Some of the new genetic loci that have been associated with the development or the severity of autoimmune diseases have been thoroughly studied, conferring a more detailed understanding of disease pathophysiology. Furthermore, single nucleotide polymorphisms (SNPs) have been described not only in coding regions of the human genome but also in non-coding areas (introns), the importance of which has not been yet clarified. Over the last years, such an SNP has been associated with the development of rheumatoid arthritis, the most frequent autoimmune disease. This SNP is at the position 122730060 of chromosome 9 in the TRAF1/C5 region and consists of a substitution of the nucleotide base guanine (G)—which is considered the ancestral phenotype— by alanine (A). It has been indicated that G is the aggravating nucleotide, and that G/G is the disease predisposing phenotype, conferring >1.3× risk for RA. On this background, we performed a genome study on a Greek population of northern Greece (Macedonia) in order to identify the association of this SNP with RA in our group.

Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma:A systematic review

BACKGROUND Despite the use of current standard therapy,the prognosis of patients with unresectable hepatocellular carcinoma(HCC)is poor,with median survival times of 40 mo for intermediate HCC(Barcelona Clinic Liver Cancer[BCLC]stage B)and 6-8 mo for advanced HCC(BCLC stage C).Although patients with earlystage HCC are usually suitable for therapies with curative intention,up to 70% of patients experience relapse within 5 years.In the past decade,the United States Food and Drug Administration has approved different immunogenic treatment options for advanced HCC,the most common type of liver cancer among adults.Nevertheless,no treatment is useful in the adjuvant setting.Since 2007,the multikinase inhibitor sorafenib has been used as a first-line targeted drug to address the increased mortality and incidence rates of HCC.However,in 2020,the IMbrave150 trial demonstrated that combination therapy of atezolizumab(antiprogrammed death-ligand 1[PD-L1])and bevacizumab(anti-vascular endothelial growth factor[VEGF])is superior to sorafenib,a single anti-programmed death 1/PD-L1 antibody inhibitor used as an anti-cancer monotherapy for HCC treatment.AIM To conduct a systematic literature review to evaluate the evidence supporting the efficacy and safety of atezolizumab/bevacizumab as preferred first-line drug therapy over the conventional sorafenib or atezolizumab monotherapies,which are used to improve survival outcomes and reduce disease progression in patients with unresectable HCC and non-decompensated liver disease.METHODS A comprehensive literature review was conducted using the PubMed,Scopus,ScienceDirect,clinicaltrials.gov,PubMed Central,Embase,EuropePMC,and CINAHL databases to identify studies that met the inclusion criteria using relevant MeSH terms.This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and risk of bias(RoB)were assessed using the Cochrane RoB 2 tool and Sevis.RESULTS In the atezolizumab/bevacizumab group,an improvement in overall tumor response,reduction of disease progression,and longer progression-free survival were observed compared to monotherapy with either sorafenib or atezolizumab.Hypertension and proteinuria were the most common adverse events,and the rates of adverse events were comparable to those with the monotherapy.Of the studies,there were two completed trials and two ongoing trials analyzed using high quality and low bias.A more thorough analysis was only performed on the completed trials.CONCLUSION Treatment of HCC with atezolizumab/bevacizumab combination therapy was confirmed to be an effective first-line treatment to improve survival in patients with unresectable HCC and non-decompensated liver disease compared to monotherapy with either sorafenib or atezolizumab.

Distinct T helper cell-mediated antitumor immunity:T helper 2 cells in focus

The adaptive arm of the immune system is crucial for appropriate antitumor immune responses.It is generally accepted that clusters of differentiation 4^(+)(CD4^(+))T cells,which mediate T helper(Th)1 immunity(type 1 immunity),are the primary Th cell subtype associated with tumor elimination.In this review,we discuss evidence showing that antitumor immunity and better prognosis can be associated with distinct Th cell subtypes in experimental mouse models and humans,with a focus on Th2 cells.The aim of this review is to provide an overview and understanding of the mechanisms associated with different tumor outcomes in the face of immune responses by focusing on the(1)site of tumor development,(2)tumor properties(i.e.,tumor metabolism and cytokine receptor expression),and(3)type of immune response that the tumor initially escaped.Therefore,we discuss how low-tolerance organs,such as lungs and brains,might benefit from a less tissue-destructive immune response mediated by Th2 cells.In addition,Th2 cells antitumor effects can be independent of CD8^(+)T cells,which would circumvent some of the immune escape mechanisms that tumor cells possess,like low expression of major histocompatibility-I(MHC-I).Finally,this review aims to stimulate further studies on the role of Th2 cells in antitumor immunity and briefly discusses emerging treatment options.

Update on Autoimmune Hepatitis

Autoimmune hepatitis (AIH),a liver disorder affecting both children and adults,is characterized by inflammatory liver histology,elevated transaminase levels,circulating nonorgan-specific autoantibodies,and increased levels of immunoglobulin G,in the absence of a known etiology.Two types of AIH are recognized according to seropositivity:smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2.AIH type 1 affects both adults and children,while AIH type 2 is mainly a paediatric disease,though it does occasionally affects young adults.AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels.AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine,with symptom free longterm survival for the majority of patients.For those who do not respond to standard treatment,or who are difficult-totreat,mycophenolate mofetil and,in the absence of a response,calcineurin inhibitors should be tried in addition to steroids.The pathogenesis of AIH is not fully understood,although there is mounting evidence that genetic susceptibility,molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack.Liver damage is thought to be mediated primarily by CD4 T-cells,although recent studies support the involvement of diverse populations,including Th17 cells.A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments,such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells,which ultimately aim at restoring tolerance to liver-derived antigens.