Regulation Of Humoral Immune Responses Research Articles

COL10A1 as a Prognostic Biomarker in Association with Immune Infiltration in Prostate Cancer.

The collagen type X alpha 1 (COL10A1) has recently been found to play an important role in the development and progression of cancer. However, the link between COL10A1 and the tumor immune microenvironment remains understood scantily. In the current study, the pan-cancer data of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used to investigate the expression mode, the clinical prognostic and diagnostic value of COL10A1 in different tumors. We used TCGA data to assess the correlations between COL10A1 and clinical symptoms of prostate cancer. The R packages "edgR" and "clusterProfiler" were used for differential expression gene and enrichment analysis of COL10A1. Immunohistochemistry was further employed to corroborate the expression of COL10A1 gene in prostate cancer. After that, we used TIMER to evaluate the pertinence of COL10A1 expression to immune infiltration level in prostate cancer. On the whole, COL10A1 was expressed at significantly higher levels in a variety of tumor tissues than in the corresponding normal tissues. Besides, significant correlations with tumor prognosis and relative exactitude in predicting tumors show that COL10A1 may be a probable prognostic and diagnostic biomarker of prostate cancer. In addition, the evidence indicates a significant correlation between COL10A1 and clinical symptoms of prostate cancer. Furthermore, the main molecular functions of COL10A1 included humoral immune response, complement activation, immunoglobulin, regulation of complement activation, and regulation of humoral immune response. Finally, we found that COL10A1 expression is positively correlated with enhanced macrophage and M2 macrophage infiltration in prostate cancer. The study indicates that COL10A1 might participate in M2 macrophage polarization in prostate cancer. COL10A1 might be an innovative biomarker to evaluate tumor microenvironment immune cell infiltration and prognosis in prostate cancer.

Type 2 Cystatins and Their Roles in the Regulation of Human Immune Response and Cancer Progression.

Cystatins are a family of intracellular and extracellular protease inhibitors that inhibit cysteine cathepsins-a group of lysosomal cysteine proteases that participate in multiple biological processes, including protein degradation and post-translational cleavage. Cysteine cathepsins are associated with the development of autoimmune diseases, tumor progression, and metastasis. Cystatins are categorized into three subfamilies: type 1, type 2, and type 3. The type 2 cystatin subfamily is the largest, containing 10 members, and consists entirely of small secreted proteins. Although type 2 cystatins have many shared biological roles, each member differs in structure, post-translational modifications (e.g., glycosylation), and expression in different cell types. These distinctions allow the type 2 cystatins to have unique biological functions and properties. This review provides an overview of type 2 cystatins, including their biological similarities and differences, their regulatory effect on human immune responses, and their roles in tumor progression, immune evasion, and metastasis.

Exploration of the Perturbation of PKIG in Lung Squamous Cell Carcinoma and the Role in Tumor Microenvironment Based on Bioinformatics Method

Lung cancer is the leading cause of cancer-related death worldwide, and patients have limited survival benefits from traditional treatments such as surgery, radiotherapy and chemotherapy. As a new treatment for lung cancer, immunotherapy has significantly prolonged the overall survival (OS) of patients. However, only some patients can benefit from it. We need to explore immunotherapy biomarkers more deeply to screen for advantages. The original data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, and the immunological and prognostic genes of lung squamous cell carcinoma (LUSC) were screened using R software and TIMER database. The expression of target genes was studied in TCGA and GEO databases, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and correlation analysis with tumor immune characteristics were performed by R software and TISIDB database. We screened out a gene related to immunity and prognosis, cAMP dependent protein kinase inhibitor γ (PKIG), which is significantly differentially expressed in LUSC and normal tissues, and has important reference value for the diagnosis and prognosis assessment of LUSC. PKIG differential genes are mainly concentrated in the regulation of humoral immune response and other processes. The expression of PKIG was positively correlated with the infiltration level of regulatory T cells (Tregs) (r=0.340, P<0.001). In addition, the expression level of PKIG was positively correlated with the expression of chemokines/chemokine receptors such as chemokine C-C motif ligand 2 (CCL2) (r=0.503, P<0.001), CXC chemokine ligand 12 (CXCL12) (r=0.386, P<0.001) and CXC-chemokine receptor 4 (CXCR4) (r=0.492, P<0.001), and immunoinhibitors such as programmed cell death protein 1 (PDCD1) (r=0.359, P<0.001), cytotoxic T-lymphocyte associated antigen 4 (CTLA4) (r=0.375, P<0.001) and T cell immunoglobulin and ITIM domains (TIGIT) (r=0.305, P<0.001) in LUSC. The immunological and prognostic gene PKIG in lung squamous cell carcinoma was screened through bioinformatics analysis. PKIG is highly correlated with LUSC prognosis and immune microenvironment, and is expected to be a potential biomolecular marker for LUSC immunotherapy.

Two venom serpins from the parasitoid wasp Microplitis mediator inhibit the host prophenoloxidase activation and antimicrobial peptide synthesis

Endoparasitoid wasps inject venom proteins into the hemocoel of host insects to ensure survival, growth, and development of their progenies by blocking host immunity. We previously identified ten serine protease inhibitors of the serpin superfamily in venom of the endoparasitoid wasp, Microplitis mediator, but it is unclear how these inhibitors may interact with host immune serine proteases. In this study, we investigated the functions of two serpins, MmvSPN-1 and MmvSPN-2, in the regulation of humoral immune responses in two hosts, the oriental armyworm Pseudaletia separate and the cotton bollworm Helicoverpa armigera, by dsRNA knockdown and biochemical assays using recombinant proteins. Knockdown of the two serpins resulted in increases in prophenoloxidase (PPO) activation and antimicrobial peptide (AMP) production in the hosts. After injection into the host hemocoel, the recombinant serpins inhibited PPO activation and AMP transcription. Mass spectrometry analysis of the pull-downs and in vitro reconstitution experiments revealed that HacSP29, a clip-domain serine protease in H. armigera, is the target of these two serpins. Therefore, these two inhibitors in the wasp venom may protect eggs from attacks by melanization and AMPs in the host insects.

A novel N7‐methylguanosine‐related long noncoding RNAs signature for predicting prognosis and immune microenvironment in gastric cancer patients

AbstractLong noncoding RNA (lncRNA) may act as a biomarker to predict the overall survival (OS) of cancer patients. This study is to explore the prognostic signature of gastric cancer based on N7‐methylguanosine‐related lncRNAs to evaluate the prognosis and immune status of patients. The lncRNAs were identified by co‐expression analysis, univariate and, stepwise multivariate Cox regression. Then, patients were divided into the high‐ and low‐risk groups. Time‐dependent receiver operating characteristics, log‐rank test, principal component analysis, and nomogram were used to analyze the risk model. Finally, different immune status between the two groups was revealed by gene set enrichment/variation analysis (GSEA/GSVA), CIBERSORTx, and ESTIMATE algorithm. The difference in tumor mutation burden and drug sensitivity between the two groups was also explored. Three lncRNAs (LINC00412, REPIN1‐AS1, and RPH3AL‐AS1) were employed to construct the prognostic model. The OS rate of the high‐risk group was lower than the low‐risk group. GSEA and GSVA indicated this model was associated with immune‐related function, such as negative regulation of humoral immune response. Furthermore, the relative fractions of regulatory T cells, activated NK cells, and so forth, were significantly higher in the high‐risk group. And ESTIMATE revealed the different immune scores between the two groups. Finally, six compounds were screened out as candidate therapy drugs, and the prognostic model revealed higher performance than TP53 mutation status. The prognostic signature was competent in predicting the prognosis of gastric cancer and the immune microenvironment, which could guide individualized treatment for gastric cancer in the clinic.

The impact of tertiary lymphoid structures on clinicopathological, genetic and gene expression characteristics in lung adenocarcinoma

IntroductionTertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS. MethodsA total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed. ResultsAmong the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS−) (hazard ratio [HR], 0.47; 95 % confidence interval [CI]: 0.23–0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18–0.72, p < 0.01). PD-L1 expression was not significantly different between TLS+ and TLS− patients (p = 0.54). TMB in TLS+ was similar to that in TLS− patients (p = 0.39); however, it tended to be lower than that in TLS− especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+. ConclusionsTLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses.

Proteomic and Morphological Profiling of Mice Ocular Tissue During High-altitude Acclimatization Process: An Animal Study at Lhasa.

PurposeHigh-altitude environment mainly with hypobaric hypoxia could induce pathological alterations in ocular tissue. Previous studies have mostly focused on sporadic case reports and simulated high-altitude hypoxia experiments. This aim of this study was to explore the proteomic and morphological changes of ocular tissue in mice at real altitude environment.MethodsIn this study, mice were flown from Chengdu (elevation: 500 m) to Lhasa (elevation: 3600 m). After exposure for 1day, 3, 6, 10, 20, 30, and 40days, the mice were euthanatized to obtain blood and ocular tissue. Serological tests, ocular pathological examinations, integral ocular proteomics analysis, and Western blot were conducted.ResultsWe focused on acute phase (1–3 days) and chronic phase (>30 days) during high-altitude acclimatization. Serum interleukin-1 was increased at 3 days, while superoxide dismutase, interleukin-6, and tumor necrosis factor-α showed no statistical changes. H&E staining demonstrated that the cornea was edematous at 3 days and exhibited slower proliferation at 30 days. The choroid showed a consistently significant thickening, while there existed no noticeable changes in retinal thickness. Overall, 4073 proteins were identified, among which 71 and 119 proteins were detected to have significant difference at 3 days and 40 days when compared with the control group. Functional enrichment analysis found the differentiated proteins at 3 days exposure functionally related with response to radiation, dephosphorylation, negative regulation of cell adhesion, and erythrocyte homeostasis. Moreover, the differential profiles of the proteins at 40 days exposure exhibited changes of regulation of complement activation, regulation of protein activation cascade, regulation of humoral immune response, second-messenger-mediated signaling, regulation of leukocyte activation, and cellular iron homeostasis. Interestingly, we found the ocular proteins with lactylation modification were increased along high-altitude adaptation.ConclusionThis is the first work reporting the ocular proteomic and morphological changes at real high-altitude environment. We expect it would deep the understanding of ocular response during altitude acclimatization.

Transcriptome profiles of red swamp crayfish Procambarus clarkii hematopoietic tissue in response to WSSV challenge

The crayfish Procambarus clarkii could achieve a high cumulative mortality after WSSV infections. To better understand the immune response to WSSV in hematopoietic tissue, the present study investigated the immunological response of P. clarkii and analyzed the expression of some hematopoietic cytokines. After assembly, there was an average of 47,712,411 clean reads were obtained in control and treatment groups. A total of 35,945 unigenes were discovered with N50 length of 1554 bp. Under functional classification, enrichment, and pathway analysis using different database, there were about 257 differentially expressed genes (DEGs) identified, of which 139 were up-regulated and 118 were down-regulated. The GO function analysis of these DEGs were mostly participated in activation of immune response, complement activation, complement binding, negative regulation of humoral immune response and secretory granule membrane. Under KEGG analysis, these DEGs were involved in ECM-receptor interaction, HIF-1 signaling pathway, Glycolysis/Gluconeogenesis, Thyroid hormone signaling pathway and Glucagon signaling pathway. The real-time quantitative PCR (RT-qPCR) analysis of 9 selected genes confirmed the reliability of RNA-Seq results. The present research provide for the first time the transcriptomic profile of P. clarkii hematopoietic tissue in response to WSSV infection and reveals the astakines may play important roles in antiviral immune response. The results of the present study will further enrich the theoretical basis of the crayfish immune system and provide new ideas for disease prevention and control.

Identifying a Ferroptosis-Related Gene Signature for Predicting Biochemical Recurrence of Prostate Cancer.

Ferroptosis induced by lipid peroxidation is closely related to cancer biology. Prostate cancer (PCa) is not only a malignant tumor but also a lipid metabolic disease. Previous studies have identified ferroptosis as an important pathophysiological pathway in PCa development and treatment, but its role in the prognosis of PCa is less well known. In this study, we constructed a nine-ferroptosis-related gene risk model that demonstrated strong prognostic and therapeutic predictive power. The higher risk score calculated by the model was significantly associated with a higher ferroptosis potential index, higher Ki67 expression, higher immune infiltration, higher probability of biochemical recurrence, worse clinicopathological characteristics, and worse response to chemotherapy and antiandrogen therapy in PCa. The mechanisms identified by the gene set enrichment analysis suggested that this signature can accurately distinguish high- and low-risk populations, which is possibly closely related to variations in steroid hormone secretion, regulation of endocrine processes, positive regulation of humoral immune response, and androgen response. Results of this study were confirmed in two independent PCa cohorts, namely, The Cancer Genome Atlas cohort and the MSK-IMPACT Clinical Sequencing Cohort, which contributed to the body of scientific evidence for the prediction of biochemical recurrence in patients with PCa. In addition, as the main components of this signature, the effects of the AIFM2 and NFS1 genes on ferroptosis were evaluated and verified by in vivo and in vitro experiments, respectively. The above findings provided new insights and presented potential clinical applications of ferroptosis in PCa.

Copy number variation in triple negative breast cancer samples associated with lymph node metastasis

Triple negative breast cancer (TNBC) is a highly metastatic and aggressive subtype of breast cancer and cases presenting with lymph node involvement have worse outcomes. This study aimed to determine the regions of copy number variation (CNV) associated with lymph node metastasis in TNBC patients. CNV analyses were performed in a study cohort of 23 invasive ductal carcinomas (IDCs), 12 lymph node metastases (LNmets), and 7 normal adjacent tissues (NATs); as well as in an independent cohort containing 70 TNBC IDCs and the same 7 NATs. CNV-associated genes were analyzed using GO-enrichment and Pathway analysis. The prognostic role for genes showing CNV-based changes in messenger RNA expression was determined using the Kaplan-Meier plotter database. For the IDCs, there were a number of variations that were common in both the study and independent cohorts in the amplified regions of 1q, 8q, 19 (p and q), 2p, 5p and the deleted regions in 8p followed by 5q, and 19p. The most frequently amplified regions in the LNmets of the study cohort were 4q28.3, 2p, 3q24, 1q21.2, 10p, 12p11.1, 8q, 20p11.22-20p11.21, 21q22.13, 6p22.1 and the most frequently deleted regions were in 1p36.23, 4q21.1 and 5q. A total of 686 (441 amplified and 245 deleted) genes were associated with LNmets. The LNmet-associated genes were highly enriched for “regulation of complement activation,” “regulation of protein activation cascade,” “regulation of humoral immune response,” “oxytocin signalling pathway,” and “TRAIL binding” pathways. Moreover, 6/686 LNmet-associated genes showed CNV-based changes in their mRNA expression of which, high expression of ASPM and KIF14 was significantly associated with worse relapse-free survival. This study has identified several CNV regions in TNBC that could play a major role in metastasis to the lymph node.

Regulation of humoral immune response by HIF-1α-dependent metabolic reprogramming of the germinal center reaction

Hypoxia-inducible factor-1α (HIF-1α) has been implicated in the regulation of many genes responsible for aerobic glycolysis; however, the role of HIF-1α in B-cell metabolism has not been well defined. Here, we analyzed patterns of gene expression and oxygen consumption rates in B-cell subpopulations from humans and mice and described a model of HIF-1α-mediated B-cell metabolic reprogramming during the germinal center (GC) reaction. Importantly, we found that HIF-1α was highly expressed in GC B-cells, and HIF-1α deficiency in B-cells impaired a functional GC reaction, resulting in defective class-switch recombination and generation of high-affinity plasma cells. These results identified an important role of HIF-1α in regulating humoral immunity through metabolic reprogramming during the GC response. This newly discovered metabolic character of GC B-cells will advance our understanding of GC biology and B-cell lymphomagenesis.

CC chemokine receptor 6 (CCR6) in the pathogenesis of systemic lupus erythematosus.

The CC chemokine receptor 6 (CCR6) and its sole chemokine ligand, CCL20, are an intriguing pair that have been implicated in a growing number of inflammatory, autoimmune and malignant disease processes. Recent observations have also highlighted this chemokine axis in the regulation of humoral immune responses. Through this review article, we explore the emerging links of CCR6-CCL20 with an archetypal autoimmune disease of humoral dysregulation: systemic lupus erythematosus (SLE). CCR6 is expressed prominently on several immune cells involved in the pathogenesis of SLE, such as dendritic cells and T-helper 17 cells. CCR6's expression is correlated with disease activity and serological markers of disease severity, suggesting a possible role in disease pathogenesis. However, there are numerous holes in our understanding of the functions of CCR6 and CCL20, and future studies are required to determine if there are any diagnostic, prognostic or monitoring roles for these important molecules.

Plasma proteomic profiling and pathway analysis of normal and overconditioned dairy cows during the transition from late pregnancy to early lactation

This study applied a quantitative proteomics approach along with bioinformatics analyses to investigate changes in the plasma proteome of normal and overconditioned dairy cows during the transition period. Fifteen weeks before their anticipated calving date, 38 multiparous Holstein cows were selected based on their current and previous body condition scores (BCS) and allocated to either a high or a normal BCS group (19 cows each). They received different diets until dry-off to reach targeted differences in BCS and back fat thickness (BFT) until dry-off. At dry-off, normal BCS cows had a BCS <3.5 (minimum, 2.75) and BFT <1.2 cm (minimum, 0.58), and the high BCS cows had a BCS >3.75 (maximum, 4.50) and BFT >1.4 cm (maximum, 2.90). The proteomics study used a subset of 5 animals from each group. These cows were selected based on their circulating concentrations of fatty acids (FA) on d 14 postpartum and β-hydroxybutyrate (BHB) on d 21 postpartum, representing the greater or the lower extreme values within their BCS group, respectively. The high BCS subset (HE-HBCS) had 4.50 < BCS > 3.75, FA = 1.17 ± 0.46 mmol/L, and BHB = 2.15 ± 0.42 mmol/L (means ± SD), and the low BCS subset (LE-NBCS) had 3.50 < BCS > 2.75, FA = 0.51 ± 0.28 mmol/L, and BHB = 0.84 ± 0.17 mmol/L. Plasma samples from d -49, +7, and +21 relative to parturition were used for proteome profiling by applying the quantitative tandem mass tags (TMT) approach. Nondepleted plasma samples were subjected to reduction and digestion and then labeled with TMT 10plex reagents. High-resolution liquid chromatography-tandem mass spectrometry analysis of TMT-labeled peptides was carried out, and the acquired spectra were analyzed for protein identification and quantification. In total, 254 quantifiable proteins (criteria: 2 unique peptides and 5% false discovery rate) were identified in the plasma samples. From these, 24 differentially abundant proteins (14 more abundant, 10 less abundant) were observed in the LE-NBCS cows compared with the HE-HBCS cows during the transition period. Plasma α-2-macroglobulins were more abundant in HE-HBCS versus LE-NBCS cows at d +7 and +21. Gene Ontology enrichment analyses of differentially abundant proteins revealed that the acute inflammatory response, regulation of complement activation, protein activation cascade, and regulation of humoral immune response were the most enriched terms in the LE-NBCS group compared with the HE-HBCS group. In addition, we identified 24 differentially abundant proteins (16 in the LE-NBCS group, and 8 in the HE-HBCS group) during the transition period. The complement components C1q and C5 were less abundant, while C3 and C3d were more abundant in LE-NBCS compared with HE-HBCS cows. Overall, overconditioning around calving was associated with alterations in protein pathways related to acute inflammatory response and regulation of complement and coagulation cascades in transition cows.

Regulation of Humoral Immune Responses and B Cell Tolerance by the IgM Fc Receptor (FcμR).

Immunoglobulin (Ig) M is the first antibody isotype produced during an immune response and is critical for host defense against infections. Recent studies have revealed that IgM also plays an important role in immune regulation and immunological tolerance. Mice lacking secretory IgM not only exhibit impaired production of antigen-specific IgG and are more susceptible to bacterial and viral infections, but also produce autoantibodies and are prone to develop autoimmune diseases. For many years, IgM has been thought to function predominantly by binding to antigen and activating complement (C') system. It is now clear that IgM can also elicit its function through the IgM Fc receptor (FcμR). In this chapter, we will review the role of FcμR in B cell development, maturation, survival and activation, antibody production, host defense against bacterial and viral infections, and B cell tolerance. We will also discuss the relative contribution of IgM-C' and IgM-FcμR pathways in humoral immune responses. Finally, we will discuss the possible involvement of FcμR in human chronic lymphocytic leukemia.

Computational Network Analysis Identifies Evolutionarily Conserved miRNA Gene Interactions Potentially Regulating Immune Response in Bovine Trypanosomosis.

Bovine trypanosomosis is a devastating disease that causes huge economic loss to the global cattle industry on a yearly basis. Selection of accurate biomarkers are important in early disease diagnosis and treatment. Of late, micro-RNAs (miRNAs) are becoming the most useful biomarkers for both infectious and non-infectious diseases in humans, but this is not the case in animals. miRNAs are non-coding RNAs that regulate gene expression through binding to the 3′-, 5′-untranslated regions (UTR) or coding sequence (CDS) region of one or more target genes. The molecular identification of miRNAs that regulates the expression of immune genes responding to bovine trypanosomosis is poorly defined, as is the possibility that these miRNAs could serve as potential biomarkers for disease diagnosis and treatment currently unknown. To this end, we utilized in silico tools to elucidate conserved miRNAs regulating immune response genes during infection, in addition to cataloging significant genes. Based on the p value of 1.77E-32, we selected 25 significantly expressed immune genes. Using prediction analysis, we identified a total of 4,251 bovine miRNAs targeting these selected genes across the 3′UTR, 5′UTR and CDS regions. Thereafter, we identified candidate miRNAs based on the number of gene targets and their abundance at the three regions. In all, we found the top 13 miRNAs that are significantly conserved targeting 7 innate immune response genes, including bta-mir-2460, bta-mir-193a, bta-mir-2316, and bta-mir-2456. Our gene ontology analysis suggests that these miRNAs are involved in gene silencing, cellular protein modification process, RNA-induced silencing complex, regulation of humoral immune response mediated by circulating immunoglobulin and negative regulation of chronic inflammatory response, among others. In conclusion, this study identifies specific miRNAs that may be involved in the regulation of gene expression during bovine trypanosomosis. These miRNAs have the potential to be used as biomarkers in the animal and veterinary research community to facilitate the development of tools for early disease diagnosis/detection, drug targeting, and the rational design of drugs to facilitate disease treatment.

FCGR3A and FCGR2A Genotypes Differentially Impact Allograft Rejection and Patients' Survival After Lung Transplant.

Fc gamma receptors (FcγRs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 FcγRs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTRs and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p < 0.0001, 95% CI 2.37–9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR's DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p = 0.024, 95% CI 1.08–3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.

Chemotherapy Alters the Phylogenetic Molecular Ecological Networks of Intestinal Microbial Communities.

Intestinal microbiota is now widely known to play key roles in nutritional uptake, metabolism, and regulation of human immune responses. There are multiple studies assessing intestinal microbiota changes in response to chemotherapy. In this study, microbial phylogenetic molecular ecological networks (pMENs) were firstly used to study the effects of chemotherapy on the intestinal microbiota of colorectal cancer (CRC) patients. Based on the random network model, we demonstrated that overall network structures and properties were significantly changed by chemotherapy, especially in average path length, average clustering coefficient, average harmonic geodesic distance and modularity (P < 0.05). The taxa in the module tended to co-exclude rather than co-occur in CRC patient networks, indicating probably competition relationships. The co-exclude correlations were decreased by 37.3% from T0 to T5 in response to chemotherapy. Significantly negative correlations were observed in positive/negative OTU degree and tumor markers (P < 0.05). Furthermore, the topological roles of the OTUs (module hubs and connectors) were changed with the chemotherapy. For example, the OTU167, OTU8, and OTU9 from the genera Fusobacterium, Bacteroides, and Faecalibacterium, respectively, were identified as keystone taxa, which were defined as either “hubs” or OTUs with highest connectivity in the network. These OTUs were significantly correlated with tumor markers (P < 0.05), suggesting that they probably were influenced by chemotherapy. The pMENs constructed in this study predicted the potential effects of chemotherapy on intestinal microbial community co-occurrence interactions. The changes may have an effect on the therapeutic effects. However, larger clinical samples are required to identify the conclusion.

Effect of Oleanolic Acid on Inflammatory Cytokines on Rats Fed with High Fructose Diet &amp; Metformin.

Inflammatory cytokines are signaling molecules that play a crucial role in regulation of human immune response. Current research has demonstrated that inflammatory processes also play a significant role in the etiology of type‐2 diabetes (T2D) and obesity. High levels of circulating inflammatory concentration of cytokines have been linked to insulin resistance, the hallmark of T2D. In this study we have assessed the effect of oleanolic acid on some inflammatory cytokine biomarkers (TNF‐α, IL‐6, IL‐10, MCP‐1 and VEGF). Oleanolic acid is a plant derived compound that has shown some promising therapeutic effects on insulin resistance and T2D.In this study, Sprague Dawley rats were fed with high fructose diet (HFD) and also metformin. Analysis of inflammatory cytokines concentration in blood plasma was done using Bio‐Plex Pro magnetic bead‐based assay. Results showed that all five cytokines were decreased when OA was used and also increased when HFD was used. Similar pattern when gene expression was studied was also observed.These results clearly indicate that OA influences their concentration and also their gene expression. On the contrary HFD, showed the opposite by increasing both the concentration as well as the gene expression of these cytokines.In conclusion these study further suggests that OA plays a key role on inflammatory cytokine regulation and it can be used as an effective therapeutic agent to ameliorate insulin resistance and T2D.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Possible involvement of chemokine C-C receptor 7- programmed cell death-1+ follicular helper T-cell subset in the pathogenesis of autoimmune hepatitis.

Recent studies have demonstrated that B cells and follicular helper T (Tfh) cells, which are central regulators of humoral immune response, contribute to the development and progression of autoimmune diseases. Because Tfh cells can be divided into several subsets with distinct functional properties, this study aimed to examine the roles of different subsets of circulating Tfh cells in the immune pathogenesis of autoimmune hepatitis (AIH). Thirty-five patients with AIH, 28 patients with primary biliary cholangitis, 22 patients with chronic hepatitis B (CHB), and 44 health controls (HC) were enrolled. The frequencies of different Tfh subsets in the blood and liver were examined by flow cytometry and immunohistochemical staining. The function of circulating Tfh subsets was examined after in vitro stimulation. In newly diagnosed AIH patients, the frequency of circulating chemokine C-C receptor 7- programmed cell death-1+ Tfh subset was significantly increased compared with that in CHB patients and HC, significantly correlated with clinical parameters, including serum IgG, prothrombin time and albumin levels, and significantly decreased after corticosteroid treatment. In the liver of AIH patients, the frequencies of activated Tfh subsets were significantly increased and positively correlated with those in the blood. Moreover, the ability to produce interleukin-21 and interleukin-17 from circulating Tfh cells was significantly increased in AIH patients compared with HC. These results significantly extend our understanding of Tfh subsets in AIH and suggest a potential role of dysregulated chemokine C-C receptor 7- programmed cell death-1+ Tfh subset in the pathogenesis and disease progression of AIH.

The Transcription Factor c-Maf Promotes the Differentiation of Follicular Helper T Cells.

Follicular helper T cells (Tfh) have been identified as the primary cell subpopulation regulating B cell responses in germinal centers, thus supporting high-affinity antibody production. Among the transcription factors orchestrating Tfh cell differentiation and function, the role played by the proto-oncogene c-Maf remains poorly characterized. We report herein that selective loss of c-Maf expression in the T cell compartment results in defective development of Tfh cells in response to both antigen/adjuvant vaccinations and commensal intestinal bacteria. Accordingly, c-Maf expression in T cells was essential for the development and high-affinity antibody secretion in vaccinated animals. c-Maf was expressed early, concomitantly to BCL6, in Tfh cell precursors and found to regulate Tfh fate in a cell-autonomous fashion. Altogether, our findings reveal a novel, non-redundant, function for c-Maf in the differentiation of Tfh cells and the regulation of humoral immune responses to T-cell-dependent antigens.