BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear.
METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes.
RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer.
CONCLUSIONS: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.

In humans, loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3) gene is frequently associated with susceptibility to bacterial as well as fungal infections including aspergillosis, although its pathogenesis remains largely unknown. In the present study, we investigated the immune responses obtained after stimulation with Aspergillus fumigatus in STAT3-deficient patients. A. fumigatus conidial killing efficiencies of both monocytes and neutrophils isolated from whole blood samples of STAT3-deficient patients were not different compared to those of healthy controls. After stimulation with A. fumigatus conidia, lower concentrations of adaptive cytokines (IFN-γ, IL-17 and IL-22) were secreted by peripheral blood mononuclear cells from STAT3-deficient patients compared to those from healthy controls. Moreover, the frequency of IFN-γ and IL-17 producing CD4+ T cells was lower in STAT3-deficient patients vs. healthy controls. Among the STAT3-deficient patients, those with aspergillosis showed further lower secretion of IFN-γ upon stimulation of their PBMCs with A. fumigatus conidia compared to the patients without aspergillosis. Together, our study indicated that STAT3-deficiency leads to a defective adaptive immune response against A. fumigatus infection, particularly with a lower IFN-γ and IL-17 responses in those with aspergillosis, suggesting potential therapeutic benefit of recombinant IFN-γ in STAT3-deficient patients with aspergillosis.

Influenza virus M2 protein has a highly conserved ectodomain (M2e) as a cross-protective antigenic target. We investigated the antigenic and immunogenic properties of tandem repeat M2e (5xM2e) proteins and virus-like particles (5xM2e VLP) to better understand how VLP and protein platform vaccines induce innate and protective adaptive immune responses. Despite the high antigenic properties of 5xM2e proteins, the 5xM2e VLP was superior to 5xM2e proteins in inducing IgG2a isotype antibodies, T cell responses, plasma cells and germinal center B cells as well as in conferring cross protection. Mice primed with 5xM2e VLP were found to be highly responsive to 5xM2e protein boost, overcoming the low immunogenicity and protective efficacy of 5xM2e proteins. Immunogenic differences between VLPs and proteins in priming immune responses might be due to an intrinsic ability of 5xM2e VLP to stimulate dendritic cells secreting T helper type 1 (Th1) cytokines. We also found that 5xM2e VLP was effective in inducing inflammatory cytokines and chemokines, and in recruiting macrophages, monocytes, neutrophils, and CD11b⁺ dendritic cells at the injection site. Therefore, this study provides evidence that 5xM2e VLP is an effective vaccine platform, inducing cross-protection by stimulating innate and adaptive immune responses.

The aim of this study was to assess modulatory effects of dietary supplements mannan oligosaccharide (MOS) and clinoptilolite (CPL) as potential alternatives to antibiotic growth promoters (AGP) given to 4-week old pigs at weaning (Day 0) on their innate/adaptive immunity by determining: alterations in C-reactive protein (CRP) and haptoglobin (HpG) serum levels, efficiency of blood monocytes (MO) and neutrophilic granulocytes (GR) for in vitro phagocytosis (PHC)/microbicidity (MBC) and proportion of extrathymic double positive CD4 CD8 (CD4+CD8+) T cells throughout 35 days of the study. Neither MOS nor CPL changed the serum concentrations of CRP, whereas that of HpG was significantly increased in the CPL supplemented pigs (p<0.05) at Day 35. Activity of PHA of GR was significantly increased by both dietary supplements (p<0.05) from Day 7 to Day 35. Also, the GR from pigs fed with both supplements had significantly increased MBC at Day 7 (p<0.05), but at Day 35 such an increase was observed only for CPL. The in vitro PHC/MBC of MO did not change in either group of supplemented pigs. The pigs supplemented with MOS had a significantly higher proportion of CD4+CD8+ T lymphocytes at Day 28 (p<0.05). Although both supplements showed a promising ability to stimulate rather innate than adaptive cellular immunity, it does not appear that any solely applied natural substance such as MOS or CPL in the current study could be a competitive alternative to conventional AGP for improving health and promoting growth in weaned pigs.

HIV-1 infection results in long-lasting activation of the immune system including elevated production of pro-inflammatory cytokine/chemokines, and bacterial product release from gut into blood and tissue compartments, which are not fully restored by antiretroviral therapies. HIV-1 has also developed numerous strategies via viral regulatory proteins to hijack cell molecular mechanisms to enhance its own replication and dissemination. Here, we reviewed the relationship between viral proteins, immune activation/inflammation, and deregulated metabolism occurring in HIV-1-infected patients that ultimately dampens the protective innate and adaptive arms of immunity. Defining precisely the molecular mechanisms related to deregulated immuno-metabolism during HIV-1 infection could ultimately help in the development of novel clinical approaches to restore proper immune functions in these patients.

Non-celiac gluten sensitivity is an undefined syndrome with gastrointestinal and extra-intestinal manifestations triggered by gluten in patients without celiac disease and wheat allergy. The pathogenesis involves immune-mediated mechanisms requiring further research. Symptoms disappear in a few hours or days after gluten withdrawal and recur rapidly after gluten ingestion. Besides gluten, other wheat proteins as well as fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) may contribute to this syndrome. This syndrome occurs mainly in young women, being rare in children. Its prevalence ranges from 0.6% to 6%, based on primary or tertiary care center estimates. No biomarker is available, but half of patients tests positive for IgG anti-gliadin antibodies, which disappear quickly after gluten-free diet together with symptoms. Also, genetic markers are still undefined. Although currently limited to a research setting, double-blind, placebo-controlled, cross-over trial strategy is recommended to confirm the diagnosis. Treatment is based on dietary restriction with special care to nutrient intake.