IRGM gene polymorphisms and risk of gastric cancer

OBJECTIVE: The study aimed to assess the possible association of polymorphisms in the autophagy gene IRGM (rs13361189 and rs4958847) with the risk of gastric cancer. METHODS: A total of 102 patients with gastric adenocarcinoma, 52 with chronic gastritis and 351 healthy controls were included in this study. IRGM allelic variants were genotyped by quantitative real‐time polymerase chain reaction. The association between polymorphisms and gastric cancer risk was estimated by odds ratios (OR) and 95% confidence interval (CI). RESULTS: A significant difference was found for rs4958847 A allele. Carriers of the A allele were protected against gastric cancer (OR = 0.58, 95% CI 0.35–0.97, P = 0.038). Moreover, the presence of this allele seems to play an important role in decreasing the risk for the intestinal type of gastric cancer (OR = 0.47, 95% CI 0.23–0.94, P = 0.03). In contrast, the rs13361189 IRGM polymorphism was not associated with susceptibility to gastric cancer. None of the targeted polymorphisms were associated with chronic gastritis. CONCLUSION: IRGM rs4958847 polymorphism influences susceptibility to gastric cancer, mainly for the intestinal type.     

The interleukin‐1 receptor antagonist anakinra improves first‐phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance

Inflammation at the level of the β cell appears to be involved in progressive β‐cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin‐1 (IL‐1) by anakinra [recombinant human interleukin‐1 receptor antagonist (IL‐1Ra)] on β‐cell function. Sixteen participants with impaired glucose tolerance were treated with 150 mg anakinra daily for 4 weeks in a double blind, randomized, placebo‐controlled cross‐over study with a wash‐out period of 4 weeks. At the end of each treatment period, oral glucose tolerance tests (OGTTs) and hyperglycaemic clamps were performed. First‐phase insulin secretion improved after anakinra treatment compared with placebo, 148 ± 20 versus 123 ± 14 mU/l, respectively (p = 0.03), and the insulinogenic index was higher after anakinra treatment. These results support the concept of involvement of IL‐1β in the (progressive) decrease of insulin secretion capacity associated with type 2 diabetes.     

Human TLR10 is an anti-inflammatory pattern-recognition receptor

Toll-like receptor (TLR)10 is the only pattern-recognition receptor without known ligand specificity and biological function. We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects. Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1β, specifically after exposure to TLR2 ligands. Blocking TLR10 after stimulation of peripheral blood mononuclear cells with pam3CSK4 (Pam3Cys) led to production of 2,065 ± 106 pg/mL IL-1β (mean ± SEM) in comparison with 1,043 ± 51 pg/mL IL-1β after addition of nonspecific IgG antibodies. Several mechanisms mediate the modulatory effects of TLR10: on the one hand, cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2; on the other hand, cross-linking experiments showed specific induction of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra, 16 ± 1.7 ng/mL, mean ± SEM). After cross-linking anti-TLR10 antibody, no production of IL-1β and other proinflammatory cytokines could be found. Furthermore, individuals bearing TLR10 polymorphisms displayed an increased capacity to produce IL-1β, TNF-α, and IL-6 upon ligation of TLR2, in a gene-dose–dependent manner. The modulatory effects of TLR10 are complex, involving at least several mechanisms: there is competition for ligands or for the formation of heterodimer receptors with TLR2, as well as PI3K/Akt-mediated induction of the anti-inflammatory cytokine IL-1Ra. Finally, transgenic mice expressing human TLR10 produced fewer cytokines when challenged with a TLR2 agonist. In conclusion, to our knowledge we demonstrate for the first time that TLR10 is a modulatory pattern-recognition receptor with mainly inhibitory properties.Highly conserved molecular structures of invading microorganisms are recognized by immune cells through pattern-recognition receptors, of which Toll-like receptors (TLRs) are the most documented family. In humans, 10 members of the TLR family have been described (1). In general, specific ligation of TLRs leads to induction of proinflammatory mediators, such as cytokines and chemokines. One member of the TLR family however, TLR10, is considered an orphan receptor because of its still-unknown ligands and function.Human TLR10 is encoded on chromosome 4 within the TLR2 gene cluster, together with TLR1, TLR2, and TLR6, and shares all structural characteristics of the TLR family (2, 3). However, TLR10 differs from other TLRs by its lack of a classic downstream signaling pathway (4), despite its interaction with the myeloid differentiation primary response gene 88 adaptor protein (3). TLR10 is predominantly expressed in tissues rich in immune cells, such as spleen, lymph node, thymus, tonsil, and lung (2). Expression of TLR10 can be induced in B cells, dendritic cells, eosinophils, and neutrophils (3, 5, 6), as well as on nonimmune cells, such as trophoblasts (7). TLR1 and TLR6 are known to form heterodimers with TLR2, and this was shown for TLR10 as well (3, 8). It is therefore rational to hypothesize that if TLR10 has a biological function, which it exerts through the formation of heterodimers with TLR2. In the present study we report the surprising modulatory function of human TLR10 on TLR2-driven cytokine production exerted through competition for ligands, on the one hand, and specific induction of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra), on the other hand. In addition, we demonstrated that hTLR10 transgenic mice produced fewer cytokines in vivo when exposed to a potent TLR2 ligand.     

From the Cover: Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes

Adaptive features of innate immunity, recently described as “trained immunity,” have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte–independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.     

Chronic yersiniosis due to defects in the TLR5 and NOD2 recognition pathways

Infection with Yersinia enterocolitica leads to a self-limiting disease, but in a small number of cases a protracted course can develop. The host genetic factors contributing to the advancement of the disease to the chronic phase are not known. We describe a patient suffering from an abdominal inflammatory mass due to chronic yersiniosis. Functional assays revealed defects in the recognition of flagellin by Toll-like receptor 5 (TLR5) and of muramyl dipeptide by NOD2, leading to a defective inflammatory response to Yersinia enterocolitica. Genetic sequencing showed that the patient was compound heterozygous for five different mutations in TLR5, while being homozygous for the 3020insC NOD2 mutation. In conclusion, we describe a patient in whom specific defects in the TLR5 and NOD2 recognition pathways led to chronic yersiniosis.