Immune Response in H. pylori-Associated Gastritis and Gastric Cancer

Abstract

Helicobacter pylori (H. pylori) is the dominant member of the gastric microbiota and has infected more than half of the human population, of whom 5-15% develop gastric diseases ranging from gastritis and metaplasia to gastric cancer. These diseases always follow inflammation induced by cell surface and intracellular receptors and subsequent signaling, such as the NF-κB pathway and inflammasomes. Some types of immune cells are recruited to enforce an antibacterial response, which could be impeded by H. pylori virulence factors with or without a specific immune cell. Following decreased inflammation, neoplasm may appear with a little immune surveillance and may inhibit antitumor immunity. Therefore, the balance between H. pylori-associated inflammation and anti-inflammation is crucial for human health and remains to be determined. Here, we discuss multiple inflammation and immunoregulatory cells in gastritis and summarize the main immune evasion strategies employed by gastric cancer.

Figure 1

NF-κB signal activation and NLRP3 inflammasome active proinflammation factors. TLR recognition induces NF-κB signal activation in various pathways and then produces pro-IL-1 and pro-IL-18. NOD-2 and HK-1 receptor, impaired mitochondria, and lysosome could activate NLRP3 inflammasomes as well. Inflammasomes are capable of activating caspase-1 to cleave pro-IL-1 and pro-IL-18 into a mature molecule. Besides, gasdermin-D is assembled on the membrane to facilitate inflammation factor translocation and lead to an inflammatory cell death called pyroptosis. Abbreviations: TLR: toll-like receptors; NOD: nucleotide-binding oligomerization domain; NLRP3: NOD-, LRR-, and pyrin domain-containing 3; mTOR: mammalian target of rapamycin; HK1: hexokinase 1.

Figure 2

CTLA-4 inhibits T cell activation and function via CD80/CD86. In normal, CD28 combines with CD80/CD86 and delivers subsequent phosphorylation signals to maintain T cell survival. Binding of CTLA-4 to CD80/CD86 inhibits T cell activation via two various pathways. The one is CTLA-4 competition with CD28 which will block phosphorylation processes by PP2A, to disturb the normal T cell activation. Another one is that T cell motility can also be promoted and thus leads to a relative decrease in the contact time between T cells and APC and T cell activation. In addition, this signal causes some changes in APC and induces IDO. IDO has an effect on inhibiting immunity and facilitating metaplasia. Abbreviations: CD80/CD86: B7 family; CTLA-4: cytolytic T lymphocyte-associated antigen 4; LCK: lymphocyte-specific protein tyrosine kinase; ITAMs: immunotyrosine activation motifs; PP2A: protein phosphatase 2A; ZAP70: zeta-chain-associated protein of 70 kDa; IDO: indoleamine 2,3-dioxygenase.

Figure 3

Adenosine obstructs immunity by activating A2AR and migration. Hypoxia induces the release of ATP via ATP-binding cassette (ABC) transporters, pannexin 1 or connexins. Accumulated ATP has two destinations, one of which is to stimulate P2 purinergic receptors (P2XRs and P2YRs) and CD39. The other is that ATP can further be degraded to adenosine to stimulate some various signal pathways, including activation of CD73 and adenosine receptors. The former is capable of releasing MMPs to facilitate the breakdown of ECM and tumor cell migration. The latter activation promotes tumor cell proliferation and angiogenesis through the secretion of VEGF. Moreover, the exosome of some tumor coexpresses CD39 and CD73. Abbreviations: A2AR: a kind of adenosine receptors; MMPs: releasing matrix metalloproteinases; ECM: extracellular matrix; VEGF: vascular endothelial growth factor.