**6. Mechanism of immune evasion of** *H. pylori*

The outer membrane proteins in *H. pylori* are found to be less immunogenic compared to proteins from other pathogens; therefore, the immune response elicited by the innate immune system is less powerful [7, 9]. It is known that *H. pylori*'s lipopolysaccharide has a 500- to 1000-fold lower endotoxic activity than lipopolysaccharide from S. typhimurium and *E. coli* [3]. The presence of arginase enzyme coded by rocF gene in *H. pylori* may decrease L-arginine, the substrate for NO, level. Decreased NO level will impair phagocytosis by macrophage and prevent *H. pylori* elimination. Additionally, this will promote the apoptosis of macrophages [1–3, 6, 7, 20]. *H. pylori* are also capable of producing urea from L-arginine and further ammonia from urea. The process is mediated by the urease enzyme and α-carbonic anhydrase. Ammonia is known for its ability to neutralize gastric HCl and sustain the survival of *H. pylori* [1, 5, 6, 20]. Glucosylation of cholesterol also aids *H. pylori's* survival. This process protects the microorganism from macrophage phagocytosis [5, 6]. *H. pylori* may also evade innate immune recognition by avoiding PRR, a subset of pathogen-associated molecular patterns. It modulates its surface molecules including lipopolysaccharide and flagellin to avoid recognition by toll-like receptors on antigen-presenting cells. The molecules are recognized as self molecules and thus do not trigger the immune response [2, 3, 5]. Even after being phagocytized, *H. pylori* may survive from killing by the aid of cag PAI and VacA. Both delay actin polymerization and phagosome formation inside macrophages [2].

Chronic exposure of dendritic cells to *H. pylori* decreases the ability of dendritic cells to induce Th1 response and support the persistence of infection [1–6]. The

malfunction of dendritic cells is due to *H. pylori*-controlled maturation. *H. pylori* restore transcription factor in dendritic cells and inhibit their maturation [2]. Lewis antigen form *H. pylori* may also bind dendritic cell-specific ICAM-3-grabbing nonitegrin (DC-SIGN) and blocked Th1 cell recruitment [4]. Examination of patients with chronic *H. pylori* infection also shows elevation of Treg cells in the gastric tissue compared to healthy subjects [2, 4–6, 20]. *H. pylori* are suggested to promote the expansion of the Treg population and their recruitment to the site of infection [4]. As we know that Treg suppresses the activity of memory T cells, it will relieve inflammation and gastritis severity [1, 2, 4, 6] but at the same time hamper the ability of the host to eliminate pathogens, including *H. pylori* [2, 4, 6, 20]. The condition is hypothesized from the increased level of TGF-β and IL-10 independent of VacA and cag PAI [2, 20]. *H. pylori* inhibits lymphocyte proliferation via IL-2 inhibitory effect from VacA and induction of cell cycle arrest from VacA-independent produced protein [1–6]. The process is made possible via an interference signaling pathway at the level of calciumcalmodulin-dependent phosphatase calcineurin [4]. Gamma-glutamyl transpeptidase (GGT) is another low-molecular-weight protein of *H. pylori* that is capable of inhibiting the proliferation of lymphocytes. The mechanism involves extracellular cleavage of glutathione and the production of reactive oxygen species. The depletion of L-arginine level due to arginase activity of *H. pylori* is also hampering lymphocyte T cell proliferation [4, 5]. Furthermore, VacA may induce T cell apoptosis by reducing Bcl-2, an anti-apoptotic protein [2, 5].

Studies from chronic gastritis found that *H. pylori* may induce autoimmunity which affects gastric parietal cells. Both cellular and humoral antigens damage the cell in patients with gastritis due to *H. pylori* infection [1, 3, 6, 11]. The origin of autoantibody is suspected from the presence of Lewis x and Lewis y antigens which are similar to the H<sup>+</sup> /K<sup>+</sup> -ATPase β subunit of parietal cells. Parietal cell loss occurs via IFNγ-mediated inflammation and Fas-mediated apoptosis or cytotoxicity [2, 3, 6, 7, 9, 11]. The presence of pro-inflammatory cytokines also inhibits acid secretion from parietal cells. IL-1β and TNFα are the most potent inhibitors [6]. The resulting hypochlorhydria situation allows *H. pylori* to persist and cause prolonged infection [3, 6]. In contrast, those pro-inflammatory cytokines stimulate gastrin secretion by disrupting the negative feedback signal of somatostatin [6].

Coinfection between *H. pylori* and parasitic helminths will cause an imbalance in Th1 and Th2 responses with predominantly Th2 activity [6, 9, 10]. This situation is clearly observed in the African population and referred to as 'African enigma'. 'African enigma' is marked by low gastric cancer despite a high prevalence of *H. pylori* in Africa. Lately, it is known that high rate of helminth coinfection is high in the corresponding population [10]. The variation in Lewis antigen also moderates Th1 response and favors Th2 activity [7]. This condition is supported by a study in mice infected with *H. pylori* showing dysfunctional Th1 response [4]. The imbalance will alleviate inflammation in gastritis but hamper Th1-mediated *H. pylori* elimination [2, 6, 7].

Host factor also contributes to immune response toward H. pylori infection. Host genetic polymorphisms affecting the IL-1 gene cluster elevate the level of IL-1 and lead to the reduction of gastric acid secretion. Low gastric acid secretion promotes infection and colonization of *H. pylori*. A similar situation is induced by a polymorphism in the TNF-α gene. In contrast with the IL-10 gene, the polymorphism causes higher expression of IL-10 and favors anti-inflammatory activity [9]. Defects in cytokine coding genes are involved in the persistence of *H. pylori* infection. Defects in gene coding IL-1 and TNF are associated with decreased cytokines production and *Immunology of* Helicobacter pylori *Infection DOI: http://dx.doi.org/10.5772/intechopen.104592*

increased risk for gastric cancer [7]. Single nucleotide polymorphism in gene coding IL-10 which resulted in increased IL-10 will promote Th2 activity and resulted in prolonged *H. pylori* infection and an elevated risk for recurrent gastric cancer [16]. The presence of *H. pylori* in the macrophages alters the expression of miRNA. The alteration in miRNA, particularly miR-4270 causes increased expression of CD300E, a surface protein on macrophages that affects the antigen presentation capacity of macrophages. Increased CD300E expression is negatively correlated with antigen presentation capacity [21]. Shakhatreh, et al conducted a study on the Jordanian population to determine the association between IL-1 gene polymorphism and *H. pylori* infection. -31T/C polymorphism was found significantly associated with *H. pylori* infection, particularly the TT genotype [22]. Those statements are reinforced by a meta-analysis by Ma et al. They focused on polymorphism in genes that code IL-1. Increased risk for *H. pylori* infection is observed in IL-1B-31C/T polymorphism with an odds ratio of 1.134. Furthermore, IL-1B-511C/T and IL-8-251A/T polymorphisms increase the risk for gastric cancer with odds ratios of 1.784 and 1.810, respectively [23]. Zeyaullah et al. also proposed the role of gene polymorphism in gastric cancer. IL-10-592A/C, IL-10-819T/C, and IL-17-197G/A are all found to be related to gastric cancer. Besides polymorphism in cytokine genes, toll-like receptor genes are also involved. TLR4+ 1196C/T polymorphism is one genetic rearrangement that increases the risk of gastric cancer in *H. pylori*-infected individuals [24].
