**5. Immune response toward** *H. pylori* **infection**

Many diseases, including infection due to *H. pylori*, involve dysregulation of the immune system. Infection is both active, marked by neutrophilic accumulation, and chronic, marked by lymphocytic deposition [1, 5, 6, 9]. These findings are positive 2 weeks after infection. Anti-*H. pylori* antibodies are also detected at 4 weeks after initial infection, marked by the high levels of immunoglobulin (Ig) M, IgG, and IgA in gastric mucosa of infected patients [1, 3, 11]. A study in mice demonstrated that transient infiltration of macrophages and neutrophils into the glandular stomach is observed in the first 2 days after infection. By day 10 after infection, the numbers of macrophages and neutrophils are decreased to baseline levels. The adaptive immune response is started to appear in the 3rd week, marked by infiltration of T lymphocytes in paragastric lymph nodes and elevated expression of TNFα and IFNγ [19]. The levels of IgM and IgA anti-*H. pylori* in biopsy specimens from the gastric antral region of patients infected with *H. pylori* are 40- to 50-fold higher compared to non-infected subjects [3]. However, the presence of *H. pylori* in the stomach for a long period of time supports the suspected ineffective immune response [2, 6, 9]. The presence of this microorganism causes a persistent and chronic infection [9]. Chronic infection leads to chronic inflammation, gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and ultimately, gastric cancer [1, 6].

*H. pylori* infection activates innate and adaptive immunity, along with humoral and cellular immunity as the parts of the adaptive immune system. There are cytotoxin-associated gene pathogenicity islands (cag PAI) and vacuolating toxin A (VacA) which act as major virulence factors in *H. pylori* infection. Cag PAI encodes a type IV bacterial secretion system that injects bacterial products into gastric epithelial cells resulting in inflammation and increased risk of malignancy [1, 6, 7, 9]. Cag PAI is a protein with a molecular mass of 140 kDa. It is highly immunogenic and present in approximately 50–70% of *H. pylori* strains [9]. VacA, on the other hand, is associated with cellular damage and inflammation [6]. VacA is a protein-sized 95 kDa and secreted from approximately 50% of all *H. pylori* strains. It damages cells by inducing massive vacuolization. The process ends with apoptosis and immune modulation [9]. *H. pylori* enters the gastrointestinal tract, penetrates the mucus

### *Immunology of* Helicobacter pylori *Infection DOI: http://dx.doi.org/10.5772/intechopen.104592*

gastric layer, and interacts with macrophages, dendritic cells, and monocytes [1, 6, 7]. *H. pylori* adhere to the gastric epithelial cell with the assistance of outer membrane proteins such as BabA, SabA, AlpA, AlpB, and HopZ [1, 5, 20]. After adherence, cag PAI and VacA disrupt gastric epithelial cell polarity, acid secretion (via control of gastrin and H<sup>+</sup> /K<sup>+</sup> -ATPase), and induce inflammation [1]. TLR on epithelial cells also recognizes bacterial products, such as flagella and lipopolysaccharide. The interaction elicits inflammation and supports the activation of the adaptive immune response [9]. *H. pylori* which have been ingested by antigenpresenting cells activate the adaptive immune response [2, 5]. Macrophages and neutrophils may also eliminate *H. pylori* through nitric oxide (NO)-dependent phagocytosis or reactive oxygen species production [5, 6]. They release cytokines such as IL-12, IL-10, and IL-23 which in turn stimulate naïve Th cells [2, 6]. In the other way, dendritic cells present *H. pylori* antigen to naïve Th cells. Naïve Th cells then differentiate into Th1 or Th2/Treg [1, 6]. However, Th1 is more prominent compared to Th2/Treg cells. Th1 then produces IFNγ, TNFα, and IL-2 [1, 2, 4, 6]. Elevation of pro-inflammatory cytokines, such as IL-1β, TNFα, IL-8, and IL-6, is observed. The release of cytokines promotes inflammation in the stomach and leads to gastritis [1, 6]. In contrast, the role of lymphocyte B cells in *H. pylori* infection is indeterminate. Studies reported that antibodies against *H. pylori* are produced but they might be counterproductive [1, 2, 6]. It is suspected that the immunoglobulins against *H. pylori* are easily degraded and unstable in structure [1, 6]. Other literature states that the presence of IgA anti-*H. pylori* gives a protective effect against infection and gastric malignancy [11]. Further investigation is mandatory regarding the role of humoral antibodies in *H. pylori* infection [6].
