**17. Discussion**

hepatocytes and results in accumulation of collagen, thereby causing fibrosis [63]. Some of the risk factors for these cancers are population genetics, geographical and environmental factors,

Both Graves' disease and Hashimoto's thyroiditis are autoimmune diseases in the thyroid. Graves' disease is characterized by hyperthyroidism and an enlarged gland, while Hashimoto's thyroiditis is characterized by hypothyroidism and the destruction of thyroid tissue. There is an association between Graves' disease and *H. pylori*, where CagA is most likely an important virulence factor [95]. A study by Bassi et al. showed that 82% (43/52) of patients with Graves' disease were positive for *H. pylori*, where 84% (36/43) of *H. pylori*-positive Graves' disease patients were positive for CagA antigens. Also, a different study by Bertalot et al. showed a reduction in thyroid autoantibodies following *H. pylori* eradication [96]. Amino acid sequences of thyroid peroxidase and CagA are very similar, and cross-reactivity is a possible mechanism by which *H. pylori* increases the risk of developing Graves' disease [18, 95]. In addition, Graves' disease is often found with other autoimmune diseases which may reflect the ability of *H. pylori* to induce multiple autoimmune diseases simultaneously [97]. However, the same cannot be said about Hashimoto's thyroiditis where a significant associa-

cholelithiasis, obesity, chronic inflammation, and obstruction of the bile duct [92, 94].

tion between Hashimoto's thyroiditis and *H. pylori* was not found by Bassi et al. [95].

eradiation is in terms of reducing the incidence and severity of PE [100].

The first study investigating the association between *H. pylori* infection and preeclampsia (PE) was conducted in Italy and published in 2006 [98]. It was found that 32% of women with a normal pregnancy harbored anti-*H. pylori* antibodies compared to 51% of preeclamptic women. The difference was even bigger when looking at the presence of anti-CagA antibodies: 15 vs. 81% in women with a normal pregnancy vs. preeclamptic women. The authors concluded that the increased inflammatory activity in *H. pylori*-infected patients may contribute to the development of PE, especially in CagA strains. Interestingly, no *H. pylori* DNA was present in the placentas that were studied, and therefore the inflammation is probably not locally induced. A review from 2014 concluded that there is evidence indicating that *H. pylori* negatively influences human reproductivity, including PE [99]. This is probably due to both increased inflammatory activity and antigenic mimicry with CagA-positive strains appearing to be the most important culprits [99]. A recent meta-analysis of observational studies with 9787 women (879 preeclamptic) confirmed these theories, with an OR of 2.32 for anti-*H. pylori* antibodies in cases compared to controls and an OR of 3.97 for having anti-CagA antibodies in preeclamptic patients [100]. A review on the topic of infections and the risk of PE mentions *H. pylori* as a possible cause of PE and recommends that screening (and treatment) of known infectious organisms causing PE should be included in antenatal programs [101]. However, as mentioned by Bellos et al., it is yet unknown if *H. pylori* predisposes to mild or severe PE, at which gestational age optimal screening should be conducted, and most importantly how effective

**15. Autoimmune thyroid diseases**

22 Helicobacter Pylori - New Approaches of an Old Human Microorganism

**16. Preeclampsia**

*H. pylori* can induce many pathogenic reactions in infected individuals. There are mainly three different ways *H. pylori* acts. (1) The bacteria have several virulence factors (Cag PAI, Vac A, etc.) that can cause direct damage and apoptosis of epithelial cells in the stomach and can stimulate mast cells to liberate PAF which affects the angiogenesis in the stomach. This may be some of the main actions on gastric diseases such as peptic ulcers and gastric cancer (**Figure 1**). (2) There is a strong cellular and humoral immune response to *H. pylori* with the release of different cytokines and chemokines. Cytokines and chemokines subsequently react both in the stomach and in extra-gastric organs (**Figure 2**). In addition, several *H. pylori* antigens are structurally like antigens of the human body and therefore may cause cross-reactions (antigenic mimicry) (**Figure 3**). All these pathogenic mechanisms of *H. pylori* may result in different diseases both in the stomach and in extra-gastric organs.

The role of *H. pylori* in relation to gastritis, peptic ulcers, MALT lymphomas, and gastric cancer is well known and established. However, there is confusion about the difference between

**Figure 1.** The roles of the main virulence factors in pathogenesis of *Helicobacter pylori* infection [6]. Adherence of *Helicobacter pylori* to gastric epithelial cells is mediated by BabA and SabA binding Leb and Lewis x/a, respectively. CagA is translocated into epithelial cells through T4SS and then tyrosine-phosphorylated at EPIYA sites by Src and Abl kinases. CagA contributes to alteration of myriad signaling transduction, which affects host cell physiology with disruption of intercellular junctions, loss of cell polarity, promotion of inflammation, dysregulation of cellular apoptosis, and proliferation. VacA inducts cytoplasmic vacuolation, apoptosis, and immune suppression [6, 103].

**Figure 2.** The inflammatory response in *Helicobacter pylori* infection. Immune cells are recruited to the lamina propria of the gastric epithelium by chemokines and cytokines (IL-8, MCP-1, GRO-α, IL-1β, TNF-α) produced by epithelial cells or directly by bacterial products including *H. pylori* neutrophil-activating protein, VacA, and urease. At the site of infection, the immune cells are activated and exert their effector functions, including the production of cytokines (IL-1β, TNFα, IL-6, IL-12, IFN-γ), chemokines (IL-8, MCP-1), proteolytic enzymes, oxide nitric (NO), and reactive oxygen species (ROS). PG, peptidoglycan; T4SS, type IV secretion system; IL, interleukin; TNF, tumor necrosis factor; MCP, macrophage chemotactic protein; GRO, growth-regulated oncogene [104].

**18. Conclusion**

urgently needed.

A variety of diseases are may be caused by *H. pylori*; some such as peptic ulcer and gastric cancer by a direct effect on the gastric epithelial cells cause cell damage and apoptosis. The complex immune response to *H. pylori* contributes to the pathogenesis such as mast cells liberating PAF which affect the angiogenesis in the stomach. The complex immune response to *H. pylori* is also involved in the pathogenesis of extra-gastric manifestations of *H. pylori* infection. In addition to the immune response to *H. pylori*, *H. pylori* also contains a lot of antigens which cross-react with human antigens (antigenic mimicry) that is responsible for many autoimmune diseases such as thrombocytopenia purpura, B12 deficiency anemia, neuromyelitis optica, Graves' disease, etc. Thus, *H. pylori* causes or may cause a lot of wellknown and less well-investigated diseases, and these patients should be tested for *H. pylori*. However, many of these diseases are rather rare especially in children that need larger, and more well-designed multicenter studies with better stratification of patients and better diagnostics of *H. pylori* for prober studies are needed. In addition, little is known about the exact virulence and pathogenic mechanisms of *H. pylori*, and basic research in these diseases is

**Figure 3.** Hypothesis of autoimmune disorders due to molecular mimicry between *Helicobacter pylori* and the host components. Chronic exposure of the host immune system to *Helicobacter pylori* (*H. pylori*) components that have homologous sequences with the host cellular or soluble compounds may initiate the production of autoantibodies. However, how often the autoantibodies arising during *H. pylori* infection are involved in various post-infectious pathologies should be elucidated. The graph shows the examples of host targets for the antibodies induced by *H. pylori* components. GP, glycoproteins; HSP, heat shock protein; H+/K+ ATPase, H+/K + −adenosine triphosphatase; HLA,

Clinical Manifestations of the *Epsilonproteobacteria* (*Helicobacter pylori*)

http://dx.doi.org/10.5772/intechopen.80331

human leukocyte antigens; CCRL1, CC chemokine receptor-like 1; Le, Lewis antigens [105].

functional dyspepsia and *H. pylori*-induced gastritis even though *H. pylori* is always followed by a strong cellular and humoral immune response and fulfills the criteria for a true infection.

As with many other infections, *H. pylori* infection does not always cause symptoms. The evidence-based associations between *H. pylori* and ITP and unexplained IDA are less well known. Patients with these diseases should be tested for *H. pylori*. There are slightly weaker associations found between *H. pylori* and B12 deficiency anemia, neuromyelitis optica, and Graves' disease, and patients with these diseases should also be tested for *H. pylori* [21].

Weaker associations between *H. pylori* and cardiovascular disease, pancreatic cancer, pancreatitis, obesity and type 2 diabetes, Parkinson's disease, asthma, liver diseases, and preeclampsia have been found. *H. pylori* possibly causes these diseases through antigenic mimicry, and affected patients should be considered for *H. pylori* testing.

In conclusion, a variety of diseases may be caused by *H. pylori*, and affected patients should be tested for *H. pylori*. However, further larger and more well-designed studies with better stratification of patients and better diagnostics of *H. pylori* are needed.

Clinical Manifestations of the *Epsilonproteobacteria* (*Helicobacter pylori*) http://dx.doi.org/10.5772/intechopen.80331 25

**Figure 3.** Hypothesis of autoimmune disorders due to molecular mimicry between *Helicobacter pylori* and the host components. Chronic exposure of the host immune system to *Helicobacter pylori* (*H. pylori*) components that have homologous sequences with the host cellular or soluble compounds may initiate the production of autoantibodies. However, how often the autoantibodies arising during *H. pylori* infection are involved in various post-infectious pathologies should be elucidated. The graph shows the examples of host targets for the antibodies induced by *H. pylori* components. GP, glycoproteins; HSP, heat shock protein; H+/K+ ATPase, H+/K + −adenosine triphosphatase; HLA, human leukocyte antigens; CCRL1, CC chemokine receptor-like 1; Le, Lewis antigens [105].

#### **18. Conclusion**

functional dyspepsia and *H. pylori*-induced gastritis even though *H. pylori* is always followed by a strong cellular and humoral immune response and fulfills the criteria for a true infection. As with many other infections, *H. pylori* infection does not always cause symptoms. The evidence-based associations between *H. pylori* and ITP and unexplained IDA are less well known. Patients with these diseases should be tested for *H. pylori*. There are slightly weaker associations found between *H. pylori* and B12 deficiency anemia, neuromyelitis optica, and Graves' disease, and patients with these diseases should also be tested for *H. pylori* [21].

**Figure 2.** The inflammatory response in *Helicobacter pylori* infection. Immune cells are recruited to the lamina propria of the gastric epithelium by chemokines and cytokines (IL-8, MCP-1, GRO-α, IL-1β, TNF-α) produced by epithelial cells or directly by bacterial products including *H. pylori* neutrophil-activating protein, VacA, and urease. At the site of infection, the immune cells are activated and exert their effector functions, including the production of cytokines (IL-1β, TNFα, IL-6, IL-12, IFN-γ), chemokines (IL-8, MCP-1), proteolytic enzymes, oxide nitric (NO), and reactive oxygen species (ROS). PG, peptidoglycan; T4SS, type IV secretion system; IL, interleukin; TNF, tumor necrosis factor; MCP, macrophage

Weaker associations between *H. pylori* and cardiovascular disease, pancreatic cancer, pancreatitis, obesity and type 2 diabetes, Parkinson's disease, asthma, liver diseases, and preeclampsia have been found. *H. pylori* possibly causes these diseases through antigenic mimicry, and

In conclusion, a variety of diseases may be caused by *H. pylori*, and affected patients should be tested for *H. pylori*. However, further larger and more well-designed studies with better

affected patients should be considered for *H. pylori* testing.

chemotactic protein; GRO, growth-regulated oncogene [104].

24 Helicobacter Pylori - New Approaches of an Old Human Microorganism

stratification of patients and better diagnostics of *H. pylori* are needed.

A variety of diseases are may be caused by *H. pylori*; some such as peptic ulcer and gastric cancer by a direct effect on the gastric epithelial cells cause cell damage and apoptosis. The complex immune response to *H. pylori* contributes to the pathogenesis such as mast cells liberating PAF which affect the angiogenesis in the stomach. The complex immune response to *H. pylori* is also involved in the pathogenesis of extra-gastric manifestations of *H. pylori* infection. In addition to the immune response to *H. pylori*, *H. pylori* also contains a lot of antigens which cross-react with human antigens (antigenic mimicry) that is responsible for many autoimmune diseases such as thrombocytopenia purpura, B12 deficiency anemia, neuromyelitis optica, Graves' disease, etc. Thus, *H. pylori* causes or may cause a lot of wellknown and less well-investigated diseases, and these patients should be tested for *H. pylori*. However, many of these diseases are rather rare especially in children that need larger, and more well-designed multicenter studies with better stratification of patients and better diagnostics of *H. pylori* for prober studies are needed. In addition, little is known about the exact virulence and pathogenic mechanisms of *H. pylori*, and basic research in these diseases is urgently needed.
