Helicobacter pylori Suppresses Serum Immunoglobulin Levels in Smokers with Peptic Ulcer: Probable Interaction Between Smoking and H. pylori Infection in the Induction of Th1 Predominant Immune Response and Peptic Ulceration

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Possible mechanisms by which H. pylori infection induces Th1 skew
Although a Th1 skew in H. pylori-infected patients is suggested by the vast majority of research conducted on this subject, the precise mechanism by which Th1 differentiation is induced has yet to be elucidated. However, some investigators have conducted crucial studies that may explain this phenomenon: Eaton et al. reported CD4+ T cells to be essential for the development of H. pylori-induced gastritis [Eaton et al., 2001], and Nagai et al. showed the coccoid form of H. pylori to reach to Peyer's patches and then be phagocytosed by dendritic cells thereby sensitizing CD4+ T cells, and that these sensitized CD4+ T cells homed to the lamina propria of the gastric mucosa [Nagai et al., 2007]. Finally, such dendritic cells produce IL-12 which promotes Th1 differentiation after phagocytosis of H. pylori . We therefore conducted the current study to assess the influence of both H. pylori and smoking on serum immunoglobulin levels for the purpose of evaluating the presence of Th1 skew in patients with peptic ulcers.

Patients and method
2.1 Study design Study 1. Effects of current smoking on levels of serum immunoglobulins To evaluate the influences of smoking on serum immunoglobulin levels, serum IgG, IgA, and IgM levels were measured in both peptic ulcer and non-ulcer gastritis patients with and without H. pylori infection. Study 2. Effects of H. pylori infection on levels of serum immunoglobulins in peptic ulcer patients To evaluate the influences of H. pylori infection on serum immunoglobulin levels, serum IgG, IgA, and IgM were measured in peptic ulcer patients, both current smokers and nonsmokers. Study 3. As a control for study 2, serum IgG, IgA, and IgM levels were measured in nonulcer gastritis patients with and without current smoking.

Patients
Dyspeptic patients and those recommended to undergo fiberscopic examination received gastroduodenoscopic examinations. Those endoscopically diagnosed as having gastric or duodenal ulcers were included in the current study. Following informed consent to check H. pylori status and immunohematologic parameters, dyspeptic patients underwent gastrofiberscopic examination. Patients with hematologic, immunologic, rheumatic, malignant, and infectious diseases were excluded. Those taking corticosteroids, antibiotics, and/or immunosuppressive drugs were also excluded. Because non-steroidal antiinflammatory drugs (NSAIDs) [ 2007] have increasingly been reported to skew the T helper response toward type 2, patients taking these drugs were also excluded. Both smokers and non-smokers with endoscopically diagnosed non-ulcer gastritis were also evaluated as control groups.

Methods
Following informed consents to measure titers of serum anti-H. pylori IgG antibody, serum immunoglobulins and complete blood cell counts, patients with gastric or duodenal ulcer was diagnosed according to the classification of Sakita and Miwa [Matsukawa et al., 1997], and those with non-ulcer gastritis did according to the updated Sydney System [Dixon et al., 1996] under gastrofiberscopic observation. To evaluate H. pylori status, biopsy specimens were obtained from the antrum and lower body of the greater curvature in the stomach and from the major lesions. The samples from the antrum and lower body were placed in rapid urease test (RUT) kits, and the results were evaluated 24 hr later. These samples were also prepared for pathologic evaluation. Immediately after completion of the procedure, blood samples were collected to measure IgG, IgA, IgM, and anti-H. pylori IgG antibodies. Serum levels of IgG, IgA, and IgM were measured by an automated turbidimetric immunoprecipitation method [Matsukawa et al., 1997], and the anti-H. pylori antibody was measured by a commercially available ELISA kit. Confirmed H. pylori infection required www.intechopen.com

Statistical analysis
Data were expressed as means+/-SD. The statistical significance of differences was anlyzed employing the Student unpaired t-test and the -square test. We evaluated statistical differences using Macintosh StatView version 4, and p values less than 0.05 were accepted as statistically significant.  Table 2b. Profiles of patients with non-ulcer gastritis There were 146 patients with gastric ulcer, 58 with duodenal ulcer, and 32 with both types (Table 3). There were no differences in these lesions between smokers and non-smokers.      (Table 6a). In contrast to smokers, among patients with peptic ulcers, non-smokers with H. pylori infection showed no difference in IgG, IgA, or IgM levels.

Discussion
We initially showed definite suppression of serum immunoglobulin levels in current smokers with H. pylori-associated peptic ulcer (Tables 4a), and this suppression was observed even in patients without H. pylori infection, although the difference did not reach statistical significance possibly due to our small sample size (Table 4b). In contrast to patients with peptic ulcer, those with non-ulcer gastritis showed suppressed levels of serum immunoglobulins, regardless of H. pylori status. These observations support the notion that smoking causes a skewed Th1 response in current smokers, regardless of whether or not H. pylori infection or peptic ulceration is present. As to the Th skew in smokers, there are conflicting reports, with some reporting a Th2 skew in smokers [Hagiwara et al., 2001;Zeidel et al., 2002;Cozen et al., 2004] [Mohammadi et al., 1997]. The current data from the control group in study 3 are also in accordance with this theory, i.e., H. pylori infection raises levels of serum immunoglobulins in both smokers (IgM) and non-smokers (IgG) with non-ulcer gastritis. This differs from the situation in patients with peptic ulcer, in whom H. pylori infection did not suppress serum immunoglobulin levels, of non-ulcer patients suggesting the unique phenomenon of Th1 skew seen only in patients with peptic ulcer (Table 7). Taking our current observations together, suppression, i.e., a lack of upregulation of serum immunoglobulins appears to be a unique feature of smokers with both peptic ulcer and H. pylori infection. Th1 skew observed in H. pylori-infected patients with peptic ulcer appeared to exceed the expected Th2 skew in patients infected with extracellular bacteria such as H. pylori itself, especially in smokers. In addition, vast majority of gastric T cells may be already polarized to produce Th1 cytokine even in the absence of H. pylori infection [Itoh, et al., 1999]. We therefore stress that the Th1 skew induced by H. pylori, smoking, and the presence of peptic ulceration may synergistically exert a Th1 response which prevails over the expected Th2 skew, i.e., upregulation of serum immunoglobulin levels induced by the presence of extracellular bacterial infection by H. pylori itself. The Th1 skew observed in patients with H. pylori infection indicated a Th1-polarized response to be associated with mucosal damage that can induce peptic ulcer, while a mixed Th1 and IL-4-drived Th2 polarized response appeared to be associated with a low degree of gastric inflammation and reduced bacterial load resulting in the prevention of ulcer

Conclusion
As shown herein, current smoking is consitently associated with suppressed serum immunoglobulin levels (study 1), and H. pylori infection definitely reduced these levels in smokers with peptic ulcer (study 2). Furthermore H. pylori infection up-regulated IgG, IgA, and IgM in the absence of peptic ulcer. Current smoking, H. pylori infection, and the presence of peptic ulceration may interact to suppress the levels of serum immunoglobulins as a result of a Th1 shift which overwhelms the Th2 shift expected with extracellular bacterial infection.