Gastric Th17 Cells Specific for H+/K+-ATPase and Serum IL-17 Signature in Gastric Autoimmunity

Abstract

Human gastric autoimmunity [autoimmune gastritis (AIG)] is characterized by inflammation of the gastric mucosa and parietal cell loss. The gastric parietal cell proton pump H+/K+-adenosine triphosphatase (H+/K+-ATPase) is the major autoantigen in AIG. Our work aimed to investigate the gastric H+/K+-ATPase-specific T helper 17 (Th17) responses in AIG and serum interleukin (IL)-17 cytokine subfamily in AIG patients, in healthy subjects [healthy controls (HCs)], and in patients with iron deficiency anemia (IDA) without AIG. We analyzed the activation of gastric lamina propria mononuclear cells (LPMCs) by H+/K+-ATPase and the IL-17A and IL-17F cytokine production in eight patients with AIG and four HCs. Furthermore, we compared serum levels of IL-17A, IL-17F, IL-21, IL-17E, IL-22, and IL-23 in 43 AIG patients, in 47 HCs, and in 20 IDA patients without AIG. Gastric LPMCs from all AIG patients, but not those from HCs, were activated by H+/K+-ATPase and were able to proliferate and produce high levels of IL-17A and IL-17F. AIG patients have significantly higher serum IL-17A, IL-17F, IL-21, and IL-17E (393.3 ± 410.02 pg/ml, 394.0 ± 378.03 pg/ml, 300.46 ± 303.45 pg/ml, 34.92 ± 32.56 pg/ml, respectively) than those in HCs (222.99 ± 361.24 pg/ml, 217.49 ± 312.1 pg/ml, 147.43 ± 259.17 pg/ml, 8.69 ± 8.98 pg/ml, respectively) and those in IDA patients without AIG (58.06 ± 107.49 pg/ml, 74.26 ± 178.50 pg/ml, 96.86 ± 177.46 pg/ml, 10.64 ± 17.70 pg/ml, respectively). Altogether, our results indicate that IL-17A and IL-17F are produced in vivo in the stomach of AIG patients following activation with H+/K+-ATPase and that serum IL-17A, IL-17F, IL-21, and IL-17E levels are significantly elevated in AIG patients but not in patients without AIG. These data suggest a Th17 signature in AIG and that IL-17A, IL-17F, IL-21, and IL-17E may represent a relevant tool for AIG management.

Increased IL-17A Serum Levels and Gastric Th17 Cells in Helicobacter pylori-Infected Patients with Gastric Premalignant Lesions

“…A significant increase in serum IL-17A was found in the peripheral blood of subjects with gastric intestinal metaplasia and dysplasia, compared to patients with non-atrophic gastritis and to controls. Thus, IL-17A is not only a key player of gastric mucosa inflammation in patients with autoimmune atrophic gastritis with no Helicobacter pylori infection [ 35 ], but also a relevant cytokine for the immune pathogenesis of gastric intestinal metaplasia and gastric dysplasia in Helicobacter pylori -infected patients on the basis of the findings obtained in the present study, both in the stomach and in the sera. Given that this investigation represents a pilot single-center study, future multi-center research activities dealing with serum IL-17A levels in gastric adenocarcinoma would be very important for a better definition of the test.…”

“…Several reports demonstrated the relevance of Th17 in gastric adenocarcinoma. It has been demonstrated that Helicobacter pylori -specific T lymphocytes produce huge amount of IL-17 in patients with gastric adenocarcinoma [ 33 , 35 , 36 ]. However, it is still not clear whether Helicobacter pylori antigens might be able to drive Th17 responses in Helicobacter pylori patients with preneoplastic gastric malignancies, such as gastric intestinal metaplasia and dysplasia.…”

“…It has been recently shown that there is a predominant T helper 17 response in Helicobacter pylori -infected patients with gastric adenocarcinoma and in Helicobacter pylori negative patients with autoimmune atrophic gastritis [ 33 , 34 , 35 , 36 , 37 ]. However, there are no clues on the pathogenic process mediated by Helicobacter pylori specific T helper 17 lymphocytes in human gastric intestinal metaplasia and gastric dysplasia.…”

Autoimmune gastritis serological biomarkers in gastric cancer patients

“…T cells, specifically Th1 cells secreting interferon-γ, and Th17 cells specific to gastric H+/K+-ATPase, play a role in AIG (D’Elios et al ., 2001; Della Bella et al ., 2022). B cells activated by T cells produce antiparietal cells (anti-PCA) and anti-intrinsic factor antibodies (anti-IFA) used for serological evaluation of AIG.…”