Mechanism of Mucosal Injury
The bacterium resides predominantly within the supra-epithelial mucus, with only 20% of the population binding to mucous cells. Pathogenesis begins via type IV bacterial secretion: the microbe injects a protein—the product of the cagA gene—into the host cell. Inside the epithelial cell, this protein is phosphorylated and triggers the synthesis of IL-8.
Interleukin-8 acts as a potent chemoattractant for neutrophils. They migrate massively into the mucous membrane and die during phagocytosis (the "respiratory burst"). The release of lysosomal hydrolases and proteases destroys the protective barrier, while lipid peroxidation damages the epithelium. Additional damage is caused by the VacA toxin, which induces cell vacuolization, alters the cytoskeleton, and triggers apoptosis.
Immune Response and the "African Enigma"
Breaching the epithelial barrier allows antigens access to the lamina propria. Macrophages present antigens and secrete IL-1. Subsequent events depend on the polarization of the immune response:
- Th1 response (cellular): accompanied by aggressive inflammation and severe tissue damage.
- Th2 response (humoral): stimulates antibody production with minimal mucosal alteration.
The genetically fixed predominance of the Th2 response explains the "African enigma": despite a nearly universal infection rate among the African population, peptic ulcer disease is extremely rare. To avoid elimination, the bacterium can also block phagolysosome maturation in macrophages, suppressing antigen presentation and the Th1 response.
Two Disease Scenarios: Ulcer vs. Cancer
The outcome of the infection largely depends on the age at which initial infection occurred.
- Ulcer phenotype (infection in adolescence). The bacterium colonizes the antrum. Inflammation reduces somatostatin production and increases gastrin levels, resulting in persistent hyperchlorhydria. Excess acid enters the duodenum, causing protective gastric metaplasia there. Helicobacter pylori colonizes these patches, provoking duodenitis and duodenal ulcer formation.
- Cancer phenotype (infection in early childhood). Against the background of high salt intake and deficiencies in vitamins C and E, pangastritis develops. Acid secretion initially rises but eventually drops due to depletion of the parietal cell pool. Gastric body mucosal atrophy, achlorhydria, and intestinal metaplasia develop, ultimately leading to hyposecretion and a high risk of gastric cancer.
How Glandular Atrophy Develops
Glandular atrophy is the result of regenerative exhaustion. Due to continuous damage to the pit-lining epithelium by the VacA toxin, cells of the generative zone begin to differentiate massively into surface mucous cells to compensate for their loss. No resources remain to replenish the glandular epithelium, leading to atrophy of the glands.
Concurrently, due to the loss of parietal cells (from infection or autoimmune reactions), hydrochloric acid production decreases. The rise in luminal pH activates the CDX-2 transcription factor, which shifts gastric differentiation toward an intestinal phenotype—thus resulting in intestinal metaplasia, which accompanies atrophy.