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bioRxiv · 10.1101/2025.11.23.690054

Autoimmunity and H. pylori infection cooperatively promote epithelial tumorigenic differentiation and systemic immune modulation

Vazquez, E. N.·Lozano, C.·Honan, A. M.·Zaika, E.·Houghton, J.·El-Rifai, W.·Zaika, A.·Chen, Z.
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Abstract

Background and AimsGastric cancer (GC) demographics have shifted, with a growing impact on younger populations, particularly women. Chronic Helicobacter pylori (HP) infection is the leading risk factor for GC; however, decreasing HP prevalence means it is unlikely the cause of rising incidence of early-onset GC. Autoimmunity, which is more prevalent in women, has been proposed as a contributing factor. As autoimmunity prevalence increases, HP and gastric autoimmunity are likely to converge within one individual. This study aimed to examine how combinatorial HP infection and autoimmunity affect tumorigenesis and the immune landscape. MethodsA mouse model mimicking human CTLA4 insufficiency and its risk of autoimmunity-driven GC development, CTLA4KD, was infected with HP strain PMSS1 by oral gavage. Tumorigenesis was histologically assed. Hematopoietic and non-hematopoietic cells were analyzed using 40-color spectral flow cytometry. Human PBMCs were co-cultured with HP, followed by flow cytometry and qRT-PCR for gene expression of sorted PBMC subsets. ResultsHP infection in CTLA4KD mice advanced dysplasia and increased tertiary lymphoid structures within the gastric mucosa. Loss of E-Cadherin and DMBT1 was exacerbated in the combinatorial setting of autoimmunity and HP infection. In the innate immune system HP and autoimmunity showed an additive effect in systemic NK cell decreases. In the adaptive immune system, HP and autoimmunity cooperatively elevated the proportion of CD4+Foxp3- cells expressing the transcription factor Helios, persisting 6-8 months post infection. The Helios-expressing CD4 cells co-expressed inhibitory markers PD-1, CD200 and CD39. ConclusionAutoimmunity and HP infection cooperatively elicit long-lasting suppression of innate and adaptive immunity while promoting epithelial tumorigenic differentiation in the stomach. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/690054v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@1096623org.highwire.dtl.DTLVardef@1099e7org.highwire.dtl.DTLVardef@1e8493forg.highwire.dtl.DTLVardef@120e5d3_HPS_FORMAT_FIGEXP M_FIG C_FIG Background and contextAutoimmunity is emerging as a contributing factor for early-onset gastric cancer especially in young women, but it is unknown how it interacts with the most prevalent etiology factor, Helicobacter pylori. New findingsThis study provides the initial evidence that Helicobacter pylori and autoimmunity cooperatively cause long-lasting suppression of innate and adaptive immunity while promoting epithelial tumorigenic differentiation in the stomach. LimitationsEven with the murine-adapted Helicobacter pylori strain PMSS1, a human pathogen, the mouse modeling remains technically and conceptually challenging and can only capture some aspects of human Helicobacter pylori infection. Clinical research relevanceThis study showcases how autoimmunity predisposed by host genetics may cooperate with a prevalent environment factor, Helicobacter pylori, to promote gastric cancer development, with cellular and histopathological changes in the stomach, as well as local and systemic alteration of immune profiles. The lasting effects long after the elimination of Helicobacter pylori suggest the necessity of remedies besides Helicobacter pylori eradication. Basic research relevanceThis study provides molecular and cellular clues for how a convergence of autoimmunity and Helicobacter pylori cooperatively downregulates tumor suppressors in gastric epithelial cells while causing long-lasting suppression of innate and adaptive immunity. More studies are needed for better understanding of the interaction between Helicobacter pylori and autoimmunity, to help develop interventions against the alarming trend of early-onset gastric cancer. Lay summaryThis study provides initial insight into how autoimmunity and Helicobacter pylori in combination may impinge on multi-pronged effect on the stomach and the immune system to accelerate gastric cancer development.

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Vazquez, E. N., Lozano, C., Honan, A. M., Zaika, E., Houghton, J., El-Rifai, W., Zaika, A., Chen, Z.. 2025-11-26. Autoimmunity and H. pylori infection cooperatively promote epithelial tumorigenic differentiation and systemic immune modulation. https://doi.org/10.1101/2025.11.23.690054

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