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. 2022 May 31:13:834137.
doi: 10.3389/fimmu.2022.834137. eCollection 2022.

Contribution of Helicobacter pylori to the Inflammatory Complications of Common Variable Immunodeficiency

Adriana Motta-Raymundo  1   2 , Pedro Rosmaninho  1   2 , Diana F Santos  1   2 , Ruben D Ferreira  1   2 , Sara P Silva  1   2   3 , Cristina Ferreira  1   2   3 , Ana E Sousa  1   2 , Susana L Silva  1   2   3
Affiliations

Contribution of Helicobacter pylori to the Inflammatory Complications of Common Variable Immunodeficiency

Adriana Motta-Raymundo et al. Front Immunol. .

Abstract

Common Variable Immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is frequently associated with severe inflammatory complications that determine its morbidity and mortality. We hypothesize that Helicobacter pylori (HP), a very common worldwide infection, may contribute to the clinical and immune phenotype of CVID. We stratified 41 CVID patients into HP+ (n=26) and HPneg (n=15) groups, according to previous urease breath test and/or gastric biopsies, and compared their clinical manifestations and immune profile evaluated by flow cytometry. No genetic variants with known potential impact in HP infection were found upon WES/WGS. Gastric complications were significantly more frequent in HP+ patients. Importantly, the six CVID patients with gastric cancer were infected with HP. In contrast, a significantly higher frequency of cytopenias was observed in the HPneg. Moreover, HP+ did not feature higher prevalence of organ auto-immunity, as well as of lung, liver or intestinal inflammatory manifestations. We observed the same B-cell profiles in HP+ and HPneg groups, accompanied by marked CD4 and CD8 T-cell activation, increased IFNγ production, and contraction of naïve compartments. Notably, HP+ patients featured low CD25 despite preserved Foxp3 levels in CD4 T cells. Overall, HP impact in CVID inflammatory complications was mainly restricted to the gastric mucosa, contributing to increased incidence of early onset gastric cancer. Thus, early HP screening and eradication should be performed in all CVID patients irrespective of symptoms.

Keywords: Helicobacter pylori; common variable immunodeficiency (CVID); gastric cancer; inborn error of immunity (IEI); inflammatory CVID complications; primary immunodeficiency.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
HP infection and clinical manifestations. (A) Frequency of HP infection in the total cohort. (B, C) Comparison between the group of patients with evidence of HP infection (orange) with the group without HP infection (blue) regarding: (B) prevalence of persistent viral and bacterial infections, (C) non-infectious manifestations. (D) Prevalence of HP infection in the group of patients with gastric diseases and those without. The statistical test used was Fisher´s exact test and p values <0.05 are shown. LNRH, Liver Nodular Regenerative Hyperplasia; GLILD, Granulomatous Lymphocytic Interstitial Lung Disease.
Figure 2
Figure 2
HP infection and immune phenotype. Comparison of the groups of patients with evidence of HP infection (orange), without HP infection (blue) and healthy controls (green) regarding the following immunological markers evaluated by flow cytometry: (A) Number of circulating T and B cells; (B) B-cell subsets; (C) CD4 T-cell subsets (top) and CD8 T-cell subsets (bottom); (D) frequency of CD4 T cells able to produce IL-17; and (E) Frequency of CD4 T cells expressing regulatory T-cell markers. Ordinary One-way ANOVA and Fisher’s Least Significant Difference (LSD) test were used for the statistical analysis and the following p values are shown: ***<0.0001; **<0.01; *<0.05 as compared to healthy controls; #<0.05 as compared between patient groups. TEMRA, Terminally effector memory RA.
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