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Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency
Hsi-en Ho, … , Ahmed El-Shamy, Charlotte Cunningham-Rundles
Hsi-en Ho, … , Ahmed El-Shamy, Charlotte Cunningham-Rundles
Published October 8, 2021
Citation Information: JCI Insight. 2021;6(19):e144777. https://doi.org/10.1172/jci.insight.144777.
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Research Article Immunology Inflammation

Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency

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Abstract

Common variable immunodeficiency (CVID) is characterized by profound primary antibody defects and frequent infections, yet autoimmune/inflammatory complications of unclear origin occur in 50% of individuals and lead to increased mortality. Here, we show that circulating bacterial 16S rDNA belonging to gut commensals was significantly increased in CVID serum (P < 0.0001), especially in patients with inflammatory manifestations (P = 0.0007). Levels of serum bacterial DNA were associated with parameters of systemic immune activation, increased serum IFN-γ, and the lowest numbers of isotype-switched memory B cells. Bacterial DNA was bioactive in vitro and induced robust host IFN-γ responses, especially among patients with CVID with inflammatory manifestations. Patients with X-linked agammaglobulinemia (Bruton tyrosine kinase [BTK] deficiency) also had increased circulating bacterial 16S rDNA but did not exhibit prominent immune activation, suggesting that BTK may be a host modifier, dampening immune responses to microbial translocation. These data reveal a mechanism for chronic immune activation in CVID and potential therapeutic strategies to modify the clinical outcomes of this disease.

Authors

Hsi-en Ho, Lin Radigan, Gerold Bongers, Ahmed El-Shamy, Charlotte Cunningham-Rundles

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Figure 1

Serum circulating bacterial DNA, sCD14, and LBP levels in CVID as compared with XLA and healthy individuals.

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Serum circulating bacterial DNA, sCD14, and LBP levels in CVID as compar...
(A) Serum 16S rDNA, (B) serum sCD14, and (C) serum LBP levels in healthy controls (HCs), patients with CVID, and patients with XLA. Kruskal-Wallis test revealed significant differences between groups for bacterial 16S rDNA (P < 0.0001); 1-way ANOVA revealed significant differences between groups for sCD14 (P < 0.0001) and LBP (P < 0.0001). The data are expressed as the mean ± SEM. ***P < 0.001, ****P < 0.0001 by Kruskal-Wallis with Dunn’s multiple-comparison post hoc test (A) and 1-way ANOVA with Tukey’s post hoc test (B and C). NS, not significant.

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