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

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 5

Bacterial DNA is an immune stimulant for IFN-γ production in CVID.

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Bacterial DNA is an immune stimulant for IFN-γ production in CVID. (A) S...
(A) Serum IFN-γ levels in healthy controls (HCs), patients with XLA, and patients with CVID with or without autoimmune/inflammatory complications (CVID+, CVID, respectively). One-way ANOVA revealed significant differences between groups (P < 0.0001) (B) Serum IFN-γ levels in patients with CVID with low versus high serum bacterial 16S rDNA. High serum bacterial 16S rDNA is defined as levels higher than the 90th percentile of healthy controls. Unpaired t test revealed significant differences between groups (P = 0.0258) (C) IFN-γ levels in the culture supernatants of PBMCs isolated from HCs and XLA, CVID, and CVID+ patients on day 3 after coculture with bacterial DNA (7.5 pg/mL). One-way ANOVA revealed significant differences between groups (P < 0.0001). (D) IFN-γ levels in the culture supernatants of PBMCs isolated from CVID+ patients on day 3 after coculture with bacterial DNA (7.5 pg/mL), with or without a BTK inhibitor (BTKi; PCI 29732, 0.5 nM; left panel). Unpaired t test revealed significant differences between groups (P < 0.0001). Bacterial DNA-induced IFN-γ levels in response to BTKi treatment over time (PCI 29732, 0.5 nM; 0–12 hours) in PBMCs isolated from CVID+ and healthy individuals (right panel). The data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 1-way ANOVA with Tukey’s post hoc test (A and C) and unpaired t test (B and D). NS, not significant.