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

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

doi:10.1172/jci.insight.144777

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.

Highlights

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is characterized by low levels of serum IgG, IgA, and/or IgM, and a lack of production of specific antibodies [1,2,3]
Bacterial 16S rDNA levels were significantly elevated in CVID sera as compared with healthy controls
We investigated whether the loss of Bruton tyrosine kinase (BTK) signals in X-linked agammaglobulinemia (XLA) could lead to the differential IFN-γ response to bacterial stimuli between patients with CVID and patients with XLA

Summary

Introduction

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is characterized by low levels of serum IgG, IgA, and/or IgM, and a lack of production of specific antibodies [1,2,3]. At least 50% of patients with CVID develop additional inflammatory complications [4, 5]. These noninfectious manifestations include autoimmunity, interstitial lung disease, enteropathy, nodular regenerative hyperplasia of the liver, systemic granulomatous disease, lymphoid hyperplasia, and lymphoid malignancy [4,5,6,7]. These complications are a major clinical challenge because they are not substantially ameliorated by standard IgG replacement therapy. Inflammatory conditions lead to an estimated 11-fold increased morbidity and mortality in patients with CVID [5]

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Conclusion