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.
Keywords:
Beta cells; Genetic diseases; Immunoglobulins; Immunology; Inflammation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Agammaglobulinemia / blood*
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Agammaglobulinemia / immunology
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Aged
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Anemia, Hemolytic, Autoimmune / blood
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Anemia, Hemolytic, Autoimmune / complications
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Anemia, Hemolytic, Autoimmune / immunology
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B-Lymphocytes / immunology
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Bacterial Translocation
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Child
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Child, Preschool
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Common Variable Immunodeficiency / blood*
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Common Variable Immunodeficiency / complications
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Common Variable Immunodeficiency / immunology
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DNA, Bacterial / blood*
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DNA, Bacterial / immunology
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DNA, Ribosomal / blood*
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DNA, Ribosomal / immunology
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Female
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Gastrointestinal Microbiome / genetics*
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Genetic Diseases, X-Linked / blood*
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Genetic Diseases, X-Linked / immunology
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Granuloma / blood
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Granuloma / complications
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Granuloma / immunology
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Humans
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Immunoglobulin Class Switching
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Immunologic Memory / immunology
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Inflammation / blood*
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Inflammation / immunology
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Interferon-gamma / blood
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Lung Diseases, Interstitial / blood
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Lung Diseases, Interstitial / complications
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Lung Diseases, Interstitial / immunology
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Male
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Middle Aged
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Polyendocrinopathies, Autoimmune / blood
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Polyendocrinopathies, Autoimmune / complications
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Polyendocrinopathies, Autoimmune / immunology
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Purpura, Thrombocytopenic, Idiopathic / blood
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Purpura, Thrombocytopenic, Idiopathic / complications
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Purpura, Thrombocytopenic, Idiopathic / immunology
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Splenomegaly / blood
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Splenomegaly / complications
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Splenomegaly / immunology
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Young Adult
Substances
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DNA, Bacterial
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DNA, Ribosomal
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Interferon-gamma
Supplementary concepts
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Autoimmune enteropathy
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Bruton type agammaglobulinemia