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

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

doi:10.1172/jci.insight.144777

Cited by 28 publications

(33 citation statements)

References 75 publications

(116 reference statements)

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“…Multiple studies had previously reported elevated circulating LBP and sCD14 in CVID compared to healthy controls (49,50). This was also confirmed in a larger CVID cohort (n=76), where we found that the highest sCD14 levels were amongst CVID+ patients, supporting innate immune activation as an important hallmark of CVID, especially for those with non-infectious manifestations (28). Here, we also observed a positive trend between serum sCD14 and LBP(Spearman r = 0.21, P = 0.0735).…”

Section: Lps Binding Protein Soluble Cd14 Soluble Cd25 and Hdlsupporting

confidence: 88%

“…Further investigation revealed that serum bacterial rDNA was closely associated with multiple disease biomarkers previously reported in CVID ( 28 ). These include a positive association with markers of monocyte activation in CVID (sCD14, as discussed above; Spearman r = 0.28, P = 0.0166).…”

Section: Markers Of Host-microbial Dysregulationmentioning

confidence: 60%

“…IFN-γ abnormalities in CVID had differed between cell types and patient subgroups ( 25 , 26 ). However, in a larger cohort, we had found abundant serum IFN-γ in CVID+ patients, along with an IFN mRNA signature that distinguished CVID+ from CVID patients and healthy volunteers (further discussed below) ( 27 , 28 ). A number of other cytokines had also been examined in CVID, though the results often varied between studies: IL-4 (elevated serum levels in most studies, but reduced in some) ( 29 , 30 ), IL-5 (potentially reduced) ( 31 ), IL-6 (increased production in some studies) ( 32 , 33 ), IL-7 (varied) ( 34 ), IL-10 (varied) ( 35 , 36 ), and IL-12 (varied) ( 37 , 38 ).…”

Section: Circulating Biomarkersmentioning

confidence: 91%

“…These findings were compatible with our observation of IFNγ+ ILC3 expansion in these mucosal tissues ( 27 ). In our recent study, we also sought evidence of a dysfunctional mucosal barrier in CVID by examining two biomarkers in the serum: zonulin and intestinal fatty-acid binding protein (I-FABP) ( 28 ). Zonulin is a modulator of intercellular tight junctions between epithelial cells and elevated serum zonulin levels have been linked to increased intestinal wall permeability ( 62 ).…”

Section: Markers Of Host-microbial Dysregulationmentioning

confidence: 99%

“…Taking a direct approach, we recently measured bacterial 16S rDNA levels in serum samples from 92 CVID patients ( 28 ). We found that bacterial 16S rDNA was significantly elevated in CVID patients (mean 19.15, range 0.4-237.4 copies/μl) compared to healthy controls (mean 5.99, range 1.2-18.88 copies/μl, P<0.0001).…”

Section: Markers Of Host-microbial Dysregulationmentioning

confidence: 99%

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Seeking Relevant Biomarkers in Common Variable Immunodeficiency

Cunningham‐Rundles

2022

Front. Immunol.

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Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency. More than 50% of patients in some series suffer from autoimmune or inflammatory complications (the “CVID+” phenotype), and these are not adequately addressed by current treatments. Despite major advancements in genetics, the pathogenesis of the CVID+ phenotype has remained unexplained for most patients, necessitating the need for relevant biomarkers in both the clinic and research settings. In the clinics, reduced isotype-switched memory B cells (≤ 0.55% of B cells) and reduced T cells (CD4) can be utilized to identify those with increased complication risks. Additionally, condition-specific markers have also been suggested for lymphoma (normal or elevated IgM) and progressive interstitial lung disease (increased BAFF, normal or elevated IgM). Additional biomarkers have provided insights into disease pathogenesis, demonstrating wider systemic inflammation (increased LBP, sCD14, and sCD25; expanded ILC3), mucosal defects (increased zonulin, I-FABP), and perhaps reduced anti-inflammatory capability (reduced HDL) in CVID. Most recently, efforts have revealed elevated circulating bioactive bacterial DNA levels – marking microbial translocation and potentially linking the causation of multiple inflammatory changes previously observed in CVID. The implementation of high throughput profiling techniques may accelerate the search of relevant biomarker profiles in CVID and lead to better clinical risk stratification, revealing disease insights, and identifying potential therapeutic targets.

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Section: Lps Binding Protein Soluble Cd14 Soluble Cd25 and Hdlsupporting

confidence: 88%

Section: Markers Of Host-microbial Dysregulationmentioning

confidence: 60%

Section: Circulating Biomarkersmentioning

confidence: 91%

Section: Markers Of Host-microbial Dysregulationmentioning

confidence: 99%

Section: Markers Of Host-microbial Dysregulationmentioning

confidence: 99%

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Seeking Relevant Biomarkers in Common Variable Immunodeficiency

Cunningham‐Rundles

2022

Front. Immunol.

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Bioinformatics in Primary Immunodeficiencies: Towards a “Computational Immunology” Era

Martínez Vásquez,

Mentis

2024

Rare Diseases of the Immune System

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Fecal Immunoglobulin Levels as a Modifier of the Gut Microbiome in Patients with Common Variable Immunodeficiency

et al. 2023

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Objective Common variable immunodeficiency (CVID) is the most common clinically relevant entity of inborn errors of immunity. In these patients, an altered gut microbiome composition with reduced diversity has been described. We sought to investigate the fecal immunoglobulin levels and their impact on the gut microflora in patients with CVID. Methods We analyzed the gut microbiome of 28 CVID patients and 42 healthy donors (HDs), including 21 healthy household controls, by sequencing the V3 and V4 regions of the bacterial 16S rRNA gene extracted from stool samples. The fecal levels of immunoglobulin A, M, and G of 27 CVID patients and 41 HDs were measured in the supernatant by ELISA and normalized for protein concentration. Results We measured decreased IgA and increased IgG in stool samples from CVID patients compared to HDs. Decreased levels of fecal IgA and IgM were associated with reduced microbial diversity and increased dysbiosis. We identified a large number of significantly differentially abundant taxa, especially in patients with decreased IgA levels, but also in patients with decreased IgM levels compared to their counterparts. Conclusions CVID patients have an altered gut microbiota composition, which is most prevalent in patients with decreased fecal IgA and IgM levels. In this study, we identify fecal immunoglobulins as a potential modifier of the gut microbiome in CVID patients.

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

Cited by 28 publications

References 75 publications

Seeking Relevant Biomarkers in Common Variable Immunodeficiency

Seeking Relevant Biomarkers in Common Variable Immunodeficiency

Bioinformatics in Primary Immunodeficiencies: Towards a “Computational Immunology” Era

Fecal Immunoglobulin Levels as a Modifier of the Gut Microbiome in Patients with Common Variable Immunodeficiency

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