Lack of IgA and IgA+ switched memory B cells are associated with bacterial translocation in CVID

Abstract

BackgroundGut bacterial translocation (BT) is linked to immune activation and inflammatory manifestations in CVID, accompanied by evidence of intestinal barrier defect. Here, we investigated the demographic, immunologic and biochemical parameters associated with BT and gut barrier dysfunction in CVID. MethodsWe measured serum biomarkers of BT (bacterial 16S rDNA [bDNA], by qt-PCR) and intestinal barrier defects (intestinal fatty-acid binding protein [I-FABP], by ELISA) in 88 CVID and 17 healthy control (HC) subjects. B cell phenotypes (% class-switched memory B cells [SMB, CD19 +CD27+IgM-IgD-/CD19+] and % IgA+ SMB [CD19+CD27+IgA+/CD19+]) were enumerated by flow cytometry. Results88 CVID subjects aged 21–62 years were recruited (baseline median IgG 202 [IQR 105–357], IgA 7 [< 5–15], IgM 11 [5–28] mg/dL, and SMB 1% [0.15–2.36%]). Serum bDNA and I-FABP were significantly elevated in CVID vs. HC (P < 0.0001, P < 0.001, respectively). Amongst CVID subjects, serum bDNA correlated with I-FABP levels (Spearman r = 0.27, P = 0.029). Serum bDNA and I-FABP levels were not age-dependent in this adult cohort. There were no sex differences in bDNA levels, though higher I-FABP was observed in males (p = 0.02). Serum bDNA and I-FABP were significantly elevated regardless of overt clinical enteropathy, though those with enteropathy had higher median levels vs. those without.Regarding immunologic and biochemical parameters, high serum bDNA was inversely correlated with 1) %IgA+ SMB (Spearman r = –0.52, P = 0.019, n = 23), and 2) serum IgA (Spearman r = –0.34, P = 0.002). Additionally, bDNA was significantly higher in those with elevated LFTs (P = 0.03). A negative trend between bDNA and total SMB was also observed. Gut barrier defect, as probed by I-FABP, was significantly higher in CVID patients with 1) undetectable IgA (p = 0.03), 2) abnormal liver function tests (p = 0.03), and negatively correlated with 3) CD4+ T cell counts (R = –0.34, p = 0.015). Serum bDNA and I-FABP were not associated with baseline IgG, IgM, or other B/T subsets examined. ConclusionLack of IgA and IgA+SMB are main immunologic parameters associated with BT in CVID, while abnormal LFTs may be an indirect indicator for BT and gut barrier defects. Our data suggest a role of IgA+ B cells/IgA as biological determinants of BT, and a link between BT and liver pathologies in CVID.