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. 2026 Jan 13;2(2):e20250080.
doi: 10.70962/jhi.20250080. eCollection 2026 Mar 2.

IgA defects in CVID lead to bacterial translocation, increased serum γ-interferon, and BAFF

Hsi-En Ho  1 , Lin Radigan  1 , Eric Meffre  2 , Charlotte Cunningham-Rundles  1
Affiliations

IgA defects in CVID lead to bacterial translocation, increased serum γ-interferon, and BAFF

Hsi-En Ho et al. J Hum Immun. .

Abstract

Common variable immunodeficiency (CVID) is a primary antibody defect that leads to frequent infections, but inflammatory complications appear in 30-50%, leading to increased morbidity and mortality. We have previously shown that circulating bacterial 16S ribosomal DNA (rDNA), originating from gut commensals, is significantly increased in the serum of patients with CVID with inflammatory conditions (P = 0.0007). Here we examined the relationships between serum 16S ribosomal DNA (rDNA), isotype-switched memory (SM) B cells, serum IgA, IgA+ SM B cells, serum IFN-γ, and serum B cell-activating factor (BAFF). We found a significant inverse correlation between serum 16S ribosomal DNA (rDNA) concentrations and the numbers of isotype SM B cells, IgA+ SM B cells, and serum IgA levels in our large cohort, suggesting that loss of IgA in the mucosal barrier permits bacterial transcytosis. Loss of SM B cells and lower serum IgA concentrations were both associated with increased serum IFN-γ, as well as increased CXCL9 and serum BAFF concentrations. Serum BAFF was also significantly associated with IFN-γ levels and inversely correlated with baseline serum IgA. We conclude that loss of IgA, accompanied by mucosal defects in CVID, may permit bacterial transcytosis, resulting in excessive IFN-γ and BAFF production, both of which promote autoimmune and inflammatory complications in this immune defect.

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Conflict of interest statement

Disclosures: H. Ho reported personal fees from Sanofi outside the submitted work. E. Meffre reported personal fees from Genentech, Boehringer Ingelheim, Anovo, and Merck outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.
Very low numbers of isotype switched memory B cells (SMB) in patients with CVID, is associated with the development of inflammatory complications. (A) Isotype-switched member B cells and bacterial DNA in patients and controls: The percentage of SM B cells of 57 CVID subjects with 2% or fewer was compared to 59 CVID subjects with more than this number, or 21 normal controls, showing highly significant differences between these groups (Mann–Whitney test P = 0.001). (B) Increased bacterial DNA in subjects with inflammatory complications: Examining 59 CVID subjects with inflammatory conditions as compared to the 57 other CVID subjects without these conditions (or controls), showing highly significant differences between these groups (Mann–Whitney test P = 0.0008).
Figure 2.
Figure 2.
Isotype-switched member B cells are inversely related to bacterial DNA in patients. The numbers of isotype SM B cells for the 114 CVID patient cohort were significantly and inversely related to the amount of bacterial DNA for 90 CVID samples (Spearman r, two tailed test, P = 0.02; r = −0.31). Subjects in Group 1 (no inflammatory complications) are distinguished from those with these complications (Group 2).
Figure 3.
Figure 3.
A higher serum IgA is related to lower levels of bacterial DNA in blood. These subjects have more IgA+ switched B cells, and fewer inflammatory complications. (A) Serum IgA and bacterial 16 ribosomal DNA (rDNA). Serum IgA is inversely related to the content of bacterial 16S ribosomal DNA (rDNA) in 111 paired samples (Spearman r, two tailed test P = 0.006; r = −0.3224). Subjects in Group 1 (no inflammatory complications) are distinguished from those with these complications (Group 2). (B) IgA+ SM B cells. The numbers of IgA+ SM B cells for 89 subjects were closely correlated with the numbers of total isotype SM B cells (Spearman r, two tailed test P = 0.002; r = −0.3265). Subjects in Group 1 (no inflammatory complications) are distinguished from those with these complications (Group 2). (C) IgA+ SM B cells and serum IgA. The numbers of IgA+ SM B cells are related to the baseline level of serum IgA of the same 92 patients (Spearman r, two tailed test P = 0.002; r = −0.322). Subjects in Group 1 (no inflammatory complications) are distinguished from those with these complications (Group 2). (D) IgA+ SM B cells and 16S ribosomal DNA (rDNA). The number of IgA+ SM B cells was also inversely related to the bacterial ribosomal DNA (rDNA) levels in the same 93 serum (Spearman r, P = 0.007; r = −0.2808). Again, CVID subjects in groups 1 and 2 are indicated.
Figure 4.
Figure 4.
Serum IFN-γ is increased in CVID subjects with very low isotype switched memory B cells; these subjects also have increased CXCL9, and more inflammatory complications. (A) Serum IFN-γ and isotype SM B cells. Serum IFN-γ was significantly increased in sera of 88 CVID subjects with the fewest numbers of circulating isotype SM B cells, <2% (Mann–Whitney test, P = 0.03). 10 serums from normal controls are included. (B) Increased CXCL9. CVID subjects (n = 94) had increased serum CXCL9 as compared to 12 healthy controls (Mann–Whitney test P < 0.001). (C) Serum IFN-γ and CXCL9. For 89 CVID subjects, CXCL9 and IFN-γ levels were significantly correlated (Spearman test 4 = 0.4556; P < 0.0001). Subjects in Group 1 (no inflammatory complications) are distinguished from those with these complications (Group 2).
Figure 5.
Figure 5.
The Serum BAFF level is related to IFN-γ content, is increased in those with fewest SMB cells, and the lowest serum IgA levels. (A) BAFF and IFN-γ. BAFF was significantly related to the amount of IFN-γ in sera of 98 paired CVID sera (Spearman r = −0.3120, P = 0.002). (B) BAFF and isotype SM B cells. Serum BAFF was significantly increased with CVID subjects with very reduced SM B cells, <2% as compared to those subjects with 2% or more of these B cells (Mann–Whitney test, P = 0.0001) or normal controls. (C) BAFF and serum IgA. BAFF levels were inversely related to baseline serum IgA in 95 paired CVID serum samples (Spearman correlation, r = −0.2065; P = 0.04).
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