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

## TL;DR

This study shows that IgA deficiency in CVID allows bacteria to enter the bloodstream, causing inflammation and autoimmunity through increased IFN-γ and BAFF.

## Contribution

The study links IgA loss in CVID to bacterial translocation and elevated IFN-γ and BAFF, revealing a novel mechanism for inflammatory complications.

## Key findings

- Loss of IgA in CVID is associated with increased serum 16S ribosomal DNA from gut bacteria.
- Lower IgA levels correlate with higher serum IFN-γ and BAFF, promoting inflammation and autoimmunity.
- Bacterial transcytosis due to IgA deficiency may drive autoimmune complications in CVID.

## Abstract

Inflammatory complications occur in many subjects with common variable immunodeficiency. We show that microbial bacterial 16S ribosomal DNA, significantly increased in the serum of these subjects, is associated with loss of IgA, leading to excess IFN-γ and increased serum B cell–activating factor (BAFF), both of which promote autoimmunity and inflammation.

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.