# Immunometabolism of IgA-Microbiota Interaction in Gut Homeostasis and Inflammation

> **NIH NIH P01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $462,270

## Abstract

The commensal microbiota establishes a mutualistic relationship with the gut immune
system by activating B cells via T cell-dependent (TD) and T cell-independent (TI)
pathways that generate secretory immunoglobulin A (SIgA) with high and low affinity
for antigen, respectively. High-affinity (HA)-SIgA emerges from a relatively well-
understood TD pathway involving CD40L and is generally viewed as essential for gut
homeostasis due to its specific recognition of bacterial cells. However, recent studies
indicate that also (LA)-SIgA from a poorly understood TI pathway specifically
recognizes commensal bacteria. Additional evidence shows that HA-SIgA coats
colitogenic bacteria in patients with inflammatory bowel disease (IBD), raising the
possibility that gut homeostasis requires balanced HA-SIgA and LA-SIgA responses.
This proposal will combine an in-depth analysis of primary immunodeficiency (PID)
specimens with studies of knockout, germfree and gnotobiotic mouse models to dissect
the regulation, microbiota reactivity and function of LA-SIgA and HA-SIgA responses.
Preliminary data show that TI production of LA-SIgA involves CD40-independent
activation of gut B cells by TACI, a BAFF/APRIL receptor that triggers IgM-to-IgA class
switching through the kinase mTOR. Additional preliminary evidence shows that TACI
deficiency impairs microbiota diversity and gut homeostasis by decreasing the coating
of bacterial cells by LA-SIgA. Here, we hypothesize that TACI and CD40 orchestrate
LA-SIgA and HA-SIgA responses through mTOR-regulated TI and TD pathways
targeting non-overlapping consortia of gut bacteria. Three specific aims are proposed.
Aim 1 is to elucidate the regulation of LA-SIgA and HA-SIgA responses by TACI and
CD40 and dissect their reactivity for the gut microbiota. Aim 2 is to characterize the
composition and function of bacterial communities targeted by LA-SIgA and HA-SIgA
antibodies; Aim 3 is to dissect the functional interplay of LA-SIgA and HA-SIgA
responses induced by TACI and CD40 with B cell signals from mTOR. This kinase
activates B cells by engaging TACI through MyD88. The proposed studies (Project 3)
will take advantage of cells, stool and tissues made available by this consortium and of
the complementary and integrative expertise of the Cunningham-Rundles group, which
evaluates the role of TACI in B cell proliferation and differentiation (Project 1), the
Meffre group (Project 2), which explores the role of TACI and other key antibody-
regulating molecules in B cell tolerance, and the Casanova group (Project 4), which
seeks to identify new causative genes in PIDs.

## Key facts

- **NIH application ID:** 9984944
- **Project number:** 5P01AI061093-16
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** ANDREA CERUTTI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $462,270
- **Award type:** 5
- **Project period:** 2004-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984944

## Citation

> US National Institutes of Health, RePORTER application 9984944, Immunometabolism of IgA-Microbiota Interaction in Gut Homeostasis and Inflammation (5P01AI061093-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9984944. Licensed CC0.

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