# Microbiota, Tertiary Lymphoid Structures and Chronic Inflammation in the Human Gut

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $253,875

## Abstract

PROJECT SUMMARY
Tertiary lymphoid structures (TLS) are ectopic disorganized lymphoid aggregates with the cellular composition
resembling secondary lymphoid organs. Although the exact function of TLS remains elusive, the accumulated
evidence suggests that TLS significantly contribute to the pathogenesis of chronic disorders including
autoimmune and inflammatory diseases, graft versus host disease, transplant rejection, and various types of
cancer. Therefore, better understanding of the composition of TLS and specificity of the immune response that
they initiate in the context of a specific disease may help decode the disease pathogenesis and provide novel
therapeutic strategies.
 Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is
thought to result from the dysregulated immune response to commensal microbes driven by a convergence of
genetic, environmental and microbial factors. Studies in humans and animal models indicate that IBD
pathogenesis is associated with dysregulated mononuclear phagocyte (MP) system and abnormal T and B cell
responses. We recently identified the mechanisms that drive TLS development in mice with Salmonella colitis.
In this new study we will take advantage of our expertise, established collaboration and clinical resources
available at UMass Medical School (UMMS) to understand the mechanisms that drive TLS development and
function in human IBD. Our overarching hypothesis is that TLS in IBD are dysregulated towards a preferential
generation of local proinflammatory IgG response instead of IgA and are induced by specific inflammatory MP
subsets in response to pathobionts that colonize the mucosa. To test the hypothesis, we are going to analyze
intestinal surgical resections from patients with IBD by applying a combination of multi-OMICs approaches. Our
actively collaborating multi-disciplinary team that consists of experts in MP biology, computational biomedicine,
bacterial microbiome, virome, gastroenterology and clinical GI pathology is uniquely positioned to address the
following specific aims:
 Aim 1. Establish cellular composition and predict intercellular interactions in TLS in human IBD;
 Aim 2. Identify pathobionts that drive TLS formation via MP activation in human IBD.
 As the outcome of this project, we will establish a model of cell-cell and cell-microbe interactions and
identify key regulatory molecules required for development of intestinal TLS in human IBD. Short term, these
results will provide a basis for our future R01 proposal that will test computational predictions of host-microbial
interactions and link them to disease pathogenesis with the underlying rationale to identify novel therapeutic
avenues aimed at TLS in IBD. In the long term, information and methodology gained from this study will be
applied to other inflammatory and autoimmune conditions as well as cancers in which TLS formation is evident.

## Key facts

- **NIH application ID:** 10154604
- **Project number:** 1R21AI157369-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Milena Bogunovic
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $253,875
- **Award type:** 1
- **Project period:** 2021-04-06 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154604

## Citation

> US National Institutes of Health, RePORTER application 10154604, Microbiota, Tertiary Lymphoid Structures and Chronic Inflammation in the Human Gut (1R21AI157369-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10154604. Licensed CC0.

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