# Adaptive immunity in primary sclerosing cholangitis patients at risk for colorectal cancer

> **NIH NIH F30** · UNIVERSITY OF CHICAGO · 2022 · $51,752

## Abstract

PROJECT SUMMARY/ABSTRACT
Primary sclerosing cholangitis (PSC) is a class II human leukocyte antigen (HLA-II) associated autoimmune
disease of the liver, characterized by the progressive fibrosis of the bile ducts, for which there is no cure.
Upwards of 80% of individuals with PSC also have inflammatory bowel disease (IBD), and are at five times
greater risk for colorectal cancer (CRC) than individuals with IBD alone. PSC is a major health concern, as
50% of individuals with PSC-IBD develop CRC within 25 years of diagnosis. The mechanisms causing the high
risk of CRC in PSC-IBD, however, are unknown. Our group took an unbiased transcriptional approach to
analyzing human colonic tissue in order to investigate the mechanisms of the increased risk of CRC and other
pathologies in PSC. Our analysis revealed that expression of immunoglobulin G1 (IgG1) and genes
downstream of interleukin-17 (IL-17) signaling accurately predicted all cases of dysplasia (the precursor to
CRC) in patients with PSC-IBD. Further investigation suggests that these transcriptional signals may originate
from an increase in adaptive immune cells, namely IgG plasma cells and IL-17+ CD4 T-cells, in the colon of
PSC subjects that develop dysplasia. The objective of this study is to use primary human tissue samples to
better understand the relationship between these cell types and the development of dysplasia in PSC-IBD
patients. Previous work demonstrates that in HLA-II associated autoimmunity, a pathogenic antigen causes
clonal expansion of plasma cells and T-cells which leads to tissue destruction. We hypothesize that in PSC,
IgG plasma cells and IL-17+ CD4 T-cells are clonally expanded in response to a pathogenic antigen. Moreover,
we hypothesize that these cells induce dysplasia in PSC subjects. To address this hypothesis, we propose to
1) dissect the relationship between plasma cells, T-cells, and dysplasia in PSC-IBD as compared to IBD alone;
and 2) further characterize the nature and clonality of these cellular responses, and use this to identify the
causative antigen. We will take a multidisciplinary approach, including single cell transcriptional analysis, to
complete this investigation. As this study will be done on human tissue, the results will be directly applicable to
understanding of the development of CRC in PSC-IBD. Additionally, this work may help identify a causative
antigen driving dysplasia in PSC-IBD. Ultimately, this will allow for the development of therapeutics specific for
individuals with PSC. This work will also contribute to our understanding of how adaptive immunity can induce
cancer.

## Key facts

- **NIH application ID:** 10409786
- **Project number:** 5F30DK121470-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Dustin Shaw
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409786

## Citation

> US National Institutes of Health, RePORTER application 10409786, Adaptive immunity in primary sclerosing cholangitis patients at risk for colorectal cancer (5F30DK121470-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10409786. Licensed CC0.

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