# Immunogenetic control of autoimmune biliary disease

> **NIH VA I01** · VA NORTHERN CALIFORNIA HEALTH CARE SYS · 2020 · —

## Abstract

Primary biliary cholangitis (PBC) is an incurable autoimmune biliary disease (“ABD”) in which
the immune system destroys bile ducts by targeting cholangiocytes. Many immune based
therapies have been applied to PBC, but none have been successful and the disease is
currently incurable. Progress in finding new therapies for PBC has been blocked because the
clinical symptoms of disease often arise many years after initiation of disease; thus data derived
from human patients has not permitted fundamental insights into the immunopathogenesis of
the disease. Fundamental new insights that can generate new therapeutic targets require
information about the earliest pathogenesis of PBC, which must come from animal models of
disease. We developed the first spontaneous animal model of PBC: NOD.ABD mice that
develop autoimmune biliary disease remarkably similar to human including 1) anti-mitochondrial
antibodies highly specific for human PBC; 2) disease transferable by autoreactive T cells; and
3) immunohistopathology highly characteristic of PBC with granuloma formation, T cell infiltrates
in the biliary lining, and destructive cholangitis. Recently we discovered a novel genetic mutation
in NOD ABD. Understanding how this novel genetic system controls the aberrant cholangiocyte:
immune system interaction which drives ABD is the goal of the current grant. Here we have
constructed a novel congenic mouse (NOD.Abd3) that allows us to mechanistically analyze the
very earliest basis of disease. We also show that a genetic background which enhances
autoimmunity (the NOD genetic background, which predisposes to many autoimmune
conditions including T1D, Sjogren’s syndrome, and thyroiditis) must be present. This complex
genetic etiology is similar to human disease. Therefore our unique model offers new insights
into basic immunopathology relevant to human PBC and other cholangiopathies. We propose 3
aims: Aim 1: Determine the genetic basis of NOD autoimmune biliary disease. We show
that disease in congenic NOD.Abd3 mice requires a region on chromosome 1, “Abd3”, which
includes a 1.0 Mb B6 interval (“B6-Abd3”) as well as mutated Pkhd1del36-67 upstream of it. Our
hypothesis is that early expression of aberrant Pkhd1 in cholangiocytes breaks immune
tolerance to cholangiocytes. We can prove/disprove this hypothesis by sophisticated genetic
approaches. Aim 2: Determine the role of early cholangiocyte “ductular reaction” in
NOD.Abd3 pathogenesis. By 4 weeks of age, NOD.Abd3 bile ducts show massive immune
infiltration which then ascends into intrahepatic bile ducts. Our hypothesis is that the aberrant
immune response is due to an early “ductular reaction” of NOD.Abd3 cholangiocytes, which
stimulates the innate immune system. Aim 3: Mechanistic role of myeloid derived
suppressor cells (MDSCs) and activated macrophages in NOD.Abd3 and human PBC
pathogenesis. The immune system is required for clinical ABD in our model. We hypothesize
that the Abd3 genetic region alters macrophag...

## Key facts

- **NIH application ID:** 9898256
- **Project number:** 5I01BX003821-04
- **Recipient organization:** VA NORTHERN CALIFORNIA HEALTH CARE SYS
- **Principal Investigator:** William M Ridgway
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898256

## Citation

> US National Institutes of Health, RePORTER application 9898256, Immunogenetic control of autoimmune biliary disease (5I01BX003821-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898256. Licensed CC0.

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