# Organ-specific autoimmunity resulting from two genetic defects in tolerance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $402,916

## Abstract

Project Summary
 A diversity of tolerance mechanisms work together to prevent autoimmune disease in most individuals
by limiting the activity of self-reactive lymphocytes. How genetically determined defects in particular tolerance
pathways may interact to lead to autoimmune disease is not well understood. The goal of this project is to
provide insights into the basis of multigenic autoimmune susceptibility by modeling it in mice using two genetic
defects with especially well understood immunologic mechanisms, namely a complete deficiency in Lyn and
partial deficiency in Aire. Aire controls the expression of a large number of tissue-restricted self antigens in the
thymus and therefore promotes central tolerance of T cells. Lyn is a protein tyrosine kinase that restrains the
activities of dendritic cells, macrophages, and B cells due to its importance in mediating the signaling of
inhibitory receptors on the surface of these cells. Remarkably, mice containing both a hypomorphic allele of
Aire, which by itself leads to little autoimmunity on the autoimmune resistant C57BL/6 background, and a
deficiency in Lyn spontaneously develop a highly destructive autoimmune attack on their retinas. This disease
occurs in 50% of Lyn-/- AireGW/+ mice, all of which have severe disease by 8 weeks of age, whereas the other
50% are protected. The disease prevalence in the double mutant mice is strikingly similar to results of identical
twin studies in humans with autoimmune diseases. Moreover, this new animal model of spontaneous organ-
specific autoimmune disease has several features that are especially favorable for mechanistic dissection and
may make it possible to provide new conceptual insights into the nature of autoimmune disease susceptibility
and initiation. The proposed studies will determine the epitope specificity and avidity of the CD4 T cells that
break tolerance and initiate autoimmune attack. How reduced self-antigen expression in the thymus enables
the pathogenic potential of these T cells will be determined. In addition, for mice that do not develop uveitis,
there is a small expansion of retinal autoantigen-specific CD4 T cells in the eye-draining lymph nodes. The
immunological mechanisms that prevent these T cells from initiating autoimmune attack in 50% of animals will
be determined. We shall determine whether tolerance in the protected animals is primarily due to anergy of
effector T cells, to dominant suppression by retina-specific Treg, or to a tissue-specific checkpoint. In these
protected mice, we shall determine whether immunological perturbations can unleash disease in otherwise
protected animals, a situation that may be relevant to the organ-specific autoimmunity seen in some cancer
patients treated with checkpoint blockade. These studies will provide novel and valuable insights into the
question of how genetic defects in two different immune tolerance pathways can interact to result in genetic
susceptibility to autoimmune disease and in u...

## Key facts

- **NIH application ID:** 9879673
- **Project number:** 5R01AI138479-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anthony L Defranco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,916
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879673

## Citation

> US National Institutes of Health, RePORTER application 9879673, Organ-specific autoimmunity resulting from two genetic defects in tolerance (5R01AI138479-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9879673. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*