# Modulation of immunodominance in HLA class I associated uveitides

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $457,650

## Abstract

ABSTRACT/PROJECT SUMMARY
Variants at ERAP1 modulate the risk for several forms of non-infectious uveitis in the presence of disease-
associated HLA class I, strongly suggesting a so far unproven change in immunodominance with impact on
disease causation and protection.
The overall objective of this application is to determine through which mechanism ERAP1 allotypes cause and
protect from HLA I-associated uveitis. Our long-term goal is to understand and therapeutically target HLA class
I associated autoimmunity in uveitis.
 Our central hypothesis is that allotypic ERAP1 alters the HLA I-bound peptidome to include epitopes that
are immunogenic when presented by disease-relevant HLA I, which induces or controls disease through a
change in immunodominance. The rationale for this study is that mechanistic understanding of ERAP1-mediated
pathogenesis in HLA I immunity will enable targeted therapy design aimed at specific ERAP1-HLA I-uveitis
subsets.
 Based on these considerations we will implement two specific aims. In Aim 1 we will determine through
which mechanism the allotype ERAP1 Hap10 initiates immune dysfunction in HLA-B*51+ Behçet’s uveitis (BU)
but protects from HLA-B*27+ acute anterior uveitis (AAU) via a series of CRISPR/Cas9 genome editing
experiments. These experiments will allow us to define its functional contribution to the HLA I restricted
peptidomes relevant to each of these disorders and their effect on the generation of immunogenic or tolerogenic
immune responses. In Aim 2 we will establish how HLA I restricted pathogenic epitopes depend on allotype-
specific ERAP1 function through the exploitation of clonally expanded CD8 T cells from active BU and AAU
patients for cellular cloning, genome-editing and functional assessment of immunogenicity.
 We expect the following outcomes 1) knowledge of the immunogenic and tolerogenic effects mediated
by allotypic ERAP1 in two highly disease-relevant HLA restriction contexts: HLA-B27 and B51, 2) identity of
epitopes that induce or prevent immunogenicity in these contexts, 3) proof of principle that allotypic ERAP1
regulates autoimmunity and that manipulation of its activity modulates pathogenicity providing irrefutable
rationale for targeting ERAP1 enzyme activity pharmacologically, or through gene therapy. This will have a
positive impact on the field through the identification of molecular targets allowing the design of therapy for
patient groups defined by genotypes, and through mechanistic understanding extending beyond the scope of
BU and AAU to additional MHC-I-opathies with immense impact on human health, such as IBD, psoriasis, and
psoriatic arthritis.

## Key facts

- **NIH application ID:** 10771950
- **Project number:** 5R01EY033495-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Johannes Nowatzky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $457,650
- **Award type:** 5
- **Project period:** 2022-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771950

## Citation

> US National Institutes of Health, RePORTER application 10771950, Modulation of immunodominance in HLA class I associated uveitides (5R01EY033495-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10771950. Licensed CC0.

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