# Project 1: Profiling anti-Ro preclinical and clinical autoimmunity

> **NIH NIH P50** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $346,928

## Abstract

ABSTRACT
Mounting evidence suggests that autoantibodies can antecede overt clinical disease, with anti-SSA/Ro among
the earliest reactivities. Yet, predicting who remains protected from overt disease or who will progress would
be a game-changing discovery for understanding the pathogenesis of Systemic Lupus Erythematosus (SLE).
Mothers in the Research Registry for Neonatal Lupus (RRNL) represent a unique population at risk for overt
clinical autoimmunity. Despite the presence of high titer anti-Ro antibodies potentially pathogenic to the
developing fetus, many women are asymptomatic, with autoimmunity identified solely based on disease in their
offspring. Currently, of 521 RRNL mothers, 283 were asymptomatic, or had only minimal symptoms, at the time
of the birth of the NL child, whereas a subset developed SLE. The intertwining of genetic variation in the HLA
locus with the capacity to undergo shifts toward a pathologic gut microbiome may, in part, explain progression
from benign to pathologic autoimmunity and overt SLE. Alternatively, other HLA variants may instead associate
with a protective microbiome that halts progression so that a state of benign autoimmunity persists. In Specific
Aim 1, associations will be sought between host genetics and anti-Ro NL disease status. We will genotype an
estimated 297 RRNL mothers using an HLA next generational sequencing approach that makes no a priori
sequence assumptions. The HLA alleles will be informative to distinguish asymptomatic anti-Ro-mothers
(particularly those remaining so for >6 years) from those who initially or quickly progressed to classified SLE. In
Specific Aim 2, associations will be sought between gut microbiome taxa in the context of HLA and anti-Ro
NL maternal disease status, as we address the hypothesis that HLA is a central driver of pathobiont
associations that contribute to the pathogenesis of overt SLE. A planned longitudinal analysis of the
asymptomatic RRNL mothers will be highly informative and expected to capture women who transition to
established SLE. In Specific Aim 3, we will elucidate the relationships of serological and cellular immunity
(and CD4 T-cell subsets) and anti-Ro NL maternal disease status. Newly generated data will be continuously
shared and discussed with Drs. Silverman (Project 2) and Reizis (Project 3) to further explore associations in
the context of circulating and fecal IgA and anti-DNASE1L3 sensitive reactivity with microparticles. A molecular
basis for the specific microbial taxa that are coated with sIgA will be evaluated in context of a mimicry
hypothesis that considers cross-reactivity between T cell epitopes and bacterial peptides. From a public health
perspective, it is anticipated that conserved patterns or blueprints will be identified for host immune systems
that are best suited to arrest autoimmunity at a benign preclinical state or conversely that favor progression to
overt SLE and tissue injury. Identification of one or more predictive biom...

## Key facts

- **NIH application ID:** 10249213
- **Project number:** 5P50AR070591-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** ROBERT M CLANCY
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,928
- **Award type:** 5
- **Project period:** 2017-09-22 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249213

## Citation

> US National Institutes of Health, RePORTER application 10249213, Project 1: Profiling anti-Ro preclinical and clinical autoimmunity (5P50AR070591-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249213. Licensed CC0.

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