# Sjogren's Syndrome Pathogenic Autoantibodies

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $400,277

## Abstract

Project Summary/Abstract
 Sjögren's syndrome (SS) is a systemic autoimmune disease that most commonly targets the exocrine
glands and is characterized by persistent dry eyes and mouth as well as extra-glandular involvement. Salivary
gland lymphocytic infiltrates are a pathological finding in the disease. There are B cell expansions, hyper-
reactivity and antibody formation in exocrine glands of SS patients. Some patients have glandular ectopic
germinal center formation, as well as the presence of Type II B cells (T2) phenotypically similar to marginal
zone (MZ) B cells in the spleen serving as a checkpoint for deletion and are important in the induction/loss of
tolerance. Patient serum commonly contains autoantibodies to Ro (SS-A) and La (SS-B), and the number of
anti-Ro and -La specific B cells in salivary infiltrates correlate with antibody titer in the serum. Other
specificities are present, including those towards muscarinic 3 receptor (M3R). The evidence suggests
antibodies targeting M3R, important in para-sympathetic signaling, may induce glandular dysfunction. We, and
others have demonstrated that IgG from affected individuals, when injected into naïve mice, can transfer
disease as manifested by salivary flow impairment. Thus, the evidence strongly supports the premise that B
cells infiltrating the salivary glands of SS patients not only make autoantibodies that are in part responsible for
glandular dysfunction but are also a source of some autoantibodies in the sera. This proposal will test the
hypothesis that this is the case, and will address the pathogenic mechanisms underlying this dysfunction. In
Aim 1, using the latest cutting-edge techniques, we will sequence the V-regions and produce monoclonal
antibodies (mAb) from salivary gland plasmablasts, and compare them to the autoantibody repertoire found in
the serum of the same patients, using high-resolution Orbitrap mass spectrometric Ig protein sequencing.
Thus, we will determine whether anti-Ro in the circulation is produced by antibody-secreting cells in the
salivary glands. Given that anti-Ro clonotypes are turned over regularly, determining that this turnover involves
the B lymphocytes in the exocrine glands will be an important insight into the pathogenesis of the disease. We
have demonstrated that some patients have clonally expanded B cells infiltrating the gland, while other patients
do not. In Aim 2 we will determine the correlates and pathophysiology of clonally expanded B cells infiltrating
the salivary glands. We hypothesize that clonally expanded B cells will be related to other immunological
features in the gland and may identify populations or microenvironmental influences that drive germinal center
formation, B cell proliferation and autoantibody production. We have in hand SS mAb that bind and block M3R
activation, and thus, may be involved in the pathogenesis of the disease. In Aim 3 we will define the nature of
pathogenic mAbs that block salivary flow, and determin...

## Key facts

- **NIH application ID:** 9978030
- **Project number:** 5R01DE028001-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Kristi Ann Koelsch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,277
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978030

## Citation

> US National Institutes of Health, RePORTER application 9978030, Sjogren's Syndrome Pathogenic Autoantibodies (5R01DE028001-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9978030. Licensed CC0.

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