# Analysis of MyD88-mediated immune activation in Sjogrens syndrome pathogenesis

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $372,018

## Abstract

Project Summary
 Sjögren’s syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss
of tears and saliva. Primary SS (pSS) affects salivary and lacrimal tissue and results in many serious systemic
disease manifestations. Once diagnosis is achieved, no SS-specific curative treatment options are available; rather
treatments for SS are palliative. Thus, there is a critical need to identify etiologic events that will facilitate earlier
diagnosis of SS and development of therapeutics that mitigate the progression of this debilitating disease. Studies
in our laboratory revealed that Myeloid Differentiation Factor Primary Response Protein 88 (MyD88) is essential for
pSS development. MyD88 is an adaptor molecule that is expressed ubiquitously and is required for most Toll-like
receptor (TLR) and IL-1 receptor (IL-1R) family member signaling. Notably, TLRs and IL-1R family members are
elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting these receptors contribute
to SS. Our central hypotheses are that (i) tissue-specific MyD88 expression dictates distinct pSS disease
manifestations and that (ii) activation of MyD88-dependent signaling networks drives pSS pathogenesis. Our
objectives are to identify the tissue-specific contributions of MyD88 and to determine the MyD88-mediated signaling
networks that govern pSS disease pathogenesis. We will employ a pSS mouse model (NOD.B10) and a conditional
knockout strain of NOD.B10 mice developed in our laboratory that lacks expression of MyD88 in the hematopoietic
compartment (immune cells) specifically. These mice provide a unique model system to examine the role of MyD88
in pSS directly. The rationale for this proposal rests on the fact that activation of MyD88-mediated signaling pathways
contributes to many autoimmune diseases. Both salivary tissue and immune cells express receptors that promote
inflammation via MyD88, such as TLRs and IL-1R family members. Our studies in pSS mice deficient in MyD88
demonstrate that MyD88 is crucial for pSS pathogenesis; however, the specific cell types that express MyD88 in
disease and the MyD88-dependent signaling pathways that are activated in pSS are incompletely understood. We
will test our hypotheses by completion of three specific aims: (1) Identify immune cell-specific contributions of MyD88
to pSS pathogenesis, (2) Evaluate MyD88-dependent IL-36-related cytokines in pSS, and (3) Assess the role of the
MyD88-dependent endosomal TLRs, TLR7 and TLR9, in pSS. This study is innovative because it will uncover new
mechanisms related to the role of MyD88-dependent signaling networks in pSS and will identify specific cell types
that mediate distinct pSS disease manifestations. Targeted blockade of MyD88-dependent TLR and IL-1R family
member signaling pathways represents an innovative therapeutic approach for the treatment of pSS. This proposal
is significant because it will reveal new mechanisms that gove...

## Key facts

- **NIH application ID:** 10133046
- **Project number:** 5R01DE029472-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Jill Marie Kramer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $372,018
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133046

## Citation

> US National Institutes of Health, RePORTER application 10133046, Analysis of MyD88-mediated immune activation in Sjogrens syndrome pathogenesis (5R01DE029472-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133046. Licensed CC0.

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