2016Joint Usage and Research Report
Title of Research Project
ApplicantRole of LAMP3 in autoimmunity

Institution

National Institutes of Health (USA)Job title

Principal Investigatorand name
VisitingNameJohn Chiorini

researcher
Purpose of the Research Project

We are collaborating with the University of Hokkaido to identify(approx. 250 words)

the mechanism of cell death in Sjogren’s Syndrome patients andits connection to autoimmunity as well as characterize thechanges in cellular gene expression.

Development of the ResearchPrimary Sjögren’s Syndrome (pSS) is a systemic

Project and Results

autoimmune disorder that affects an estimated 1% of the(approx.. 850 words)

American population with a strong gender bias of 9:1 toward
females. pSS is characterized by exocrine gland lymphocytic
infiltration and dysfunction, as well as autoantibody formation.
The conventional explanation of salivary gland dysfunction
assumes an important role of autoimmune inflammation insalivary gland (SG) and lacrimal gland (LG). However, in many
patients the correlation between the focus score (FS) on SG
biopsy (a measure of lymphocytic infiltration) and decreased
saliva production is limited. This suggests a critical role of othernon-immunological factors such as gender, environment, andgenetics in this disease. To date, little is understood regarding
the changes in the epithelia associated with the loss of glandactivity. We hypothesized that changes in the acinar and ductal
cells might be key determinants of SG dysfunction.
Our analysis suggests a change in network pathways associatedwith ER stress, autophagy, and the unfolded protein response.
Because of their high secretory activity, salivary glands exhibit ahigh basal level of ER stress and consequently activation of theunfolded protein response.

Markers of this change in state(specifically LAMP3 and LC3) show a statistically significant
correlation with the level of autoimmune activity in the patients
as well as colocalization and an increase in enlarged vesicles.
We have carefully examined these pathways and in contrast toreports in the literature, our in vitro studies of these pathways
and transcriptome-associated changes associated with Sjögren’s
syndrome suggest that, instead of enhanced autophagy insalivary glands of pSS patients, we observe stalled autophagy.
Our hypothesis is the stalling in autophagy results in theaberrant release of neoantigens resulting in the creation ofautoantibodies. Our ongoing work in this project (a collaboration
with the Noguchi and Atsumi laboratories at Hokkaido
University in Sapporo Japan) will examine the question of whatis driving this change in autophagy, the mechanism of action, as
well as develop strategies that could be used to restore a balance
between autophagy and ER stress in patients. Understanding
this aspect of Sjögren’s syndrome will identify novel therapeutictargets that may be helpful in controlling systemic complicationsof this disease and will lead to a broader understanding ofautoantibody development.

Publication【Conference, symposium, workshop etc.】*Enter the names of conferenceor journal and its vol. No. where
the above work was presented.
【Journals】