Sjgren's syndrome encompasses a disease spectrum with significant heterogeneity. Accumulating data indicates that this heterogeneity reflects the predominance of different disease mechanisms in different patient subsets. Defining relevant mechanistic markers is essential for accurate diagnosis, identification of disease subsets, monitoring of disease activity and prediction of outcome, and potentially for selection of therapy in Sjgren's syndrome. While high-titer autoantibodies are a frequent feature in Sjgren's syndrome, they are not always detected, despite universal lymphocytic infiltration of salivary glands. Our preliminary data shows that there are additional Sjgren's autoantigens recognized by sera from apparently seronegative patients - these antigens are not expressed in cells used as standard antigen sources for autoantibody detection. We propose that different amplifying pathways (e.g. IFNs, cellular cytotoxicity, tissue repair and regeneration) are associated with distinct antigen expression fingerprints, and generation of novel autoantibodies. Furthermore, we propose that definition of additional new autoantibodies reflecting these pathways will provide additional tools for patient classification based on mechanisms active in their tissues. The long term goals of this program are to define novel autoantibodies and autoantigens as probes of mechanisms in Sjgren's syndrome. We will pursue the following specific aims: (i) Define and identify new autoantibodies targeting inducible and developmental autoantigens using SS sera to screen IFN-treated cells and immature epithelial cells as novel autoantigen sources, and demonstrate that B cells with these specificities can be found in the salivary gland of patients with SS; (ii) Define the associations of autoantibodies recognizing inducible and developmental autoantigens with distinct SS phenotypes, and specific autoantigen expression in the SS target tissue; (iii) Demonstrate that the components of a sustaining pathogenic loop interact directly in SS salivary glands by showing enhanced autoantigen expression, together with cytotoxic lymphocyte-specific proteolysis of the same autoantigens recognized by infiltrating T cells in those glands. Since it is likely that distinct disease mechanisms predominate in different patient subsets, phenotype-specific autoantibodies and autoantigen expression in the target tissue constitute tools for molecular subsetting - quantitatively or semi-quantitatively assessing specific pathways in vivo - and may facilitate diagnosis, classification and therefore more targeted therapy in this complex, heterogeneous disease process.

Public Health Relevance

Sj?gren's syndrome is a disease with significant morbidity, which is poorly addressed by currently available therapies. Additionally, the tools available to diagnose and classify patient subgroups are inadequate (with a sizable proportion of patients being autoantibody negative on available assays) and the specific mechanisms generating tissue injury and dysfunction in Sj?gren's syndrome remain unclear. These studies will identify new diagnostic and classification probes in Sj?gren's syndrome, based on the mechanisms operating in the glands being damaged which induce local autoantigen expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012354-17
Application #
8828667
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Chander, Preethi N
Project Start
1998-05-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
17
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Shiboski, Caroline H; Baer, Alan N; Shiboski, Stephen C et al. (2018) Natural History and Predictors of Progression to Sjögren's Syndrome Among Participants of the Sjögren's International Collaborative Clinical Alliance Registry. Arthritis Care Res (Hoboken) 70:284-294
Antiochos, Brendan; Matyszewski, Mariusz; Sohn, Jungsan et al. (2018) IFI16 filament formation in salivary epithelial cells shapes the anti-IFI16 immune response in Sjögren's syndrome. JCI Insight 3:
Baer, Alan N; Walitt, Brian (2018) Update on Sjögren Syndrome and Other Causes of Sicca in Older Adults. Rheum Dis Clin North Am 44:419-436
Igusa, Takeru; Hummers, Laura K; Visvanathan, Kala et al. (2018) Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer. Ann Rheum Dis 77:1179-1186
McCoy, Sara S; Baer, Alan N (2017) Neurological Complications of Sjögren's Syndrome: Diagnosis and Management. Curr Treatm Opt Rheumatol 3:275-288
Baer, Alan N; Walitt, Brian (2017) Sjögren Syndrome and Other Causes of Sicca in Older Adults. Clin Geriatr Med 33:87-103
Shah, Ami A; Xu, George; Rosen, Antony et al. (2017) Brief Report: Anti-RNPC-3 Antibodies As a Marker of Cancer-Associated Scleroderma. Arthritis Rheumatol 69:1306-1312
McMahan, Zsuzsanna H; Wigley, Frederick M; Casciola-Rosen, Livia (2017) Risk of Digital Vascular Events in Scleroderma Patients Who Have Both Anticentromere and Anti-Interferon-Inducible Protein 16 Antibodies. Arthritis Care Res (Hoboken) 69:922-926
Baer, A N; Okuhama, A; Eisele, D W et al. (2017) Eosinophilic sialodochitis: redefinition of 'allergic parotitis' and 'sialodochitis fibrinosa'. Oral Dis 23:840-848
Taylor, Kimberly E; Wong, Quenna; Levine, David M et al. (2017) Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry. Arthritis Rheumatol 69:1294-1305

Showing the most recent 10 out of 59 publications