Sj?gren'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 Sj?gren's syndrome. While high-titer autoantibodies are a frequent feature in Sj?gren's syndrome, they are not always detected, despite universal lymphocytic infiltration of salivary glands. Our preliminary data shows that there are additional Sj?gren'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 Sj?gren'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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012354-16
Application #
8627597
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
1998-05-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
16
Fiscal Year
2014
Total Cost
$563,321
Indirect Cost
$215,592
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
McMahan, Zsuzsanna H; Cottrell, Tricia R; Wigley, Fredrick M et al. (2016) Enrichment of Scleroderma Vascular Disease-Associated Autoantigens in Endothelial Lineage Cells. Arthritis Rheumatol 68:2540-9
Xu, George J; Shah, Ami A; Li, Mamie Z et al. (2016) Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer. Proc Natl Acad Sci U S A 113:E7526-E7534
Birnbaum, Julius; Atri, Nidhi M; Baer, Alan N et al. (2016) The Relationship Between the Neuromyelitis Optica Spectrum Disorder and Sjögren's Syndrome: Central Nervous System Extraglandular Disease or Unrelated, Co-occurring Autoimmunity? Arthritis Care Res (Hoboken) :
Baer, Alan N; Okuhama, Ayako; Eisele, David W et al. (2016) Eosinophilic sialodochitis: re-definition of "allergic parotitis" and "sialodochitis fibrinosa". Oral Dis :
Baer, Alan N; Petri, Michelle; Sohn, Jungsan et al. (2016) Antibodies to interferon-inducible protein-16 in primary Sjögren's syndrome are associated with markers of more severe diseas. Arthritis Care Res (Hoboken) :
Baer, Alan N; Kurano, Tracie; Thakur, Uma J et al. (2016) Dual-energy computed tomography has limited sensitivity for non-tophaceous gout: a comparison study with tophaceous gout. BMC Musculoskelet Disord 17:91
Baer, Alan N; Petri, Michelle; Sohn, Jungsan et al. (2016) Association of Antibodies to Interferon-Inducible Protein-16 With Markers of More Severe Disease in Primary Sjögren's Syndrome. Arthritis Care Res (Hoboken) 68:254-60
McMahan, Zsuzsanna H; Shah, Ami A; Vaidya, Dhananjay et al. (2016) Anti-Interferon-Inducible Protein 16 Antibodies Associate With Digital Gangrene in Patients With Scleroderma. Arthritis Rheumatol 68:1262-71
Fiorentino, David F; Presby, Matthew; Baer, Alan N et al. (2016) PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjögren's syndrome. Ann Rheum Dis 75:1145-51
Baer, Alan N; McAdams DeMarco, Mara; Shiboski, Stephen C et al. (2015) The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren's syndrome. Ann Rheum Dis 74:1557-61

Showing the most recent 10 out of 48 publications