Sjogren's syndrome is a chronic autoimmune disease, which results in decreased secretion from salivary and lacrimal glands. The broad, long-term objectives of this proposal are to define pathogenic mechanism(s) in Sjogren's syndrome, with a view to identifying relevant pathways for therapeutic intervention in this disease. Recent studies have implicated abnormal cholinergic signaling and the cytotoxic lymphocyte granule pathway as areas of potential importance in this regard. This proposal will focus on these pathways in Sjogren's syndrome, by defining the mechanisms by which granzyme B (GrB) induces salivary gland epithelial cell damage and dysfunction and autoantibody production.
The specific aims of the proposal are to (1) Define the mechanisms and functional effects of type 3 muscarinic acetylcholine receptor (M3R) cleavage by GrB. This will be done by elucidating GrB-induced cleavage of M3R that occurs in intact cells during granule-induced cytotoxicity, and addressing the effects of GrB cleavage on M3R ligand binding and signal transduction; (2) Identify the predominant mechanisms of salivary epithelial cell damage and dysfunction in vivo in patients with Sjogren's syndrome. Specific evidence of GrB- generated fragments of Sjogren's syndrome autoantigens in affected tissue from patients with Sjogren's syndrome will be sought, using novel antibodies that are highly specific for neo- epitopes generated by GrB-mediated cleavage. The frequency of antibodies to the M3R in patients with primary or secondary Sjogren's syndrome will be quantitated; and (3) Establish the role of GrB in the development of salivary gland dysfunction and damage in animal models in vivo. This will be accomplished by studying the development of a Sjogren's syndrome-like phenotype (inflammatory infiltrates, autoantibodies and secretory dysfunction) in wild-type and GrB-deficient NOD mice, and addressing whether immunization with granule-killed primary salivary epithelium results in an autoantibody response against salivary gland epithelial cell GrB substrates, including M3R, with functional consequences. These studies will yield an enhanced understanding of the mechanisms whereby the cytotoxic lymphocyte granule pathway participates in the pathogenesis of Sjogren's syndrome.
|Birnbaum, J; Atri, N M; Baer, A N et al. (2017) Relationship Between Neuromyelitis Optica Spectrum Disorder and Sjögren's Syndrome: Central Nervous System Extraglandular Disease or Unrelated, Co-Occurring Autoimmunity? Arthritis Care Res (Hoboken) 69:1069-1075|
|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|
|Konig, Maximilian F; Abusleme, Loreto; Reinholdt, Jesper et al. (2016) Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med 8:369ra176|
|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|
|Shah, Ami A; Casciola-Rosen, Livia; Rosen, Antony (2015) Review: cancer-induced autoimmunity in the rheumatic diseases. Arthritis Rheumatol 67:317-26|
|Duan-Porter, Wei D; Woods Jr, Virgil L; Maurer, Kimberly D et al. (2014) Dynamic conformations of nucleophosmin (NPM1) at a key monomer-monomer interface affect oligomer stability and interactions with granzyme B. PLoS One 9:e115062|
|Fiorentino, David F; Chung, Lorinda S; Christopher-Stine, Lisa et al. (2013) Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1?. Arthritis Rheum 65:2954-62|
|Hall, John C; Casciola-Rosen, Livia; Samedy, Lesly-Ann et al. (2013) Anti-melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum. Arthritis Care Res (Hoboken) 65:1307-15|
|Romero, Violeta; Fert-Bober, Justyna; Nigrovic, Peter A et al. (2013) Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis. Sci Transl Med 5:209ra150|
|Cottrell, Tricia R; Hall, John C; Rosen, Antony et al. (2012) Identification of novel autoantigens by a triangulation approach. J Immunol Methods 385:35-44|
Showing the most recent 10 out of 63 publications