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.
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.
|Sule, Sangeeta; Rosen, Antony; Petri, Michelle et al. (2011) Abnormal production of pro- and anti-inflammatory cytokines by lupus monocytes in response to apoptotic cells. PLoS One 6:e17495|
|Fiorentino, David; Chung, Lorinda; Zwerner, Jeff et al. (2011) The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol 65:25-34|
|Andrade, Felipe (2010) Non-cytotoxic antiviral activities of granzymes in the context of the immune antiviral state. Immunol Rev 235:128-46|
|Levine, Stuart M; Raben, Nina; Xie, Dan et al. (2007) Novel conformation of histidyl-transfer RNA synthetase in the lung: the target tissue in Jo-1 autoantibody-associated myositis. Arthritis Rheum 56:2729-39|
|Grader-Beck, Thomas; Casciola-Rosen, Livia; Lang, Thomas J et al. (2007) Apoptotic splenocytes drive the autoimmune response to poly(ADP-ribose) polymerase 1 in a murine model of lupus. J Immunol 178:95-102|
|Casciola-Rosen, Livia; Garcia-Calvo, Margarita; Bull, Herbert G et al. (2007) Mouse and human granzyme B have distinct tetrapeptide specificities and abilities to recruit the bid pathway. J Biol Chem 282:4545-52|
|Gelber, A C; Pillemer, S R; Baum, B J et al. (2006) Distinct recognition of antibodies to centromere proteins in primary Sjogren's syndrome compared with limited scleroderma. Ann Rheum Dis 65:1028-32|
|Spinette, Sarah; Mahoney, James A; Rosen, Antony (2006) The MPAC domain is a novel mitotically regulated domain, removed by apoptotic protease cleavage during cell death. Biochem Biophys Res Commun 347:1103-12|
|Rosen, Antony; Casciola-Rosen, Livia (2006) Stem cells in inflammatory disease. Curr Opin Rheumatol 18:618-9|
|Nagaraju, Kanneboyina; Casciola-Rosen, Livia; Lundberg, Ingrid et al. (2005) Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 52:1824-35|
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