Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Matriptase Dificency and Primary Sjogren Syndrome Induction: From Patients to Mice.
Yin, Hongen, Kosa, Peter, Liu, Xibao, Swaim, Bill, Cabrera-Perez, Javier, Lai, Zhennan, Ambudka, Indu
The role of epithelial cells in salivary gland function has long been recognized as central to gland activity. However changes in the epithelia of the salivary gland are poorly understood. We previously reported that mice with a ductal cell-specific deletion of the serine protease matriptase display a decrease saliva production following pilocarpine stimulation. This would suggest that matriptase could have a role in the development or maintenance of salivary gland function. The purpose of this study is to determine the role of matriptase in salivary gland function and to investigate its link to salivary gland dysfunction in Sjögren's syndrome.
Matriptase expression was detected in minor salivary gland biopsy (MSG) of health volunteer (HV) and primary Sjögren's syndrome (pSS) patients by microarray and quantitative PCR (qPCR). The role of matriptase in salivary and lacrimal gland function was studied by using tissue-specific conditional knockout mice (MMTV-Cre+/0;St14LoxP/-) mice and salivary gland-specific matriptase knock out [local delivery of adeno-associated virus vector serotype 2 (AAV2) encoding the Cre gene in the submandibular gland (SMG) of St14LoxP/LoxP mice]. SMG and LG from matriptase-ablated and control mice were assessed for inflammation and activity changes by identifying lymphocytic foci (LF) (H&E), pilocarpine stimulated salivary flow rate (SFR) and tear flow rate (TFR) respectively. Autoantibody development was detected by ELISA. Alteration of T cells and cytokine productions were accessed by flow cytometry and multiplex ELISA assay respectively in SMG draining lymph nodes (DLN), spleen and serum. Immunofluorescent staining was used to identify SMG tight junction and ion transport channels. Ductal and acinar cell function was also assayed by regulatory volume decrease (RVD) following hypotonic swelling.
A significant decrease in matriptase expression was found in the MSGs from pSS patients. Furthermore, mice with reduced matriptase expression develop a number of characteristics associated with pSS, including decreased salivary and lacrimal gland function. This decrease in function correlated with a decrease in electrical potential across the epithelial membrane of the gland. In matriptase KO mice, anti-Ro, anti-La and anti-nuclear antibodies (ANA) were detected in serum and a significant increase in LF was detected in LG but not SMG. Altered T cell regulation and cytokines production was found in local and peripheral immune systems. TJ proteins and ion/water channels changes were found in the SMG of matriptase-deficient mice compared to controls. A loss of volume regulation was observed in both ductal and acinar cells after matriptase local depletion in SMG.
Our data suggest that matriptase deficiency is associated with primary Sjögren's syndrome and can induce a pSS-like phenotype in mice. The induction of pSS by matriptase depletion is correlated with a change in epithelial barrier function and subsequent impairment of immune homeostasis in natural and adaptive immunity, resulting in a systemic autoimmune condition similar to pSS.
To cite this abstract, please use the following information:
Yin, Hongen, Kosa, Peter, Liu, Xibao, Swaim, Bill, Cabrera-Perez, Javier, Lai, Zhennan, et al; Matriptase Dificency and Primary Sjogren Syndrome Induction: From Patients to Mice. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :776