B cell specificity and pattern in primary Sjögren’s syndrome - Studies in humans and a murine model
Abstract
Sjögren’s syndrome (SS) is a chronic autoimmune disease characterised by focal inflammation of exocrine glands, particularly salivary and lacrimal glands. Here, mononuclear cells, including B cells, infiltrate the glands, leading to dysfunction and later destruction of the glandular tissue. It thereby results in the common symptoms of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Another distinctive feature of this disease is the systemic production of autoantibodies such as Ro/SSA and La/SSB. This autoantibody production results from the activation of B cells into antibody secreting short- and long-lived plasma cells. Hence, although the etiology of SS remains unclear, B cells do play an important part in the pathogenesis of this disease. In this doctoral work we address the concept of B cell specificity and pattern in primary SS (pSS), where we consider both the general and the autoantigenspecific B cell pattern in the peripheral blood and the salivary glands of patients with pSS. Additionally, we also account for the expression pattern of the Ro52 autoantigen in the salivary glands of pSS patients with regard to level of inflammation. Furthermore, in order to compare the plasma cell pattern before the onset of disease in relation to advanced disease and characterise the plasma cell compartment in the parotid and submandibular salivary glands and in the bone marrow, we explore a congenic NOD mouse strain, namely NOD.B10.H2b. Our general findings disclose a low number of autoantigen-specific memory B cells that are observed alongside high levels of plasma cells both in the peripheral blood and the salivary glands of patients with pSS. Moreover, we also demonstrate a correlation between the ductal epithelial expression of Ro52 and the level of inflammation in the salivary glands of pSS patients. By the application of the NOD.B10.H2b model, we observe an accumulation of longlived plasma cells in the parotid and submandibular salivary glands of mouse that coincides with our observations in lower labial salivary glands of the pSS patients.
Has parts
Paper I: Aqrawi, L.A., Skarstein, K., Bredholt, G., Brun, J.G. & Brokstad, K.A. Autoantigen-specific memory B cells in primary Sjögren's syndrome. Scand J Immunol 75, 61-68 (2012). The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1111/j.1365-3083.2011.02625.xPaper II: Aqrawi, L.A., Brokstad, K.A., Jakobsen, K., Jonsson, R. & Skarstein, K. Low number of memory B cells in the salivary glands of patients with primary Sjögren's syndrome. Autoimmunity 45, 547-555 (2012). The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.3109/08916934.2012.712170
Paper III: Aqrawi, L.A., Skarstein, K., Øijordsbakken, G. & Brokstad, K.A. Ro52- and Ro60-specific B cell pattern in the salivary glands of patients with primary Sjögren's syndrome. Clin Exp Immunol 172, 228-237 (2013). The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1111/cei.12058
Paper IV: Aqrawi, L.A., Kvarnström M., Brokstad, K.A., Jonsson, R., Skarstein K. & Wahren-Herlenius, M. Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren’s syndrome. Clin Exp Immunol 177, 244–252 (2014). The article is not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1111/cei.12341
Paper V: Szyszko, E.A., Aqrawi, L.A., Jonsson, R., Brokstad, K.A. & Skarstein, K. Non-proliferating plasma cells detected in the salivary gland and bone marrow of NOD.B10.H2b mice, a model for primary Sjögren’s syndrome. The article is not available in BORA.