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. 2014 Jul;177(1):244-52.
doi: 10.1111/cei.12341.

Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren's syndrome

L A Aqrawi  1 , M Kvarnström, K A Brokstad, R Jonsson, K Skarstein, M Wahren-Herlenius
Affiliations

Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren's syndrome

L A Aqrawi et al. Clin Exp Immunol. 2014 Jul.

Abstract

Ro52 is an E3 ubiquitin ligase with a prominent regulatory role in inflammation. The protein is a common target of circulating autoantibodies in rheumatic autoimmune diseases, particularly Sjögren's syndrome (SS). In this study we aimed to investigate the expression of the SS target autoantigen Ro52 in salivary glands of patients with primary Sjögren's syndrome (pSS). Ro52 expression was assessed by immunohistochemical staining of paraffin-embedded and frozen salivary gland biopsies from 28 pSS patients and 19 non-pSS controls from Swedish and Norwegian registries, using anti-human Ro52 monoclonal antibodies. The degree and pattern of staining and inflammation was then evaluated. Furthermore, secreted Ro52 protein was measured in saliva and serum samples from the same individuals through a catch-enzyme-linked immunosorbent assay (ELISA). Ro52 was highly expressed in all the focal infiltrates in pSS patients. Interestingly, a significantly higher degree of Ro52 expression in ductal epithelium was observed in the patients compared to the non-pSS controls (P < 0·03). Moreover, the degree of ductal epithelial expression of Ro52 correlated with the level of inflammation (Spearman's r = 0·48, P < 0·0120). However, no secreted Ro52 protein could be detected in serum and saliva samples of these subjects. Ro52 expression in ductal epithelium coincides with degree of inflammation and is up-regulated in pSS patients. High expression of Ro52 might result in the breakage of tolerance and generation of Ro52 autoantibodies in genetically susceptible individuals. We conclude that the up-regulation of Ro52 in ductal epithelium might be a triggering factor for disease progression in SS.

Keywords: Ro52; Sjögren's syndrome; autoimmunity; inflammation; salivary glands.

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Figures

Fig. 1
Fig. 1
Ro52 expression in focal infiltrates of primary Sjögren's syndrome (pSS) patients. Ro52 is highly expressed in all the focal infiltrates in pSS patients (a,b). Mouse immunoglobulin (Ig)G1 was used as isotype control, with no staining detected (c,d). Additionally, preincubation of the Ro52 monoclonal antibody (mAb) with recombinant Ro52 protein abolishes the detection of Ro52 in SG biopsies (f). This demonstrates that staining is specific for Ro52 (e,f).
Fig. 2
Fig. 2
Ro52 expression in ductal epithelium. Ro52 is also expressed in the ductal epithelium of salivary gland (SG) tissue in both the patients and the sicca controls. However, after scoring the sections, we observed a significant up-regulation of Ro52 in ductal epithelium of the primary Sjögren's syndrome (pSS) patients compared to the non-pSS controls (P ≤ 0·03). The same structures in the left and right sections are indicated with numbers 1 and 2.
Fig. 3
Fig. 3
High ductal epithelium expression of Ro52 correlates with level of inflammation. Primary Sjögren's syndrome (pSS) patients with more evident mononuclear cell infiltration and a consequent up-regulation of Ro52 in their infiltrates also exhibited a higher Ro52 expression in their ductal epithelium; Spearman's r = 0·48, P < 0·0120 (a,b,e). Mouse immunoglobulin (Ig)G1 was used as isotype control with no staining detected (c,d).
Fig. 4
Fig. 4
Secreted Ro52 protein in serum and saliva of primary Sjögren's syndrome (pSS) and non-pSS subjects. Very little or no Ro52 protein could be detected in serum and saliva samples of both pSS patients and non-pSS controls, indicating that Ro52 is not secreted as part of the inflammatory process. Incubation with recombinant Ro52 protein is used as a positive control, and maltose binding protein (MBP) as a negative control.
Fig. 5
Fig. 5
A schematic illustration of how Ro52 over-expression may lead to the breakage of immune tolerance in genetically susceptible individuals and the development of autoimmunity. Increased Ro52 expression occurs during inflammation, and in genetically susceptible individuals carrying e.g. human leucocyte antigen (HLA)-DRB1*03, and/or one or more of several SS-associated polymorphisms, this may result in the breakage of immune tolerance and autoimmunity (a). Individuals lacking the genetic component do not have a breakage of tolerance as a result of increased Ro52 expression and therefore no autoimmune responses are mounted (b).
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