Background B lymphocytes are key players in the development of chronic autoimmune sialoadenitis and ectopic lymphoneogenesis is a milestone in the natural history of Sjögren’s syndrome (SS) (1). Much effort has been spent to shed some light on the underlying mechanisms and to date several pathways have been identified. Recruitment and activation of B cells in target organs are orchestrated by a specific milieu of well characterized cytokines and chemokines (2). In this setting, targeted therapies aimed to delete autoreactive B cell clones or B-cell activating factors have been proposed. Recently, growing evidence about the positive effects of anti-CD20 monoclonal antibody rituximab (RTX) in SS pointed out a possible therapeutic application in these patients. However conclusive data about the effective role of RTX in glandular microenvironment are still lacking.
Objectives Aim of the present study was to characterize the different histopathological and molecular features of salivary gland infiltrate following either conventional therapies or RTX in SS.
Methods Eight females with SS underwent minor salivary gland (MSG) biopsy at the diagnosis and following either conventional therapies or RTX. Four females with sicca symptomatology but neither histologic nor sierologic features of SS acted as controls. Serial sections of 3μm thickness were cut and stained with hematoxylin and eosin for the assessment of several histologic scores according to literature (3). Immunofluoscence staining for anti-CD3, anti-CD20, anti-CD21 was performed to identify the grade of lymphoid organization and the presence of germinal center-like structures. Sections were counterstained with DAPI and analyzed with Olympus BX53 microscope. Part of MSG were processed for real time PCR and the following molecules, involved in inflammation and lymphoid organization, were tested: LTa, LTb, IL-1b, TNFa, BAFF, AID, CXCR4, CXCL12, CXCR5, CXCL13, CCR7, CCL19, CCL21.
Results We observed that in SS-MSG the levels of proinflammatory cytokines and chemokines were increased with respect to control (all p<0.05). Moreover, following conventional therapy the concentration of those molecules at mRNa level was not modified. Interestingly, RTX was able to dramatically restore the concentration of CXCR4, CXCL12, CXCR5, CXCL13, CCR7, CCL19, CCL21, BAFF, AID, LTa, LTb and IL-1b as it was in control (all p<0.05). We also found a strong correlation between several of these molecules and histological scores confirming that the severity and organization of salivary gland involvement is strictly dependent on the local cytokine/chemokine milieu.
Conclusions Our results confirm that RTX is currently the only therapeutic agent able to interfere with the perpetuation of salivary gland damage during SS. Therefore, selective targeting of pathogenic B cells appears to be a promising approach to restore normal glandular function.
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Christodoulou MI et al, Journal of Autoimmunity 2010;34:400-407.
Disclosure of Interest None Declared
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