Abstract
The C57BL/6.NOD-Aec1Aec2 mouse model has been extensively studied to define the underlying cellular and molecular bioprocesses critical in the onset of primary Sjögren’s Syndrome (pSS), a human systemic autoimmune disease characterized clinically as the loss of lacrimal and salivary gland functions leading to dry eye and dry mouth pathologies. This mouse model, together with several gene knockout mouse models of SS, has indicated that B lymphocytes, especially marginal zone B (MZB) cells, are necessary for development and onset of clinical manifestations despite the fact that destruction of the lacrimal and salivary gland cells involves a classical T cell-mediated autoimmune response. Because migrations and functions of MZB cells are difficult to study in vivo, we have carried out ex vivo investigations that use temporal global RNA transcriptomic analyses to profile autoimmunity as it develops within the salivary glands of C57BL/6.NOD-Aec1Aec2 mice. Temporal profiles indicate the appearance of Notch2-positive cells within the salivary glands of these SS-susceptible mice concomitant with the early-phase appearance of lymphocytic foci (LF). Data presented here identify cellular bioprocesses occurring during early immune cell migrations into the salivary glands and suggest MZB cells are recruited to the exocrine glands by the upregulated Cxcl13 chemokine where they recognize complement (C’)-decorated antigens via their sphingosine-1-phosphate (S1P) and B cell (BC) receptors. Based on known MZB cell behavior and mobility, we propose that MZB cells activated in the salivary glands migrate to splenic follicular zones to present antigens to follicular macrophages and dendritic cells that, in turn, promote a subsequent systemic cell-mediated and autoantibody-mediated autoimmune T cell response that targets exocrine gland cells and functions. Overall, this study uses the power of transcriptomic analyses to provide greater insight into several molecular events defining cellular bioprocesses underlying SS that can be modelled and more thoroughly studied at the cellular level.
Highlights
B cells and B cell products, including auto-antibodies, have long been known to be important components of autoimmune responses in rheumatoid diseases, especially systemic lupus erythematosus (SLE) [4,5] and Sjögren’s syndrome (SS) [6,7,8,9]
In the second intermediate phase, this inflammatory response subsides, but is quickly followed by the third phase characterized by short-lived innate cellular immunity that transitions to a prolonged classical T cell-mediated autoimmune response
The transcriptome data profiles presented in the current study indicate the presence of an marginal zone B (MZB) cell population in the salivary glands of our SS-susceptible C57BL/6.NODAec1Aec2 mouse model at 4 months (16 weeks) of age, the time when autoantibodies are detected in sera and lymphocytic foci rapidly form in salivary and lacrimal glands [14,16]
Summary
B cells and B cell products, including auto-antibodies, have long been known to be important components of autoimmune responses in rheumatoid diseases (reviewed in [1,2,3]), especially systemic lupus erythematosus (SLE) [4,5] and Sjögren’s syndrome (SS) [6,7,8,9]. Compositions of these different immune cells may be present or absent in the lesions at different stages of disease when examined by histology and FACS analyses, a fact that predicates the need for temporal studies as opposed to single timepoint analyses. This is clearly the case for SS, a systemic autoimmune disease characterized by an immune attack primarily against the salivary and lacrimal glands and having a skewed prevalence towards women presenting in clinics with a wide variety of symptoms [11]. Similar findings are strongly supported by studies in appropriate murine models [12,13,14,15,16]
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