Abstract
The C57BL/6.NOD-Aec1Aec2 mouse is considered a highly appropriate model of Sjögren’s Syndrome (SS), a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the development and onset of observed clinical manifestations. More recently, studies carried out in the C57BL/6.IL14α transgenic mouse have indicated that the marginal zone B (MZB) cell population is responsible for development of SS disease, reflecting recent observations that MZB cells are present in the salivary glands of SS patients and most likely initiate the subsequent loss of exocrine functions. Although MZB cells are difficult to study in vivo and in vitro, we have carried out an ex vivo investigation that uses temporal global RNA transcriptomic analyses to profile differentially expressed genes known to be associated with cell migration. Results indicate a temporal upregulation of specific chemokine, chemokine receptor, and Rho-GTPase genes in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice that correlate with the early appearance of periductal lymphocyte infiltrations. Using the power of transcriptomic analyses to better define the genetic profile of lymphocytic emigration into the salivary glands of SS mice, new insights into the underlying mechanisms of SS disease development and onset begin to come into focus, thereby establishing a foundation for further in-depth and novel investigations of the covert and early overt phases of SS disease at the cellular level.
Highlights
B lymphocytes in order for an overt clinical s Syndrome (SS)-like disease to develop, irrespective of earlier studies using several SS-susceptible mouse models revealed an absolute requirewhether
This differentially expressed gene profile occurs from 8 weeks of age (Figures 3–7), a timepoint corresponding with the hypothesized appearance of marginal zone B (MZB) cells within the salivary glands
We previously identified the Rac > Ras > Raf > Erk > AP gene pathway as a critically important component in development of glandular pathology [59], the current indepth analyses of the Rho-GTPases points to a highly complex biological process indicated by the upregulation of genes encoding for multiple Rho-Gap, Rho-Gef, Dock and cell division cycle-42 (Cdc42) sub-family proteins of the Rho-GTPase family
Summary
Patients most often present in clinic only after the adaptive immune phase is active and irreversible pathology is occurring For this reason, it remains necessary to identify molecular and cellular processes involved with the early covert inflammatory phase of autoimmunity as a basis to better understand the initiation of the adaptive immune response phase. It remains necessary to identify molecular and cellular processes involved with the early covert inflammatory phase of autoimmunity as a basis to better understand the initiation of the adaptive immune response phase This is especially true for Sjögren’s Syndrome (SS) where the time between disease onset and eventual diagnosis ranges from 4 to 10 or more years [7,8,9]. The pathological profile changes dramatically during the development and onset of disease in this time period
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