UNIVERSITY OF FLORIDA
Sjögren's syndrome (SjS) is a systemic autoimmune disease characterized primarily by salivary and lacrimal gland dysfunction. As with many autoimmune connective tissue diseases, there exists a sexual dimorphism in SjS with women affected 10- to 20-times more frequently than men, suggesting a role for sex hormones in disease susceptibility or progression. Even though SjS is generally not considered a lethal disease in the absence of B cell lymphoma formation, patients have an increasingly diminished quality of life as the disease progresses. One fascinating feature of SjS autoimmunity in both humans and animal models is the formation of germinal-like centers in the salivary and lacrimal glands, referred to as lymphocytic foci (LF). Although LF and LF scores are important criteria for clinical disease and depict the level of leukocytic infiltrations of the exocrine glands, the scores often do not correlate with the severity of disease. Until recently, it was thought that LF were comprised mostly of B lymphocytes and CD4+ TH1 T helper cells. However, we recently reported that LF contain significant numbers of CD4+ TH17 memory T cells plus IL-23-producing macrophages and/or dendritic cells. Recent work has shown that IL-27, the cytokine that apparently regulates TH17 activity, is expressed at very low levels in the exocrine glands, suggesting that the TH17/IL-17/ IL-23 system may be inappropriately up-regulated in the exocrine glands of SjS patients, as well as our SjS-mouse model, C57BL/6.NOD-Aec1Aec2. To better define the role of LF in SjS and determine whether the cell populations present within LF, especially the CD4+ TH17 memory T cells, are involved in the autoimmune response inducing exocrine glandular dysfunction, we have proposed to investigate the temporal nature of the leukocyte populations forming LF in salivary glands and determine the inter-relationship between CD4+ TH17 memory T cells and its regulatory cytokine, IL-27.
Goals of the proposed studies. The proposed studies utilize our C57BL/6.NOD-Aec1Aec2 mouse model of SjS. SjS-like disease of the C57BL/6.NOD-Aec1Aec2 mouse has been well-characterized and closely mimics SjS in humans. The parental strain, C57BL/6J, represents an excellent and appropriate control. The current studies are being carried out under protocol 200801756, approved by the University of Florida's IACUC.
The two Specific Aims of this study, and their sub-aims, are:
Aim 1: Characterize the IL-23 secreting and CD4+ TH17 T cell populations infiltrating the salivary glands during development of SjS-like disease in C57BL/6.NOD-Aec1Aec2 mice.
Sub-aim 1.A. Define the temporal changes in leukocyte compositions of salivary gland LF defining the appearance of CD4+ TH17 memory T lymphocytes in relationship to development of SjS-like disease.
Sub-aim 1.B. Determine the role of the IL-23 / TH17 / IL-17 system in the formation of LF during development and onset of SjS-like disease in C57BL/6.NOD-Aec1Aec2 mice.
Aim 2: Determine the possible regulatory potential of IL-27 on the CD4+ TH17 T cell populations for preventing development of SjS in the C57BL/6.NOD-Aec1Aec2 mouse model.
Sub-aim 2.A. Identify the temporal expression of IL-27 and its signaling pathway(s) during the development of SjS.
Sub-aim 2.B. Examine the potential of IL-27 to suppress TH17 cell-associated functions in-vitro:
Sub-aim 2.C. Examine the feasibility for suppression of SjS-like disease using rAAV-Il27 vectors.
The hypotheses being tested are:
Hypothesis 1: IL-23-secreting monocytes and CD4+ TH17 cells are major cell populations infiltrating the submandibular glands and are responsible for glandular pathology and dysfunction.
Hypothesis 2: IL-27 is an effector cytokine that specifically targets and suppresses development of SjS in our animal model, most likely through its regulation of pathogenic CD4+ TH17 cells.