Merri-Grace Jones (Allred)

Role of type I interferon signaling in chemokine upregulation in early pathogenesis of Sjögren syndrome in NOD mouse model

CD4 and CD8 effector T cells are the main instigators of lacrimal gland tissue damage in the autoimmune disease, Sjögren syndrome. It is unknown how these lymphocytes migrate to the tissue, and why they aggregate there and attack the glands [1]. After activation in lymph nodes, T cells receive key cytokine signals that drive differentiation and upregulation of tissue homing receptors. We study Sjögren syndrome using non-obese diabetic (NOD) mice, which spontaneously develop autoimmunity of the lacrimal and salivary glands. We’ve observed that disruption of the type I IFN signaling pathway protected NOD mice from developing lacrimal gland disease [2,3]. However, how this pathway drives pathogenic T cells to infiltrate and damage the target tissue is not known.

Microarrays have shown that the expression of the chemokine Cxcl9 is upregulated in lacrimal tissue in Sjögren syndrome [3]. CXCL9 is the ligand for the chemokine receptor CXCR3. The other ligands for this receptor, CXCL10 and CXCL11, are also upregulated in lacrimal gland disease. We have found that IFNAR -/- mice have low expression of these chemokines. Therefore, type I IFN signaling is important for the upregulations of these signaling molecules. The cell populations in lacrimal glands that produce CXCR9, CXCL10 and CXCL11 have not been identified, and the cells that respond to this cytokine milieu and upregulate CXCR3 are similarly not known.

The overall goal of my research is to elucidate the mechanisms of T cell infiltration of lacrimal glands in Sjögren syndrome, and to determine the role of type l IFN signaling in T cell recruitment. We hypothesize that antigen presenting cells in the glands require signaling through IFNAR1 leading to the upregulation of key chemokines in early disease. This catalyzes the upregulation of CXCR3 on T cells in the draining lymph nodes and their exodus to the lacrimal glands.

Merri-Grace Allred
Rexburg, ID
BS, Biology, Brigham Young University - Idaho

2191 ML
United States

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