Background/Purpose: Sjögren syndrome is an immunologically complex autoimmune disease characteristically targeting the lacrimal and salivary glands leading to progressively worsening oral and ocular health and poor quality of life. No effective treatments for reversing the exocrine gland inflammation have been identified owing in part to a lack of understanding the early immunological events responsible for initiation of lacrimal and salivary gland inflammation. Interleukin 27 (IL27) is a heterodimeric cytokine that was elevated in serum of Sjögren syndrome patients. IL27 may have immunostimulatory or immunomodulatory properties depending on the context, so this elevation in Sjögren syndrome may represent a pathologic process or a compensatory anti-inflammatory process. Similar to Sjögren syndrome in humans, nonobese diabetic (NOD) mice develop spontaneous autoimmune dacryoadenitis and sialadenitis and represent a well-characterized model of Sjögren syndrome. Our objective here was to evaluate the role of IL27 in the development of dacryoadenitis and sialadenitis in the NOD mouse model of Sjögren syndrome.

Methods: NOD mice with deletion mutations disrupting expression of genes encoding the p28 component of IL27 (Il27) or the alpha chain of the IL27 receptor (Il27ra) were developed through Zn-finger nuclease or CRISPR/Cas9 mediated gene editing, respectively. Development of dacryoadenitis and sialadenitis were determined by histological analyses, and T cell phenotypes were characterized by flow cytometry. In vivo regulatory T cell (Treg) depletion with anti-CD25 monoclonal antibody (PC61) and adoptive transfers were performed to determine the effects of disrupted IL27 signaling on development of dacryoadenitis. Studies were approved by the Institutional Animal Care and Use Committee of the University of Iowa.

Results: NOD mice lacking IL27 or IL27Ra failed to develop spontaneous autoimmune dacryoadenitis or sialadenitis. Phenotypically, T cells from IL27-deficient or IL27Ra-deficient NOD mice showed no evidence of defective T cell activation based on expression of T cell activation markers analyzed by flow cytometry ex vivo. Depletion of Treg cells in IL27-deficient NOD mice failed to drive dacryoadenitis in these mice. In our adoptive transfer model, wild-type T cells transferred dacryoadenitis to NOD-SCID recipient mice, but IL27Ra-deficient T cells failed to transfer dacryoadenitis. When co-transferred with wild-type cells, IL27Ra-deficient CD8 and CD4 effector T cells each demonstrated a significant competitive disadvantage in their ability to infiltrate lacrimal glands.

Conclusion: IL27 is required for development of dacryoadenitis and sialadenitis in NOD mice. T cell-intrinsic IL27 signaling is required to transfer disease. Defective infiltration of lacrimal glands by IL27Ra-deficient effector T cells suggests IL27 signaling may drive upregulation of homing receptors required for lacrimal gland inflammation. More extensive gene expression and flow cytometric analyses to determine the effects of IL27 signaling on pathogenic immune cell populations in NOD mice are currently underway.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pathogenic-role-of-interleukin-27-in-the-nonobese-diabetic-mouse-model-of-sjogren-syndrome/