Abstract
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (Cxcl9, Ccl19) and other potentially disease-relevant genes (Epsti1, Ubd) were upregulated in male lacrimal glands. Expression of Cxcl9 and Ccl19, in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably, Ifnar1-deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice.
Highlights
Sjögren syndrome is a complex autoimmune disease characterized by lymphocytic infiltration of lacrimal and salivary glands leading to gland dysfunction and downstream complications including profound dry eyes and dry mouth, potentially vision-threatening ocular surface damage and poor oral health
Through gene expression studies driven by analyses of prior microarray data, we identified four genes upregulated in the context of male-specific lacrimal gland inflammation in Nonobese diabetic (NOD) mice
To determine if castrated male NOD mice were protected from the development of dacryoadenitis due to the presence of a functional lacrimal gland-protective Treg population similar to female NOD mice, we treated castrated and sham-castrated male NOD mice with either the Treg-depleting anti-CD25 monoclonal antibody or with an isotype control antibody
Summary
Sjögren syndrome is a complex autoimmune disease characterized by lymphocytic infiltration of lacrimal and salivary glands leading to gland dysfunction and downstream complications including profound dry eyes and dry mouth, potentially vision-threatening ocular surface damage and poor oral health. Several animal models have been described that develop lacrimal and/or salivary gland autoimmunity with similar features as those observed in humans with Sjögren syndrome and these models have provided insights into the immunological mechanisms of autoimmunity [3,4]. Murphy Roths Large/lymphoproliferation (MRL/lpr) mice develop lymphoproliferation and spontaneous autoimmunity affecting several organs, including salivary glands (males and females) and lacrimal glands (females) [4,5]. Nonobese diabetic (NOD) mice spontaneously develop a Sjögren syndrome-like autoimmune attack on lacrimal and salivary glands with features more closely modelling human Sjögren syndrome including characteristic histopathological lesions (i.e., focal sialadenitis and focal dacryoadenitis), some relevant autoantibodies and dysfunction of the exocrine glands [3,4]. NOD mice provide a model to study cellular and molecular pathways that drive the pathogenic T cells to overcome regulatory mechanisms and invade the affected glands
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