Abstract
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. NCR3/NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the NCR3/NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 (NCR3) and its ligand B7/H6 (NCR3LG1) in pSS salivary gland tissues. Levels of NCR3/NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between NCR3/NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, NCR3/NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory foci, while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of NCR3/NKp30 within the glands.
Highlights
Primary Sjögren’s syndrome is a chronic autoimmune exocrinopathy characterized by an immune response within the salivary and lachrymal glands leading to the loss of secretory function of exocrine glands, or sicca syndrome [1]
Focusing on the expression of the natural cytotoxicity receptor (NCR) family, we looked at the expression level of NCR1 (NKp46, CD335), NCR2 (NKp44, CD336), and NCR3 (NKp30, CD337)
Given the selective NKp30 upregulation in salivary glands (SGs) tissue of Primary Sjögren’s syndrome (pSS) and the NCR evolvement in tumor surveillance, we investigated whether the NKp30 expression on circulating natural killer (NK) cells was different according to the presence of SG inflammatory infiltration, myoepithelial sialadenitis (MESA) prelymphomatous lesions, or non-Hodgkin’s MALT lymphoma in SS parotid SG
Summary
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune exocrinopathy characterized by an immune response within the salivary and lachrymal glands leading to the loss of secretory function of exocrine glands, or sicca syndrome [1]. The ductal epithelial cells (ECs) are the target of inflammation within the salivary glands (SGs), they act as unconventional antigenpresenting cells, expressing immuno-modulatory molecules able to promote immune-cell recruitment and activation, namely, dendritic cells (DCs), natural killer (NK) cells, and T cells, which results in EC apoptosis [4]. He role of adaptive immunity in the pathogenesis of pSS has been well established; far less is known about the contribution of innate immunity and its interaction with adaptive immunity. Animal models of pSS indicate a crucial role for type II IFN in the disease pathogenesis [11, 12]
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