Molecular Evidence for Precursors of Sjögren's Foci in Histologically Normal Lacrimal Glands.

Austin K Mircheff,Yanru Wang,Chuanqing Ding,Prachi Nandoskar,Leili Parsa,Billy X Pan

doi:10.3390/ijms20010223

Austin K Mircheff, Yanru Wang + Show 4 more

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https://doi.org/10.3390/ijms20010223

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Abstract

Understanding the formation of Sjogren’s lymphocytic infiltrates could permit earlier diagnosis and better outcomes. We submitted gene transcript abundances in histologically normal rabbit lacrimal glands to principal component analysis. The analysis identified a cluster of transcripts associated with Sjögren’s foci, including messenger RNAs (mRNAs) for C–X–C motif chemokine ligand 13 (CXCL13) and B-cell activating factor (BAFF), which dominated the major principal component. We interpreted the transcript cluster as the signature of a cluster of integrally functioning cells. Pregnancy and dryness increased the likelihood that the cluster would develop to high levels, but responses were subject to high levels of stochasticity. Analyzing microdissected samples from high- and low-cluster-level glands, we found that certain transcripts, including mRNAs for C–C motif chemokine ligand 21 (CCL21), CXCL13, cluster of differentiation 4 (CD4), CD28, CD25, BAFF, and interleukin 18 (IL-18) were significantly more abundant in immune cell clusters (ICs) from the high-cluster-level gland; mRNAs for CCL2, CD25, and IL-1RA were significantly more abundant in acinus-duct axis samples; mRNAs for CCL4, BAFF, IL-6, and IL-10 were more abundant in some acinus-duct samples; cells with high prolactin immunoreactivity were more frequent in interacinar spaces. In conclusion, integrated functional networks comprising Sjögren’s infiltrates, such as ICs, acinar cells, ductal cells, and interacinar cells, can form in histologically normal glands, and it is feasible to detect their molecular signatures.

Highlights

Sjögren’s syndrome is an autoimmune epithelitis characterized by production of antibodies and focal lymphocytic infiltrates that cause severe dysfunction of the lacrimal glands and salivary glands
We found that lacrimal glands express messenger RNA for PRL and messenger RNAs (mRNAs) for class II major histocompatibility complex (MHC II), cluster of differentiation 80 (CD80), and CD86, numerous cytokines, and numerous chemokines
We found that epithelial cells rarely express mRNA for MHC II, but frequently express mRNA for CD1d, which presents both bacterial and autologous glycolipids invariant α-chain natural killer (NK) T cells

Summary

Introduction

Sjögren’s syndrome is an autoimmune epithelitis characterized by production of antibodies and focal lymphocytic infiltrates that cause severe dysfunction of the lacrimal glands and salivary glands. Sjögren’s syndrome comprises two major subtypes, i.e., primary Sjögren’s syndrome and secondary Sjögren’s syndrome [1], and both subtypes present in multiple clinical phenotypes. The cellular and molecular processes that underlie the clinical subtypes are diverse. Primary Sjögren’s infiltrates may be either T-cell predominant or B-cell predominant [2], and may have either positive- or negative type I interferon (IFN) signatures [3]. B-cell predominant infiltrates may have or lack germinal centers [4]. These features imply that Sjögren’s syndrome may have multiple etiologies and may develop along multiple pathogenic pathways

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