Antecedents of Sjögren’s and Other Inflammatory Infiltrates May be Present in All Adult Lacrimal Glands

Abstract

Purpose: Lacrimal glands from 85% of humans 45 years and older present with lymphocytic infiltrates or fibrotic sequelae of previous inflammatory episodes. The etiologies are not known; this study asked whether they might be time-dependent outcomes of normal processes.

Methods: Five groups of young adult rabbits were raised out-of-doors, each under a unique combination of prevailing dryness and heat. Glands were divided for qRT-PCR and immunohistochemistry. T cell numbers and many transcripts’ abundances varied significantly across the individual glands from each group, making them amenable to Pearson’s correlation test.

Results: Several correlation clusters were detected in each group, some attributable to particular cell types, others to multiple cell types that functioned coordinately, as networks. Increasing heat was associated with increasing prolactin (PRL) mRNA, localized to epithelial cells. Increasing PRL mRNA was associated with increasing IL-4 mRNA, apparently abrogating negative crosstalk between monocyte-macrophage lineage cells (MMΦ) that express BAFF mRNA and T_H2 cells that express IL-4 mRNA. Increasing PRL mRNA also was associated with increasing IFN-γ mRNA, classically a T_H1 function, but this influence was abrogated at the highest level of IL-4 mRNA. Increasing dryness was associated with exponentially increasing activity of a novel network, apparently comprising epithelial cells, MMΦ, and CD8⁺ T cells or CD8⁺ NKT cells and expressing mRNAs for CD8, CTLA-4, IL-10, IL-17, IL-1α, IL-1β, IL-2, IL-6, and iNOS. Like the PRL-T_H2 network, it was associated with varying suppression of IFN-γ mRNA, depending on the setting. When IFN-γ mRNA expression was not eliminated, it was associated with crosstalk that altered the novel network’s transcript expression profile.

Conclusions: The PRL-T_H2 network and the novel network may have adaptive value in counterregulating autoimmune T_H1 responses. Nonetheless, the potential of the PRL-T_H2 network to recruit BAFF-expressing MMΦ may be a factor in Sjögren’s lesions and other autoimmune T_H2 processes. Likewise, IL-17 is classically associated with chronic inflammation, and high levels of certain novel network transcript products—NO, IL-1α, IL-1β, and IL-6—impair Ca²⁺ signaling, protein secretion, and fluid secretion. Thus, the novel network may come to be associated clinical presentations that differ depending on interactions with other networks.

Keywords: 576 lacrimal gland • 557 inflammation • 413 aging