Abstract
Purpose: :
Sjögren’s dacryoadenitis and common, age-related histopathology occur more frequently in women. Different levels of androgens, thought anti-inflammatory, and estrogens, thought pro-inflammatory, may shape responses to environmental stress. Hormonal events also may independently provoke lacrimal gland (LG) inflammation. Prolactin (PRL) is known to favor TH1 activation. During pregnancy, systemic- and LG epithelial PRL increase, and LG epithelia secrete increased PRL via a novel paracrine apparatus. We used an adenovirus vector (AdPRL) to transiently replicate this phenomenon in mature, virgin female rabbits.
Methods: :
AdPRL (1 × 108 pfu) was injected into OS inferior LG of three groups, studied at different times and with different underlying immunophysiological states. A comparison group was injected with AdGFP. LG were collected and analyzed by H&E staining and real time RT-PCR.
Results: :
AdPRL-induced PRL expression, maximal on d4, consistently provoked lymphocytic infiltration. PRL mRNA returned to normal at d12, but infiltrates remained. mRNAs for IL-1, IL-1β, MHC II and CTLA-4 increased only modestly. mRNA for caspase-1, which activates IL-1β, increased markedly. mRNAs for IFN-γ, TNF-, CCL4, CD80, CD86, CD28, CD4, CD3ε, CD3ζ, and BAFF also increased markedly. TH2 cytokines either did not change or decreased. When control LG had little infiltration and low inflammatory cytokine levels, pathology developed slowly but progressively. When control LG were well-populated by lymphocytes, an initial robust increase of cytokine expression subsided in OS LG but propagated to OD LG by 12d, and a chronic phase persisted at d30. AdPRL did not increase IFN-γ or TNF- in ex vivo acinar cells, but PRL from transduced cells up-regulated PRL in non-transduced cells.
Conclusions: :
Increased systemic PRL increases PRL in the LG stroma, where it up-regulates lymphocyte IFN-γ. IFN-γ induces dendritic cells to support TH1 cell proliferation in the LG and draining lymph nodes. PRL initially supports proliferation of T cells and, via BAFF, B cells, but the process quickly becomes self-sustaining.
Keywords: lacrimal gland • autoimmune disease • cornea: tears/tear film/dry eye