Abstract
The micromilieu within respiratory papillomas supports persistent human papillomavirus (HPV) infection and disease recurrence in patients with recurrent respiratory papillomatosis (RRP). These patients show polarized (TH2-/Treg) adaptive immunity in papillomas and blood, enriched immature Langerhans cell (iLC) numbers, and overexpression of cyclooxygenase-2/prostaglandin E2 (PGE2) in the upper airway. Blood monocyte-derived, and tissue-derived iLCs from RRP patients and controls were now studied to more fully understand innate immune dysregulation in RRP. Patients' monocytes generated fewer iLCs than controls, due to a reduced fraction of classical monocytes that generated most but not all the iLCs. Prostaglandin E2, which was elevated in RRP plasma, reduced monocyte-iLC differentiation from controls to the levels of RRP patients, but had no effect on subsequent iLC maturation. Cytokine/chemokine responses by iLCs from papillomas, foreskin, and abdominal skin differed significantly. Freshly derived tissue iLCs expressed low CCL-1 and high CCL-20 mRNAs and were unresponsive to IL-36γ stimulation. Papilloma iLCs uniquely expressed IL-36γ at baseline and expressed CCL1 when cultured overnight outside their immunosuppressive microenvironment without additional stimulation. We conclude that monocyte/iLC innate immunity is impaired in RRP, in part due to increased PGE2 exposure in vivo. The immunosuppressive papilloma microenvironment likely alters iLC responses, and vice versa, supporting TH2-like/Treg HPV-specific adaptive immunity in RRP.
Highlights
Recurrent respiratory papillomatosis (RRP), characterized by the recurrent growth of premalignant airway lesions, is a rare disorder predominantly caused by human papillomaviruses (HPVs) types 6 and type 11 [1]
We examined the ability of monocytes to differentiate into immature Langerhans cell (iLC) and the effect of prostaglandin E2 (PGE2) on this differentiation and on the maturation of the iLCs in response to proinflammatory stimuli, including IL-36γ that is secreted in limited amounts by HPV-infected keratinocytes [28]
Almost all of the classical monocytes from controls differentiated into iLCs (96.5 ± 0.65%), fewer of the intermediate monocytes differentiated into iLCs (9.25 ± 2.21%), and very few of the alternative monocytes generated iLCs (2.75 ± 0.62%)
Summary
Recurrent respiratory papillomatosis (RRP), characterized by the recurrent growth of premalignant airway lesions, is a rare disorder predominantly caused by human papillomaviruses (HPVs) types 6 and type 11 [1]. Recurrent respiratory papillomatosis causes significant morbidity and, on occasion, mortality, because of the location of these lesions in the upper airway and the high rate of conversion to squamous cell carcinoma when there is pulmonary involvement [3]. Recurrence of papillomas is caused by activation of latent HPV infection that is widespread throughout the airway [2, 4]. 5% of healthy individuals have latent HPV6/11 infection in their upper airway without any evidence of clinical disease [5]
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