Decreased Langerhans Cell Responses to IL-36γ: Altered Innate Immunity in Patients with Recurrent Respiratory Papillomatosis

Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36γ, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain T(H)1-like CD4(+) T-cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of T(H)2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells (iLCs). In this study, we show that papilloma cells express IL-36γ protein, and that human keratinocytes transduced with HPV11 have reduced IL-36γ secretion. We now provide the first evidence that peripheral blood-derived iLCs respond to IL-36γ by expressing inflammatory cytokines and chemokines. When stimulated with IL-36γ, iLCs from patients with RRP had lower expression levels of the T(H)2-like chemokine CCL-20 as compared with controls. Patients’ iLCs also had decreased steady state levels of CCL-1, which is a proinflammatory chemokine. Moreover, CCL-1 levels in iLCs inversely correlated with the severity of RRP. The combined decrease of T(H)1- and a T(H)2-like chemokines by iLCs from patients could have consequences in the priming of IFN-γ expression by CD8(+) T-cells. Taken together, our results suggest that, in RRP, there is a defect in the proinflammatory innate immune responses made by iLCs in response to IL-36γ. The consequence of this defect may lead to persistent HPV infection by failing to support an effective HPV-specific, T(H)1-like and/or T(c)1-like adaptive response, thus resulting in the predominant T(H)2-like and/or Treg micromilieu present in papillomas

Aortic antioxidant defense and lipid peroxidation in rabbits fed diets supplemented with different animal and plant fats.

To test the hypothesis that dietary fats, depending on the fat source, may modulate aortic lipid peroxidation and antioxidant protection. Rabbits were fed a low fat (LF, 2 g/100 g corn oil) diet or LF enriched with 16 g/100 g (w/w) of corn oil (CO), corn oil plus cholesterol (23.5 mg/100 g diet, CO + C), bovine milk fat (MF), chicken fat (CF), beef tallow (BT) or lard (L). After a 30-day feeding period, aortic lipid peroxidation, as well as antioxidant enzymes and vitamin E were measured. In rabbits fed CO or L, aortic TBARS (a marker of lipid peroxidation) and total glutathione concentrations were greater but vitamin E levels were lower compared with the LF treatment. Moreover, in rabbits fed CO, elevated activities of glutathione peroxidase and glutathione reductase but lowered activity of superoxide dismutase were observed. In rabbits fed the remaining high fat diets, including the CO + C diet, aortic lipid peroxidation and antioxidant activities/levels did not differ from those fed LF. Feeding rabbits high-fat diets for 30 days did not induce aortic lipid deposition. The present results indicate CO, and possibly L, as the fat sources which significantly increase aortic oxidative stress. Because long-term disturbances in redox status may be implicated in atherogenesis, excessive dietary intake of CO or L may significantly contribute to the injury of the vessel wall