Abstract
Recurrent respiratory papillomas (RRP) are benign airway tumors, caused primarily by human papillomaviruses (HPV) types 6 and 11. The disease is characterized by multiple recurrences after surgical removal, with limited effective therapy. To identify novel targets for future therapy, we established transcriptional profiles for actively growing papillomas compared with autologous, clinically normal, laryngeal epithelia (adjacent tissue). Total ribonucleic acid (RNA) from 12 papillomas and 12 adjacent tissues were analyzed by microarray, and the matched sets of tissues compared by paired t test, to identify differentially expressed genes in papilloma tissues while minimizing variations intrinsic to individual patients. Quantitative polymerase chain reaction (PCR) was used to confirm the relative expression levels for a subset of genes. Within the 109 differentially expressed transcripts whose expression varied at least three-fold were two large groups of genes with related functions. The first group consisted of 18 genes related to host defense, including both innate and adaptive immunity. The second group contained 37 genes that likely contribute to growth of papillomas as benign tumors, since the altered pattern of expression also had been reported previously in many cancers. Our results support our previous studies that document a systemic T(H)2-like adaptive immune response in RRP, and suggest that there is a role for altered innate immunity in RRP as well. We propose that HPV 6 and 11 infection establishes a tumorigenic microenvironment characterized by alteration of both innate inflammatory signals and adaptive immune responses that prevent effective T(H)1-like response, in conjunction with altered expression of numerous genes that regulate cellular growth and differentiation.
Highlights
Recurrent respiratory papillomatosis (RRP) is caused primarily by human papillomavirus (HPV) types 6 and 11, with all other HPV types causing less than 2% of disease [1,2]
Expressed genes could be divided into three groups: 1) immune response genes; 2) genes that likely play a role in papilloma formation since they are associated with malignant tumors; and 3) genes whose role in RRP is not yet apparent
The TH1-like chemokines CCL19 and CCL21, and the chemo attractants CCL5, CCL14, and CXCL12, which would promote TH1-like immune infiltrates, all were decreased in papillomas
Summary
Recurrent respiratory papillomatosis (RRP) is caused primarily by human papillomavirus (HPV) types 6 and 11, with all other HPV types causing less than 2% of disease [1,2]. These viruses induce the growth of benign tumors in the larynx, and less frequently, in the lower respiratory tract. Differences in host immune responses to HPV infection may explain this variability. An effective immune response to viral infection involves activation of both innate and adaptive immunity, with a balance between TH1-, TH2-like, and TH17derived chemokines and cytokines, and appropriate signaling through the recep-
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