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Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.ORCID iD: 0000-0003-3522-1842
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.ORCID iD: 0000-0002-3822-0725
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Speech and Language Pathology and Audiology, University of Pretoria, South Africa.
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2018 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 138, no 11, p. 1020-1027Article in journal (Refereed) Published
Abstract [en]

Background: Hyaluronan (HA) is a glycosaminoglycan with viscoelastic properties necessary for vocal fold (VF) vibration and voice production. Changes in HAs molecular mass, possibly related to human papilloma virus, could affect formation/persistence of recurrent respiratory papillomatosis (RRP).

Aims/Objective: Describing mass and localization of HA and localization of HA receptor CD44 in VF and false vocal folds (FVF) in RRP.

Materials and Methods: Biopsies from VF and FVF from 24 RRP patients. Twelve were studied with histo-/immunohistochemistry for HA and CD44 in epithelium, stroma and RRP lesions. Twelve samples were analyzed for HA molecular mass distribution with gas-phase-electrophoretic-molecular-mobility-analyzer (GEMMA).

Results: Three of 23 stains (VF and FVF combined) showed faint HA staining in the epithelium; there was more extensive staining in the stroma. CD44 was present throughout all areas in FVF and VF, it did not concur with HA. GEMMA analysis revealed very high mass HA (vHMHA) with more varying amounts in VF.

Conclusions/Significance: HA was mainly distributed in the stroma. CD44 not binding to HA might explain the non-inflammatory response described in RRP. Possibly crosslinked vHMHA was seen in VF and FVF, with more variable amounts in VF samples. Counteracting HA crosslinking could become a treatment option in RRP.

Abstract [zh]

背景:透明质酸(HA)是一种糖胺聚糖, 具有声带(VF)振动和发声所必需的粘弹性。HA 分子量的变化可能与人乳头瘤病毒相关, 还可能影响复发性呼吸道乳头状瘤病(RRP)的形成或持续。

目的:描述HA的量和定位, HA受体CD44在VF中的定位和假性声带(FVF)在RRP中的定位。

材料和方法:24名RRP患者的VF和FVF的活组织检查。用组织/免疫组织化学方法研究12个样品的上皮、基质和RRP病变中的HA和CD44。用气-相-电泳 - 分子-迁移率-分析仪(GEMMA)分析另12个样品的HA分子量分布。

结果:23个染色中的3个(VF和FVF组合)在上皮细胞中显示出微弱的HA染色;基质中有更强的染色。 CD44存在于FVF和VF的所有区域, 它与HA不同时存在。 GEMMA分析显示非常高量的HA(vHMHA), 它在VF中的量多变。

结论/意义:HA主要分布在基质中。 CD44不与HA接合可能解释所描述的RRP中的非炎症反应。在VF和FVF中观察到可能交合的vHMHA, 而在VF样品中具有更多的变量。抗HA交合可能成为RRP的治疗选择。

Place, publisher, year, edition, pages
Taylor & Francis, 2018. Vol. 138, no 11, p. 1020-1027
Keywords [en]
Vocal folds, hyaluronan, CD44, human papilloma virus, recurrent respiratory papillomatosis
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-156749DOI: 10.1080/00016489.2018.1500712ISI: 000459000600012PubMedID: 30776265Scopus ID: 2-s2.0-85061778147OAI: oai:DiVA.org:umu-156749DiVA, id: diva2:1291826
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-04-29Bibliographically approved
In thesis
1. Human papillomavirus in sinonasal inverted papilloma, recurrent respiratory papilloma and non-malignant tonsils
Open this publication in new window or tab >>Human papillomavirus in sinonasal inverted papilloma, recurrent respiratory papilloma and non-malignant tonsils
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Humant papillomvirus i respiratoriska papillom, inverterade näspapillom och vid godartad sjukdom i halsmandlarna
Abstract [en]

Background: Human papillomavirus (HPV) is known to cause recurrent respiratory papilloma (RRP) and certain types of oropharyngeal cancer. HPV has also been associated with sinonasal inverted papilloma (SIP). HPV transmission routes are under investigation and the conviction is that the infection occurs sexually at an adult stage, however, vertical transmission at birth with a dormant viral condition until disease eruption/co-activation has been stated as a possibility.

Purpose: The purpose of this work was to contribute to the understanding of HPV related chronic diseases in the airway. Specific aims were: 1. To increase understanding regarding changes in the immune system as well as of the glycosaminoglycan hyaluronan in patients with RRP. 2. To evaluate prevalence of HPV and its surrogate marker p16 in SIP as well as HPV, p16 and Epstein-Barr virus (EBV) in benign tonsillar disease. HPV and EBV in non-malignant tonsillar disease were studied due to the fact that incidence of HPV positive tonsillar cancer is increasing and the time of viral infection is unknown.

Methods: A phenotypic characterization of peripheral blood from 16 RRP patients and 12 age-matched controls, using immunoflow cytometry, and monoclonal antibodies against differentiation and activation markers, was performed. The cytokine mRNA profile of monocytes, T helper-, T cytotoxic-, and NK cells was assessed using RT-qPCR. 54 SIP samples were studied of which 53 were available for analyzation with PCR. Genotype screening for 18 high risk and six low risk HPV types was performed using the PapilloCheck® HPV-screening test (a PCR method). 54 samples were immunohistochemically (IHC) stained for p16. Biopsies from vocal folds (VFs) and false vocal folds (FVFs) were collected from 24 patients with RRP, 12 were randomly selected to histochemistry for Hyaluronan (HA) and IHC staining for CD44 in the epithelium, stroma and RRP lesions. The remaining 12 patients were analyzed for HA molecular mass distribution with a gas-phase electrophoretic molecular mobility analyzer (GEMMA). Eight VF samples and four FVF samples were successfully analyzed. Biopsies from 40 non-malignant tonsils were analyzed using Papillocheck® for HPV, IHC for p16 and EBER analysis for EBV.

Results: We found a dominance of cytotoxic T cells, activated NK cells, and high numbers of stressed MIC A/B (MHC class I chain-related molecule A/B) expressing lymphocytes. The HPV analysis was successful for 38 SIP samples and two (5%) were positive for HPV 11. Notably, p16 was present in the epithelia of all samples and in the papilloma portions in 37 of 38 samples. We found extensive HA staining in the stroma of both VFs and FVFs. CD44 was expressed throughout the epithelium, stroma, and RRP lesions in both FVFs and VFs, it did however, not concur with the expression of HA. Very high mass HA was found in both VFs and FVFs, though more variation regarding amounts of HA was seen in the VFs compared to FVFs. No HPV was found in non-malignant tonsils, the p16 levels were low and the counted EBER positive cells showed great variation in numbers.

Conclusions: Our findings demonstrate an immune dysregulation with inverted CD4+/CD8+ ratio and aberrant cytokine mRNA production in RRP patients, compared to healthy controls. We concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP and that HPV incidence was low (5%). CD44 does not seem to bind to HA, which might explain the noninflammatory response previously described in RRP. Very high mass HA possibly crosslinked was seen in both VFs and FVFs. A possibility to counteract inflammatory crosslinking of HA may be found for medical treatment options in RRP.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2019. p. 56
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1955
Keywords
Human papillomavirus, recurrent respiratory papillomatosis, sinonasal inverted papilloma, non-malignant tonsillar disease, Epstein-Barr virus, immune system, p16, Hyaluronan
National Category
Otorhinolaryngology
Research subject
Oto-Rhino-Laryngology
Identifiers
urn:nbn:se:umu:diva-158489 (URN)978-91-7601-865-1 (ISBN)
Public defence
2019-05-24, Sal D, Unod T9, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
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Titel enligt titelblad: Human papillomavirus in recurrent respiratory papilloma, sinonasal inverted papilloma, and non-malignant tonsils

Available from: 2019-05-03 Created: 2019-04-29 Last updated: 2019-05-08Bibliographically approved

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Holm, AnnaHellman, UrbanLaurent, ClaudeNylander, KarinOlofsson, Katarina

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