Abstract Collagen XVII (BP180) is a transmembrane component of hemidesmosomes, which connect basal keratinocytes to the basement membrane. The extracellular domain of collagen XVII is proteolytically shed from the cell surface and released to the extracellular matrix. Apart from its function in epithelial cell adhesion, collagen XVII has been suggested to participate in keratinocyte motility. The collagen XVII expression pattern was studied in wounds of oral mucosa and in epithelial tumors. During re-epithelialization, collagen XVII was expressed in the keratinocytes distal to the wound edge, but not in the leading cells of the epithelial tip. Collagen XVII upregulation was observed in moderate/severe dysplasias of oral mucosa. In follicular ameloblastomas and basal cell carcinomas, collagen XVII expression was reduced in peripheral cells, whereas cytoplasmic staining was detected in central tumor cells. Tongue squamous cell carcinomas showed increased collagen XVII expression in grade II/III tumors, particularly in areas of invasive growth. The results suggest a correlation between overexpression of collagen XVII and the invasive potential of the tumor. For the first time, the role of collagen XVII in the regulation of malignant migration was explored. The presence of COL15, the cell adhesion domain of collagen XVII, induced migration of tongue squamous cell carcinoma cells in transmigration assays. Experiments with specific function-blocking integrin antibodies revealed that the promigratory function of COL15 is mediated by αv and α5 integrins. The role of the matrix metalloproteinase (MMP) family of proteolytic enzymes in wound re-epithelialization was studied in a transgenic mouse model. In these mice, a specific inhibitor of MMPs, TIMP-1, was overexpressed in cells that normally produce MMP-9. The healing of cutaneous wounds was found to be significantly delayed, but not prevented, due to the impaired ability of keratinocytes to migrate to the wound area. These results suggest that collagen XVII may participate in epithelial tumor progression and invasion by promoting migration of tumor cells. Based on the present study, epithelial cell-derived MMPs play a significant role in the migration of wound keratinocytes during re-epithelialization.

Abstract Bullous pemphigoid (BP) is an autoimmune skin disease predominantly found in elderly people, which causes blistering of the skin and severe itching. The incidence of BP reported by previous studies has varied greatly between 0.05 and 42.8 per 1 million persons per year. Higher incidences have been reported in Western Europe and the USA, while countries around the Mediterranean have reported lower rates. However, the epidemiology of BP has not previously been studied in any Scandinavian country. The one-year mortality of BP is highly variable with estimates between 11% and 41% worldwide. As for comorbidities, the previous studies have shown that BP is associated with neurological disorders. The aim of this study was to investigate the incidence and mortality of BP in Finland, to assess the treatments used for BP, and the potential contribution of systemic glucocorticoid treatment to the high mortality rate found in BP patients. A further aim was to obtain more specific information about the neurological diseases associated with BP, and to clarify the less studied association with psychiatric disorders. For these purposes, we collected the records of all immunologically confirmed BP patients diagnosed in the Oulu University Hospital between 1985 and 2012, and, for a sub-study III, data for all patients diagnosed with BP in Finnish hospitals between 1987 and 2013. We found that the incidence of BP in Northern Finland has increased over the past two decades to approximately 27 new BP cases per 1 million persons per year. The one-year mortality of BP patients is 17%, and the standardized mortality ratio (SMR) is 7.6. Common comorbidities found in the sample of BP patients were: cardiovascular diseases (76%), neurodegenerative diseases (41%), skin conditions other than BP (37%) and type 2 diabetes (23%). Many neurodegenerative diseases of the central nervous system were associated with BP, as were many psychiatric disorders. The association was strongest between multiple sclerosis (MS) and BP, with MS patients having almost a 6-fold higher risk of BP than controls. The present study reports for the first time the incidence and mortality of BP in Finland, and provides new information about the association between BP and neurological and psychiatric disorders. / Tiivistelmä Rakkulainen pemfigoidi (josta jatkossa käytetään nimitystä pemfigoidi) on autoimmuunisairaus, joka esiintyy yleensä iäkkäillä, ja aiheuttaa ihon rakkulointia ja hankalaa kutinaa. Aiemmissa tutkimuksissa pemfigoidin ilmaantuvuus on vaihdellut 0,05:sta 42,8:aan tapaukseen miljoonaa ihmistä kohden vuodessa. Ilmaantuvuuden on havaittu olevan korkeampi Länsi-Euroopassa, kun taas Välimeren ympäristössä ilmaantuvuus on matalampi. Pemfigoidia sairastavien kuolleisuus vuoden kuluessa diagnoosista vaihtelee noin 11-41%:n välillä. Aiemmat tutkimukset ovat myös osoittaneet, että pemfigoidi liittyy neurologisiin sairauksiin. Pemfigoidin epidemiologiaa ei ole kuitenkaan tutkittu Suomessa tai muissa Pohjoismaissa. Tämän tutkimuksen tarkoituksena oli selvittää pemfigoidin ilmaantuvuus ja kuolleisuus Suomessa, tutkia sen hoitoon käytettyjä lääkkeitä sekä arvioida systeemisen glukokortikoidihoidon osuutta korkeaan kuolleisuuteen. Lisäksi tavoitteena oli saada yksityiskohtaista tietoa pemfigoidiin liittyvistä neurologisista sairauksista ja selvittää lisää aiemmissa tutkimuksissa ristiriitaiseksi jäänyttä yhteyttä psykiatrisiin sairauksiin. Tätä varten keräsimme tiedot kaikista Oulun yliopistollisessa sairaalassa diagnosoiduista, immunologisesti varmennetuista pemfigoiditapauksista vuosilta 1985-2012. Kolmannessa osatyössä käytimme kansallista aineistoa, joka sisälsi kaikkialla Suomessa diagnosoidut pemfigoidia sairastavat potilaat vuosilta 1987-2013. Pemfigoidin ilmaantuvuus kasvoi seuranta-aikana ollen nykyisin Pohjois-Suomessa noin 27 tapausta miljoonaa ihmistä kohden vuodessa. Kuolleisuus vuoden kuluessa diagnoosista oli 17% ja vakioitu kuolleisuussuhde (standardized mortality ratio) 7,6. Yleisiä oheissairauksia pemfigoidia sairastavilla olivat sydän- ja verisuonisairaudet (76%), neurodegeneratiiviset sairaudet (41%), muut ihosairaudet (37%) sekä tyypin 2 diabetes (23%). Tutkimuksessa todettiin, että monet neurogeneratiiviset sairaudet ja monet psykiatriset sairaudet liittyvät pemfigoidiin. Yhteys oli vahvin pesäkekovettumataudin (MS-tauti) ja pemfigoidin välillä, ja MS-tautia sairastavilla riski sairastua pemfigoidiin oli lähes 6-kertainen verrattuna kontrollipotilaisiin. Tämä tutkimus on ensimmäinen, joka raportoi pemfigoidin ilmaantuvuuden ja kuolleisuuden Suomessa. Tutkimus antaa lisäksi uutta tietoa pemfigoidin yhteydestä neurologisiin ja psykiatrisiin sairauksiin.