Introdução: Penfigoide bolhoso (PB) resulta da produção de autoanticorpos contra proteínas hemidesmossomais BP (Bullous Pemphigoid) 180 e/ou 230, acomete os idosos, e está associado com doenças neurológicas (DN), especialmente com a demência (DEM). BP180/230 foram identificadas no Sistema Nervoso Central (SNC), aventando-se possível mimetismo antigênico entre moléculas da pele e do SNC. O fator neurotrófico derivado do cérebro (BDNF) participa da neurogênese, sinaptogênese e sobrevivência neuronal, e a sua diminuição sérica tem sido relacionada com DN. Objetivo: Quantificar o peptídeo BDNF e os anticorpos anti-BP180/230 na relação PB com DEM. Material e Métodos: Em estudo comparativo, 50 pacientes com PB, 50 com demência e 50 controles foram avaliados. A detecção dos anticorpos anti-BP180/P230 e do peptídeo BDNF foi determinada por ensaios ELISA. Imunofluorescência indireta (IFI) foi conduzida nas amostras de soro dos pacientes do grupo DEM e dos controles que apresentaram positividade para anti-BP180/230. Resultados: No grupo PB, a frequência de DN foi de 26%: DEM 16%, acidente vascular cerebral 6%, e epilepsia 4% - 5/8 (63%) pacientes apresentaram demência vascular e 3/8 (38%) demência por doença de Alzheimer. Positividade para anti-BP180/230 foi observada no grupo PB (74% e 40%, respectivamente), no grupo DEM (10% e 10%) e nos controles (14% e 0%). No grupo DEM, em 2/10 pacientes que apresentaram positividade para antiBP180/230, a IFI evidenciou depósito de IgG e C3 no lado epidérmico da clivagem, configurando quadro subclínico de PB. A mediana do BDNF resultou menor no grupo DEM (25,41 pg/ml) comparado aos controles (38,21 pg/mL), e o grupo PB apresentou os menores valores de BDNF (16,88 pg/mL). Não houve correlação dos títulos de anticorpos antiPB180/230 com a concentração do peptídeo BDNF no grupo PB. Os pacientes do grupo DEM foram alocados de acordo com a escala de demência - CDR1, CDR2 e CDR3; a mediana de BDNF do subgrupo CDR3 (23,37 pg/mL) foi inferior ao CDR1 (30,17 pg/ mL). Não houve diferença na concentração do BDNF segundo o tipo de demência. O grupo PB, quando estratificado em - com DEM, outras DN e sem DN, aqueles com associação com DEM apresentaram menores níveis de BDNF (9,1 pg/mL), comparados ao grupo sem DN e ao subgrupo CDR3 do grupo DEM. Conclusão: Marcadores para PB não são úteis para o diagnóstico de DEM. Valores sorológicos baixos de BDNF no grupo PB podem sugerir associação com DEM. BDNF pode ser utilizado como biomarcador de gravidade da DEM. / Introduction: Bullous pemphigoid (BP) is characterized by autoantibodies against the hemidesmossomal proteins BP180 and/or BP230, affects the elderly people and has been strongly associated with neurological disorders (ND), especially dementia. A possible antigenic mimicry hypothesis between the skin and the nervous system molecules is strong reasonable because BP peptides have also been identified in the central nervous system (CNS). Brain-derived neurotrophic factor (BDNF) plays a role in the synaptogenesis, neurogenesis, and neuronal survival, and some studies have been correlated the decreased serum BDNF levels with ND. The aim of this study was to quantify the BDNF peptide and the anti-BP180 and anti-BP230 antibodies in the BP and DEM relationship. Methods: AntiBP180/230 and BDNF quantification were analyzed in three groups: 50 patients with BP, 50 patients with dementia and 50 elderly individuals comprised a case-control study. Serum IgG anti-180/230, and the BDNF peptide were evaluated by using ELISA commercial kits; and immunofluorescence allied to salt split skin technique (SSS) was conducted in serum samples from patients of the dementia group and from controls who showed positive anti-BP180/230. Results: In BP group, 26% were associated with ND, and dementia was the most frequent (16%), followed by stroke (6%) and epilepsy (4%) - 5/8 (63%) patients showed vascular dementia and 3/8 (38%) patients presented dementia due to Alzheimer\'s disease. AntiBP180/230 positivity was observed in BP group (74%, 40%, respectively), in dementia group (10%, 10%) and in controls (14%, 0%). In 2/10 patients of the dementia group with positive anti-BP180/230, IIF showed IgG and C3 deposition in the epidermal side of cleavage, configuring a subclinical BP dermatosis. The medians of BDNF resulted lower in the patients of the dementia group (25.41 pg/mL) compared with controls (38.21 pg/mL), and the BP group presented the lowest BDNF values (16.88 pg/mL). There was no correlation between the anti-BP180/230 antibodies titres and the BDNF levels in BP group. There was no difference of BDNF levels accordingly with the clinical type of dementia in the dementia group. Patients of the dementia group were sub grouped accordingly with the clinical dementia severity - CDR1, CDR2 and CDR3 - being the median of BDNF in CDR3 (23.37 pg/mL) lower than in CDR1 (30.17 pg/mL) subgroup. BP group had lower levels of BDNF compared to CDR3 subgroup. BP patients when stratified with dementia, other ND and without ND, those with association with dementia presented the lowest levels of BDNF (9.1 pg/mL) compared to the PB patients without DN and to the CDR3 subgroup. Conclusion: BP biomarkers are not useful for the diagnosis of dementia. Low BDNF levels seen in BP patients may suggest an association with dementia. BDNF may be used as a biomarker of severity of dementia.

Introdução: Penfigoide bolhoso (PB) resulta da produção de autoanticorpos contra proteínas hemidesmossomais BP (Bullous Pemphigoid) 180 e/ou 230, acomete os idosos, e está associado com doenças neurológicas (DN), especialmente com a demência (DEM). BP180/230 foram identificadas no Sistema Nervoso Central (SNC), aventando-se possível mimetismo antigênico entre moléculas da pele e do SNC. O fator neurotrófico derivado do cérebro (BDNF) participa da neurogênese, sinaptogênese e sobrevivência neuronal, e a sua diminuição sérica tem sido relacionada com DN. Objetivo: Quantificar o peptídeo BDNF e os anticorpos anti-BP180/230 na relação PB com DEM. Material e Métodos: Em estudo comparativo, 50 pacientes com PB, 50 com demência e 50 controles foram avaliados. A detecção dos anticorpos anti-BP180/P230 e do peptídeo BDNF foi determinada por ensaios ELISA. Imunofluorescência indireta (IFI) foi conduzida nas amostras de soro dos pacientes do grupo DEM e dos controles que apresentaram positividade para anti-BP180/230. Resultados: No grupo PB, a frequência de DN foi de 26%: DEM 16%, acidente vascular cerebral 6%, e epilepsia 4% - 5/8 (63%) pacientes apresentaram demência vascular e 3/8 (38%) demência por doença de Alzheimer. Positividade para anti-BP180/230 foi observada no grupo PB (74% e 40%, respectivamente), no grupo DEM (10% e 10%) e nos controles (14% e 0%). No grupo DEM, em 2/10 pacientes que apresentaram positividade para antiBP180/230, a IFI evidenciou depósito de IgG e C3 no lado epidérmico da clivagem, configurando quadro subclínico de PB. A mediana do BDNF resultou menor no grupo DEM (25,41 pg/ml) comparado aos controles (38,21 pg/mL), e o grupo PB apresentou os menores valores de BDNF (16,88 pg/mL). Não houve correlação dos títulos de anticorpos antiPB180/230 com a concentração do peptídeo BDNF no grupo PB. Os pacientes do grupo DEM foram alocados de acordo com a escala de demência - CDR1, CDR2 e CDR3; a mediana de BDNF do subgrupo CDR3 (23,37 pg/mL) foi inferior ao CDR1 (30,17 pg/ mL). Não houve diferença na concentração do BDNF segundo o tipo de demência. O grupo PB, quando estratificado em - com DEM, outras DN e sem DN, aqueles com associação com DEM apresentaram menores níveis de BDNF (9,1 pg/mL), comparados ao grupo sem DN e ao subgrupo CDR3 do grupo DEM. Conclusão: Marcadores para PB não são úteis para o diagnóstico de DEM. Valores sorológicos baixos de BDNF no grupo PB podem sugerir associação com DEM. BDNF pode ser utilizado como biomarcador de gravidade da DEM. / Introduction: Bullous pemphigoid (BP) is characterized by autoantibodies against the hemidesmossomal proteins BP180 and/or BP230, affects the elderly people and has been strongly associated with neurological disorders (ND), especially dementia. A possible antigenic mimicry hypothesis between the skin and the nervous system molecules is strong reasonable because BP peptides have also been identified in the central nervous system (CNS). Brain-derived neurotrophic factor (BDNF) plays a role in the synaptogenesis, neurogenesis, and neuronal survival, and some studies have been correlated the decreased serum BDNF levels with ND. The aim of this study was to quantify the BDNF peptide and the anti-BP180 and anti-BP230 antibodies in the BP and DEM relationship. Methods: AntiBP180/230 and BDNF quantification were analyzed in three groups: 50 patients with BP, 50 patients with dementia and 50 elderly individuals comprised a case-control study. Serum IgG anti-180/230, and the BDNF peptide were evaluated by using ELISA commercial kits; and immunofluorescence allied to salt split skin technique (SSS) was conducted in serum samples from patients of the dementia group and from controls who showed positive anti-BP180/230. Results: In BP group, 26% were associated with ND, and dementia was the most frequent (16%), followed by stroke (6%) and epilepsy (4%) - 5/8 (63%) patients showed vascular dementia and 3/8 (38%) patients presented dementia due to Alzheimer\'s disease. AntiBP180/230 positivity was observed in BP group (74%, 40%, respectively), in dementia group (10%, 10%) and in controls (14%, 0%). In 2/10 patients of the dementia group with positive anti-BP180/230, IIF showed IgG and C3 deposition in the epidermal side of cleavage, configuring a subclinical BP dermatosis. The medians of BDNF resulted lower in the patients of the dementia group (25.41 pg/mL) compared with controls (38.21 pg/mL), and the BP group presented the lowest BDNF values (16.88 pg/mL). There was no correlation between the anti-BP180/230 antibodies titres and the BDNF levels in BP group. There was no difference of BDNF levels accordingly with the clinical type of dementia in the dementia group. Patients of the dementia group were sub grouped accordingly with the clinical dementia severity - CDR1, CDR2 and CDR3 - being the median of BDNF in CDR3 (23.37 pg/mL) lower than in CDR1 (30.17 pg/mL) subgroup. BP group had lower levels of BDNF compared to CDR3 subgroup. BP patients when stratified with dementia, other ND and without ND, those with association with dementia presented the lowest levels of BDNF (9.1 pg/mL) compared to the PB patients without DN and to the CDR3 subgroup. Conclusion: BP biomarkers are not useful for the diagnosis of dementia. Low BDNF levels seen in BP patients may suggest an association with dementia. BDNF may be used as a biomarker of severity of dementia.

Abstract Transmembrane collagen XVII (BP180) is a structural component of hemidesmosomes that connects the two layers of skin. Collagen XVII is associated with both autoimmune and inherited bullous skin diseases. Mutations in collagen XVII gene cause junctional epidermolysis bullosa, and in the diseases of the pemphigoid group autoantibodies target collagen XVII. In this work, collagen XVII was studied in both junctional epidermolysis bullosa and gestational pemphigoid. Two novel glycine substitution mutations were found in the largest collagenous domain of collagen XVII. Analysis of recombinantly produced mutated proteins showed that these novel mutations and previously described glycine substitution mutations decrease the thermal stability of collagen XVII ectodomain. In addition, these mutations were found to cause intracellular accumulation of the mutated proteins and affect the post-translational modifications of collagen XVII. Meanwhile, an in-frame deletion of nine amino acids had no effect on the thermal stability or secretion of the collagen XVII ectodomain. Gestational pemphigoid autoantigen collagen XVII has been mainly studied in the skin, and its expression and function during pregnancy are so far largely unknown. For the first time, collagen XVII was shown to be expressed by cytotrophoblasts of the first trimester human placenta and by cultured cytotrophoblasts. Transmigration assay of cytotrophoblasts indicated that collagen XVII promotes trophoblast invasion, and may thus have a role in placental formation. In addition, significant amounts of in vivo produced collagen XVII were found in the amniotic fluid throughout pregnancy. Collagen XVII expression was also observed in hemidesmosomes of amniotic membranes and in cells cultured from amniotic fluid. These findings suggest that collagen XVII could have a function, albeit so far unknown, during pregnancy.

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.