Tasanen-Määttä Kaisa

Group leader : professor Kaisa Tasanen-Määttä

The breakdown of immunological self-tolerance in a bullous pemphigoid mouse model and in the elderly population

Background and significance

Bullous pemphigoid (BP) is the most common blistering skin disease and a prototype of an autoimmune disorder. BP’s symptoms include large blisters and severe pruritus. It is a chronic disease that is associated with heightened mortality rate. The incidence of BP has recently increased in several countries in Europe. There is an urgent unmet need for novel treatment options for BP to reduce relapses, adverse reactions and the high mortality associated with the current immunosuppressive regimens.

The most important autoantigen in BP is collagen XVII (ColXVII) which is a transmembrane component of hemidesmosomes. Evidence for the pathogenic role of ColXVII autoantibodies comes from clinical findings and experimental BP mouse models, but the factors leading to the initiation of the autoimmunity in the aging skin are poorly understood.

Future goals

Our major aim is to understand better autoimmunization process in BP, and thereby develop better treatment strategies for elderly and fragile BP patients. In our recent mouse model (DNC14A) modification of ColXVII induces spontaneously BP-like clinical and pathological findings: Blisters, itching and development of ColXVII-specific IgG and IgA antibodies (Hurskainen et al., 2015). Our hypothesis is that the altered shedding of the ectodomain in DNC14A mice creates neoepitopes that break the self-tolerance against ColXVII. We further speculate that in aging human skin, alterations in the ColXVII molecule itself or in the structure of cutaneous basement membrane could trigger the development of autoantibodies. Our recent analyses revealed a molecular level association between BP and neurodegenerative diseases (Kokkonen et al. 2017), which strongly suggests that ColXVII acts as a shared autoantigen in neurodermatological interact. Our specific aims are:

  • To analyze risk factors, co-morbidities and the effects of treatment on morbidity and mortality in BP from a national BP cohort (n=4524) obtained from the Finnish Hospital Discharge Register (FHDR)
  • To analyze autoimmunization against ColXVII in patients with neurodegenerative diseases such as Alzheimer’s disease (AD) and multiple sclerosis (MS) and neurological defects in the DNC14A mouse model
  • To monitor the immunological mechanism connected to altered ColXVII shedding in the DNC14A mouse model and in BP patients
  • To test therapeutic interventions and predisposing factors using DNC14A mice as a preclinical animal model

Recent publications:

  • Kokkonen N. et al. Increased Levels of Bullous Pemphigoid BP180 Autoantibodies Are Associated with More Severe Dementia in Alzheimer’s disease. J Invest Dermatol, 137:71-76, 2017
  • Försti A.-K. et al. Psychiatric and neurological disorders are associated with bullous pemphigoid – a nationwide Finnish Care Register study, Sci Rep, 6: 37125, doi: 10.1038/srep37125, 2016
  • Hurskainen T. et al. Deletion of the major bullous pemphigoid epitope region of collagen XVII induces blistering and itching in mice. J Invest Dermatol, 135: 1303-1310, 2015
  • Försti A.-K. et al. Increasing incidence of bullous pemphigoid in Finland: a population-based retrospective database study. Brit J Dermatol, 171: 1223-1226, 2014

 

More than skin deep: risk factors and co-morbidities of skin diseases in Finnish population

Background and significance

Skin diseases are common and found in more than half of adult population. They are rarely fatal, but cause morbidity, disability and load for the health care. Despite the high morbidity, epidemiological studies addressing the overall prevalence of skin diseases are sparse. Additionally, the reasons for onset of dermatologic diseases are not completely understood. Population-based and longitudinal researches concerning the predictive factors of skin diseases are rare. Therefore, it is highly warranted to study the early predictive and associated factors of skin diseases of adults.

To understand better the life-course factors and pathways to skin diseases we have performed full dermatologic status investigation of 1932 members of the Northern Finland Birth Cohort 1966 (NFBC 1966). NFBC 1966 is a longitudinal epidemiological research program which included initially all 12058 live birth children whose expected time of delivery fell in the year 1966. The whole NFBC 1966 cohort has been followed on a regular basis since antenatal period by health care records, questionnaires and clinical examinations as well as data on their parents and offspring. During a 46-year follow-up survey, 1932 cohort members were evaluated by multidisciplinary examination including body mass index, blood pressure, heart echo recording, dental status and several other health measurements.

Another source for epidemiological data is the Finnish Hospital Discharge Register (FHDR) which is one of the longest-standing individual-level hospital discharge registries. It contains data from both hospitalized patients and those treated in the outpatient clinic of all hospitals across Finland, but not primary care. FHDR contains personal and hospital identification codes, data on age, gender, length of stay and three subsidiary diagnoses. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease of hair follicles with abscess formation that predominantly involves the inverse areas of the skin. In order to clarify the associations between HS and various comorbidities at a national level, we have recently built up a cohort of 4373 patients with HS.

Future goals

Our primary aim is to bring new knowledge of the epidemiology of skin diseases at population level and to study factors associated to specific skin diseases

  • To analyze the genetic, biological, social or behavioral risk factors of skin diseases and comorbidities of skin diseases in NFBC 1966
  • To analyze risk factors, co-morbidities and the effects of treatment on morbidity in HS from a national HS cohort obtained from the Finnish Hospital Discharge Register

Recent publications

  • Sinikumpu S.-P. et al. The Association of Multiple Pigmented Nevi with Education, Skinburns and Sun Vacations. A Northern Finland Birth Cohort 1966 Study with 46 Years’ Follow-up. Acta Derm Venereol (Stockh), 97:219-224, 2017
  • Sinikumpu S-P. et al. High prevalence of skin disesases and need for treatment in a middle-aged population. A Northern Finland Birth Cohort 1966 Study. PLoS ONE, Jun doi: 10.1371/journal.pone.0099533, 2014

 

Research funding

  • Academy of Finland
  • Northern Finland Health Care Support Foundation (Terttu Foundation)
  • Oulu University Hospital
  • Health and Biosciences Doctoral Programme, University of Oulu

Research group members

  • Laura Huilaja, MD, PhD
  • Hanna-Leena Kelhälä, MD, PhD
  • Nina Kokkonen, PhD
  • Minna Kubin, MD, PhD
  • Technician Anja Mattila

Doctoral students:

  • Anna-Kaisa Försti, MD
  • Suvi-Päivikki Sinikumpu, MD
  • Hannu Tiri, MD
  • Outi Varpuluoma, MD

Most important collaborators

  • Prof. Leena Bruckner-Tuderman, Dept. of Dermatology, Univ. of Freiburg, Germany
  • Dr. Claus Franzke, Dept. of Dermatology, Univ. of Freiburg, Germany
  • Prof. Anne Remes, Dept. of Neurology, Univ. of Oulu, Finland
  • Prof. Enno Schmidt, Dept. of Dermatology, University of Lübeck, Germany
  • Prof. Markku Timonen, Juha Auvinen, MD,  and Jari Jokelainen, MSc, Inst. of Health Sciences, Univ. of Oulu, Finland

 

Last updated: 21/3/2017