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 recently in several countries in Europe and, in addition, 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

The 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 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 mode and in BP patients
  • To test therapeutic interventions and predisposing factors using DNC14A mice as a preclinical animal model

Recent publications:

  • 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
  • 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. Psychiatric and neurological disorders are associated with bullous pemphigoid – a nationwide Finnish Care Register study, Sci Rep, 6: 37125, doi: 10.1038/srep37125, 2016
  • 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

 

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

Background and significance

To understand better the life-course determinants 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 research program which included initially all 12058 children whose expected time of delivery was 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 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

  • To analyze the genetic, biological, social or behavioral risk factors 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. 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
  • 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. Abnormal skin changes in toe web space as an early sign of impaired glucose metabolism. A clinical study of 1900 adults. Sci Rep, Aug 22;7(1):9125, 2017
  • Sinikumpu S-P et al. A cross-sectional survey in the Northern Finland Birth Cohort 1966 Study. Acta Derm Venereol, in press.
  • Huilaja L. et al. Patients with hidradenitis suppurative have a high psychiatric disease burden: A Finnish nationwide registry study. J Invest Dermatol, in press.

 

Research funding

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

Research group members

  • Docent Laura Huilaja, MD
  • Anna-Kaisa Försti, MD, PhD
  • Nina Kokkonen, PhD
  • Minna Kubin, MD, PhD
  • Jussi Tuusa, PhD
  • Technician Anja Mattila

Doctoral students:

  • Saana Kauppi, MD
  • Outi Lindgren, MD
  • Antti Nätynki
  • 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. Enno Schmidt, Dept. of Dermatology, University of Lübeck, Germany
  • Prof. Anne Remes, Dept. of Neurology, Univ. of Oulu, Finland
  • Prof. Markku Timonen, Juha Auvinen, MD,  and Jari Jokelainen, MSc, Inst. of Health Sciences, Univ. of Oulu, Finland
  • Docent Miia Turpeinen, Oulu University Hospital, Finland

 

Last updated: 21.9.2017