Projects in Dermatology and Venereology

 Andor Pivarcsi project

Our primary interest is the role of microRNAs in the pathogenesis of non-melanoma skin cancers. MiRNAs are short, endogenous RNAs that regulate gene expression at the posttranscriptional level and have critical functions in health and disease. Non-melanoma skin cancers, basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are the most common cancers in human. Until recently, very little was known about the expression and function of miRNAs in human skin and its diseases.

We recently performed the first global analysis of microRNA expression profile in non-melanoma skin cancers and identified a set of microRNAs that may play important roles in their pathogenesis. Our goal is to understand their function both in cancer and under physiological conditions and to determine whether they may become therapeutic targets in the future.

Methods

We use TaqMan Low-Density Arrays for microRNA expression profiling and quantitative real-time PCR to measure expression of individual microRNAs in healthy or cancer samples. We use in situ hybridization to learn about the distribution of microRNAs within the tissues. We modulate the activity of miRNAs in cancer cells by using microRNA precursors to overexpress them or inhibitors to suppress them in order to better understand their functions. We study the effect of altered microRNA activity on the phenotype of cancer cell lines using cell cycle progression, apoptosis, colony formation, wound healing, migration and invasion assays. We identify microRNA target genes by using a combination of gene expression profiling, computational approaches, western-blot- and 3UTR luciferase reporter assays.

Selected publications

 MicroRNA-125b down-regulates matrix metallopeptidase 13 and inhibits cutaneous squamous cell carcinoma cell proliferation, migration, and invasion.
Xu N, Zhang L, Meisgen F, Harada M, Heilborn J, Homey B, et al
J. Biol. Chem. 2012 Aug;287(35):29899-908

MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
Xu N, Brodin P, Wei T, Meisgen F, Eidsmo L, Nagy N, et al
J. Invest. Dermatol. 2011 Jul;131(7):1521-9

MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4.
Sonkoly E, Janson P, Majuri M, Savinko T, Fyhrquist N, Eidsmo L, et al
J. Allergy Clin. Immunol. 2010 Sep;126(3):581-9.e1-20

The expression of microRNA-203 during human skin morphogenesis.
Wei T, Orfanidis K, Xu N, Janson P, Ståhle M, Pivarcsi A, et al
Exp. Dermatol. 2010 Sep;19(9):854-6

MYCN-regulated microRNAs repress estrogen receptor-alpha (ESR1) expression and neuronal differentiation in human neuroblastoma.
Lovén J, Zinin N, Wahlström T, Müller I, Brodin P, Fredlund E, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Jan;107(4):1553-8

Protein kinase C-dependent upregulation of miR-203 induces the differentiation of human keratinocytes.
Sonkoly E, Wei T, Pavez Loriè E, Suzuki H, Kato M, Törmä H, et al
J. Invest. Dermatol. 2010 Jan;130(1):124-34

Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer.
Weber G, Chamorro C, Granath F, Liljegren A, Zreika S, Saidak Z, et al
Breast Cancer Res. 2009 ;11(1):R6

The human antimicrobial peptide LL-37 suppresses apoptosis in keratinocytes.
Chamorro C, Weber G, Grönberg A, Pivarcsi A, Ståhle M
J. Invest. Dermatol. 2009 Apr;129(4):937-44

MicroRNAs: novel regulators in skin inflammation.
Sonkoly E, Ståhle M, Pivarcsi A
Clin. Exp. Dermatol. 2008 May;33(3):312-5

MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation.
Sonkoly E, Ståhle M, Pivarcsi A
Semin. Cancer Biol. 2008 Apr;18(2):131-40

MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?
Sonkoly E, Wei T, Janson P, Sääf A, Lundeberg L, Tengvall-Linder M, et al
PLoS ONE 2007 Jul;2(7):e610

Tumor immune escape by the loss of homeostatic chemokine expression.
Pivarcsi A, Müller A, Hippe A, Rieker J, van Lierop A, Steinhoff M, et al
Proc. Natl. Acad. Sci. U.S.A. 2007 Nov;104(48):19055-60

Toll-like receptor 9-independent suppression of skin inflammation by oligonucleotides.
Pivarcsi A
J. Invest. Dermatol. 2007 Apr;127(4):746-8

Contact     

Senior researcher

Andor Pivarcsi

Phone: +46-(0)73-833 00 57
Organizational unit: Research Group M Bradley
E-mail: andor.pivarcsi@ki.se
      

Maria Bradley project

Genetic studies of skin barrier defects with focus on ATOPIC DERMATITIS

AD is an inflammatory skin disorder that results from a complex interaction between genetic and environmental factors. The disease has a high familial occurrence with twin studies showing concordance rates of 0.72-0.77 in monozygotic, and 0.15-0.23 in dizygotic twin-pairs demonstrating that genetic factors play an important role in disease development. Among several advances in this research field, the identification of Filaggrin (FLG) as a susceptibility gene in eczema stands out as a major finding. We have studied the FLG gene in several different population; Ethiopian, Colombian and ongoing a population from Greenland.

Our research is aiming to advance our understanding of the development of AD, by both genetic and functional studies mainly focusing on genes underlying the barrier dysfunction seen in AD patients. When the genetic mechanisms for AD can be further outlined it will give new insights to the pathogenesis and this will open up for new treatment strategies and preventive measures. If FLG mutations in a near future will be used as a diagnostic tool for patients with AD the results of our studies might be able to give the patients a more individually designed barrier restoring therapy. Furthermore, by studying the disease in different ethnic groups, we will increase the knowledge about possible differences regarding the genetic and the environmental contribution in developing AD in various populations in the world.

Co-workers:

  • Mårten Winge, MD, PhD
  • Agne Liedén, PhD
  • Samina Asad, PhD
  • Maria Tengvall-Linder MD, PhD
  • Kassahun Desalegn Bilcha MD
  • Carl-Fredrik Wahlgren, MD, PhD, Professor
  • Magnus Nordenskjöld, MD, PhD, Professor

Contact

     

Senior lecturer/senior physician

Maria Bradley

Organizational unit: Research Group M Bradley
E-mail: Maria.Bradley@ki.se

Liv Eidsmo project

Psoriasis is a T cell driven inflammatory disease of primarily the skin that affects 2-3 % of the Swedish population. Effective treatment suppresses the chronic inflammation but cure is currently not feasible. Psoriasis often return in the same areas of the skin and it seems that resolved skin contains a hidden disease memory.

We aim to dissect the skin resident disease memory in psoriasis. We have a particular interest in pathogenic epidermal tissue resident memory T cells (Trm) and dendritic cells (DCs). Tissue resident memory T cells (Trm) are recently described epithelial T cells that are retained in the skin after viral infection in mice (Gebhardt et al). These cells are perfectly placed to form a pathologic disease memory in recurrent and site specific inflammation.

We perform functional studies to understand what influences and activates T cells and dendritic cells in the human skin during psoriasis. We recently obtained a FACSJazz cell sorter for to facilitate in vitro experiments of tissue derived T cells and DCs. We plan to investigate how T cells affect and drive inflammation in the skin in experimental models of inflammation. Through unraveling mechanisms of tissue immunopathology in psoriasis we ultimately aim to find new ways to treat psoriasis.

Co-workers

  • Kerstin Bergh, Med lic, Laboratory Engineer
  • Stanley Cheuk, MSc - PhD student
  • Elisa Martini, MSc - PhD student
  • David Chang, BSc student

Bernt Lindelöf project

There are three major forms of skin cancer - malignant melanoma, basal cell carcinoma and squamous cell carcinoma. Sunlight is the major carcinogen for all forms. In total there are around 40 000 new cases in Sweden each year.

There are numerous studies performed on these forms of skin cancer. One group of patients who have an extremely high risk of getting skin cancer is organ transplant recipients. This group of patients have for example a 100 fold (10 000%) increased risk to develop squamous cell carcinoma compared with the normal population. The Swedish transplant cohort, at present comprising approximately of 7 000 patient, is the base for several studies. The immune system is suppressed in these patients by medication in order to prevent rejection of new organs. The effect of this immunomodulation on carcinogenesis is studied together with co-factors as virus infections (human papilloma virus and cytomegalovirus). Also genetic studies on cancers are performed.

Basal cell carcinoma of the skin, the most common form of cancer, all organ included, is presently investigated in a large epidemiological study. Approximately 100 000 patients from the Swedish Cancer Registry with basal cell carcinoma is included. Having a basal cell carcinoma is an indirect sign of having a lot of sun exposure in the past. Sun exposure is necessary to produce vitamin D in the body and recent research has indicated that vitamin D is protective against cancer and certain other diseases and conditions. Thus, the risk of having other forms of cancers before the basal cell carcinoma is calculated in order to give some new information on the importance of sun exposure.

Lentigo maligna is malignant melanoma in situ. Grenz ray therapy (ultra soft X-rays) is used to treat these lesions with good therapeutic and cosmetic results. Up to 300 patients have been treated and will have long-term follow up.

Recent publications

Increased risk of malignant melanoma in patients with systemic mastocytosis?
Hägglund H, Sander B, Gülen T, Lindelöf B, Nilsson G
Acta Derm. Venereol. 2014 Sep;94(5):583-4

Does urticaria risk increase in patients with celiac disease? A large population-based cohort study.
Ludvigsson J, Lindelöf B, Rashtak S, Rubio-Tapia A, Murray J
Eur J Dermatol ;23(5):681-7

[Synchronous multiple primary melanoma are often missed. Increased attention to the patient's entire skin is required for early diagnosis].
Lapins J, Emtestam L, Hedblad M, Girnita A, Lindelöf B, Ljung A, et al
Lakartidningen ;110(8):410-2

Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008--a Swedish population-based study.
Krynitz B, Edgren G, Lindelöf B, Baecklund E, Brattström C, Wilczek H, et al
Int. J. Cancer 2013 Mar;132(6):1429-38

No association between infections, HLA type and other transplant-related factors and risk of cutaneous squamous cell carcinoma in solid organ transplant recipients.
Ingvar , Ekström Smedby K, Lindelöf B, Fernberg P, Bellocco R, Tufveson G, et al
Acta Derm. Venereol. 2012 Nov;92(6):609-14

Time trends in risk and risk determinants of non-Hodgkin lymphoma in solid organ transplant recipients.
Fernberg P, Edgren G, Adami J, Ingvar A, Bellocco R, Tufveson G, et al
Am. J. Transplant. 2011 Nov;11(11):2472-82

Previous extensive sun exposure and subsequent vitamin D production in patients with basal cell carcinoma of the skin, has no protective effect on internal cancers.
Lindelöf B, Krynitz B, Ayoubi S, Martschin C, Wiegleb-Edström D, Wiklund K
Eur. J. Cancer 2012 May;48(8):1154-8

Lars Norlén project

Lars Norlén and his colleagues have identified the basic molecular structure of human skin. The findings pave the way for development of new drug formulations that can be delivered through the skin, reducing the risk of side effects. 

Our skin protects us from water, chemicals, microorganisms, sun radiation and dehydration. Until recently, the understanding of how this protection is accomplished has been incomplete. Now, Lars Norlen and his colleagues have identified the basic molecular structure of the skin layer that forms this protecting barrier. 

Arrangement of lipid molecules in the stratum corneum. The long chains of green balls represent hydrocarbon chains in ceramides, cholesterol and free fatty acids.

Their findings show that the barrier lies in the fat molecules, lipids, that occupy the space between the cells in the outermost layer of skin, the stratum corneum. Normally, lipids arrange themselves into a two-layered sheet, or bilayer, with all of their hydrophobic (water-repelling) tails pointing inwards and their hydrophilic (water-attracting) heads outwards. However, the lipid molecules in the stratum corneum are stretched-out, so that the two tails of each molecule point in opposite directions. The molecules are stacked on top of each other in an alternating fashion, forming a structure which is much more impermeable than a normal bilayer. The fat structure also allows for the horny layer cells to slide on each other, making the skin flexible and thereby contribute to its mechanical robustness. 

The researchers developed a novel experimental approach for this particular project, combining cryo-electron microscopy defocus series with molecular modelling and electron microscopy simulation. They freezed healthy, living, human skin to below -140 °C, preserving every molecule in its native location. They then sliced the tissue into layers 25 to 50 nanometres thick and examined the layers using an electron microscope.

The research has above all been driven by the vision of enabling drug administration through the skin instead of taking pills via the mouth, in order to increase efficacy and reduce side effects. The team now aim at developing a computer model of the skin, as well as artificial skin, for screening drugs and other chemicals that could potentially open the skin barrier. 

Group members

  • Lianne den Hollander, MSc
  • Aurelie Laloeuf, MSc
  • Sergej Masich, Dr

Selected publications

 Current understanding of skin barrier morphology.
Norlén L
Skin Pharmacol Physiol 2013 ;26(4-6):213-6

The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety.
Iwai I, Han H, den Hollander L, Svensson S, Ofverstedt L, Anwar J, et al
J. Invest. Dermatol. 2012 Sep;132(9):2215-25

Molecular cryo-electron tomography of vitreous tissue sections: current challenges.
Norlén L, Oktem O, Skoglund U
J Microsc 2009 Sep;235(3):293-307

Molecular cryo-electron tomography of vitreous tissue sections: current challenges.
Norlén L, Oktem O, Skoglund U
J Microsc 2009 Sep;235(3):293-307

Skin barrier formation: the membrane folding model.
Norlén L
J. Invest. Dermatol. 2001 Oct;117(4):823-9

Carl-Fredrik Wahlgren project

Atopic eczema: Studies of genetic and environmental factors, clinical manifestations, co-morbidity and prognosis

Atopic eczema (AE) is a pruritic, chronically relapsing, inflammatory skin disease affecting ~20% of Swedish children and some percent of adults. Its prevalence in children has doubled since the 1970s. The reason for this is still unclear. AE is a multifactorial disease caused by combined influence of genetic and environmental factors. The present project aims at identifying genetic and environmental factors of importance for AE - onset, clinical manifestations, quality of life, co-morbidity and persistence. The study is based on a birth cohort of children born in Stockholm, the BAMSE cohort, as well as more than 500 families with at least two siblings affected with AE. The work is interdisciplinary comprising collaboration with many research groups - national and international.

Selected publications

 Characterization of EGFR and ErbB2 expression in atopic dermatitis patients.
Sääf A, Pivarcsi A, Winge M, Wahlgren C, Homey B, Nordenskjöld M, et al
Arch. Dermatol. Res. 2012 Dec;304(10):773-80

Novel point mutation in the STS gene in a patient with X-linked recessive ichthyosis.
Winge M, Hoppe T, Liedén A, Nordenskjöld M, Vahlquist A, Wahlgren C, et al
J. Dermatol. Sci. 2011 Jul;63(1):62-4

Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis.
Winge M, Bilcha K, Liedén A, Shibeshi D, Sandilands A, Wahlgren C, et al
Br. J. Dermatol. 2011 Nov;165(5):1074-80

Filaggrin mutations increase the risk for persistent dry skin and eczema independent of sensitization.
Böhme M, Söderhäll C, Kull I, Bergström A, van Hage M, Wahlgren C
J. Allergy Clin. Immunol. 2012 Apr;129(4):1153-5

Ning Xu Landén project

Research profile

 microRNAs (miRNAs) are ~22 nt noncoding RNAs that can bind to the 3 untranslated region (UTR) of the target messenger RNA (mRNA) and result in translational repression or degradation of mRNA. They are proposed to regulate ~60% of all protein-coding genes in humans. Deregulation of miRNA expression has been shown to contribute many diseases. Recent studies using animal models demonstrated that modulation of miRNA expression by administration of specific miRNA mimics / inhibitors had beneficial effect on diseases. Thus, miRNAs represent targets for potential therapeutic agents. My research focus on the role of miRNAs in skin biology and skin diseases.

Project 1. The role of miRNAs in psoriasis

Psoriasis is a lifelong disease with spontaneous remissions and exacerbations, affecting the patients life quality substantially. Severe psoriasis is a systemic disease with significant comorbidities, such as psoriatic arthritis, metabolic syndrome and cardiovascular disease. Psoriasis shares pathogenetic similarities with other immune-mediated diseases such as Crohn's disease, rheumatoid arthritis and multiple sclerosis. Thus, psoriasis may be used as a model disease to understand disease mechanisms and test new concepts in chronic inflammatory diseases. We previously identified a distinct miRNA expression profile in psoriasis skin compared with healthy skin. Our current study aims at identifying the putative role(s) of these psoriasis related miRNAs in skin, using materials from a large biobank of psoriasis patients in Stockholm.

Project 2. The role of miRNAs in human skin wound healing

Wound healing is one of the most fundamental physiological processes to keep the integrity of the skin; fails of healing result in chronic wounds, which are a common medical problem with high morbidity and mortality. The molecular pathogenesis of chronic wounds remains poorly understood which impedes the development of effective treatment. We have previously shown that miRNAs play important roles in the regulation of multiple biological functions of keratinocyte and immune cells in skin. In this project we aim to extend our earlier findings and reveal the role of miRNA in wound healing. Furthermore, we will investigate how miRNAs are involved in the pathogenesis of chronic hard-to-heal wounds and explore the potential of miRNA-based therapy for skin wounds. 

Methods

In situ hybridization, Immunohistochemistry, Western blotting, Real-time PCR, Primary cell culture, Microarray, Flow Cytometry, Luciferase reporter assay.

Research funding

My research is kindly supported by

  • Svenska Läkaresällskapets fonder
  • European Skin Research Foundation
  • Svenska Sällskapet för Medicinsk Forskning
  • Pfizer AB
  • Stiftelsen Psoriasisfonden
  • HudFonden
  • Karolinska Institutet
  • Tore Nilssons Stiftelse
  • Stiftelsen Lars Hiertas Minne
  • Stiftelsen Sigurd och Elsa Goljes Minne

 Selected publications

Changes in the level of serum microRNAs in patients with psoriasis after antitumour necrosis factor-α therapy.
Pivarcsi A, Meisgen F, Xu N, Ståhle M, Sonkoly E
Br. J. Dermatol. 2013 Sep;169(3):563-70

Interleukin-8 is regulated by miR-203 at the posttranscriptional level in primary human keratinocytes.
Wei T, Xu N, Meisgen F, Ståhle M, Sonkoly E, Pivarcsi A
Eur J Dermatol 2013 Apr;():

MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
Xu N, Meisgen F, Butler L, Han G, Wang X, Söderberg-Nauclér C, et al
J. Immunol. 2013 Jan;190(2):678-88

Are BIC (miR-155) polymorphisms associated with eczema susceptibility?
Sääf A, Kockum I, Wahlgren C, Xu N, Sonkoly E, Ståhle M, et al
Acta Derm. Venereol. 2013 May;93(3):366-7

MicroRNA-125b down-regulates matrix metallopeptidase 13 and inhibits cutaneous squamous cell carcinoma cell proliferation, migration, and invasion.
Xu N, Zhang L, Meisgen F, Harada M, Heilborn J, Homey B, et al
J. Biol. Chem. 2012 Aug;287(35):29899-908

MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis.
Meisgen F, Xu N, Wei T, Janson P, Obad S, Broom O, et al
Exp. Dermatol. 2012 Apr;21(4):312-4

MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
Xu N, Brodin P, Wei T, Meisgen F, Eidsmo L, Nagy N, et al
J. Invest. Dermatol. 2011 Jul;131(7):1521-9

Klas Nordlind project

Neurocutaneous Science

The skin may be considered to be a mirror of the soul. Light from the outside world passes through the layers of epidermal cells, the first line of immune defenses, and then interacts with the neuroendocrine system. The dynamic interaction between these two extensive systems involves many molecules, among which serotonin (5-hydroxytryptamine; 5-HT) and substance P, may be of major importance.

Our research is focused at studying expression of these ligands and their receptors, also including the serotonin transporter protein, in common chronic inflammatory skin diseases, psoriasis, and the often severely itching atopic dermatitis. The patients are seen at our Neurocutaneous Reception and are characterized regarding the extent of their disease, the degree of pruritus, the degree of chronic stress, personality traits and depression. In addition, we study allergic contact dermatitis as a more well defined acute inflammatory condition.

The role of alcohol (involving these mentioned neuromediators) in psoriasis, is studied, regarding its degree of inflammation and its pruritus.

We also study these neuromediators, 5-HT and substance P, in murine models with induced allergic contact eczema (Balb/C) and atopic dermatitis (NC/Nga), respectively. In these models also the brain may be investigated.

These studies may lead to a better understanding of the complex interaction between the skin and the neuroendocrine system and lead to new treatments, both systemic and topical.

Co-workers

  • Klas Nordlind, MD, PhD, Professor and senior consultant at the Department of Dermatology
  • Sol-Britt Lonne-Rahm, MD, PhD, Senior consultant, Licensed psychotherapist
  • Husameldin El-Nour, MD, PhD, Research Assistant
  • Kristofer Thorslund, MD, PhD
  • Louise Lönndahl, postgraduate student
  • Aram Rasul, PhD
  • Kristina Dahlman-Ghozlan, MD, postgraduate student

 

GeneticsInflammationmRNASkin cancer