Dermatology and venerology

We study gene mutations and pathogenetic mechanisms underlying skin barrier defects. Ichthyosis exhibits generalized hyperkeratosis and epidermolysis bullosa (EB) shows skin fragility. Some are due to dominant keratin mutations disrupting the cytoskeleton. Others are caused by enzyme deficiencies which negatively affect the horny layer. Many patients benefit from treatment with retinoids (vitamin A analogs). Those with associated hyperhidrosis benefit from injections of botulinum toxin. We study the regulation of keratin and other genes by retinoids and RNAi, aiming at improving treatment. We work in a EU network (GeneSkin) and represents a national referral centre for genodermatoses.

Psoriasis is a common disease with three variants - psoriasis vulgaris, psoriatic arthritis and palmoplantar pustulosis (PPP). Psoriasis may have an autoimmune etiologybut no specific autoantigens have yet been identified. Exogenous factors, e g smoking can precipitate the disease.

PPP is associated with several autoimmune disorders. It affects mainly smoking women. The inflammation is directed against the palmo-plantar sweat duct. The inflammation and the influence of smoking is under study; attempts to identify autoantigens are ongoing.

In all types of psoriasis we have found increased numbers of inflammatory cells in the gut mucosa, findings which have generated new ideas concerning the pathogenesis of psoriasis.

In order to study epidermal formation in vitro, a skin explant culture technique has been developed. We utilize fluoroprobe imaging to visualize outgrowth of fresh epithelium on a substrate of cell-free dermis. Growth rates and morphological features of newly formed epidermis are studied. Current research is focused on epidermal growth factor (EGF)-mediated signaling and the effects of antibodies and tyrosine kinase inhibitors targeting EGF receptor family members. Our aim is to identify new means by which growth abnormalities in psoriatic skin and other hyperproliferative disorders can be reversed.

Projects

Etiologies and new therapies for monogenetic epidermal diseases

Hans Törmä, Marie Virtanen, Anders Vahlquist

New keratin mutations underlying various epidermolytic skin disorders are continuously searched for. Immortalized cells from epidermolytic ichthyosis (EI) and EB patients have been established and characterized in our lab. These cells are now used for screening of chemical libraries in the search novel therapies using automated fluorescence microscopy. Compounds affecting keratin filament structure will be tested in cell and organotypic cultures in vitro.

Using transgene mouse models for epidermolytic disorders (collaboration with Irwin McLean et al, Dundee), we explore the effects of substances that in our cell culture experiments on keratinocytes have shown the most promising results as stabilizers (chaperons) of mutated cytoskeleton. Provided these animal experiments continue to show promising results on inducible EB/EI and no toxicity is observed, then a next step will be to plan phase I trials in humans.

In other projects, the genetic causes of autosomal recessive congenital ichthyosis (ARCI) other rare keratinisation disorders, which are currently diagnosed at the Genodermatosis Centre in Uppsala (a national referral centre), are investigated. This has already resulted in new knowledge about the pathoetiology of these diseases. The analyses are performed within the framework of a EU-sponsored network (GeneSkin).

In order to find new targets for treatment of ARCI and hyperkeratinisation, the interplay between known ARCI-associated gene products is studied in patients´ skin and keratinocytes and in siRNA knock-down keratinocytes exposed to retinoids and other drug candidates.

Mast cell apoptosis in psoriatic skin

Ola Rollman, Eva Hagforsen

Mast cells are major effector cells in allergic reactions such as atopic asthma and urticaria. These effects are mainly due to release of histamine from cytoplasmatic granules. More diverse and complex functions of cutaneous mast cells have recently been recognized in non-allergic diseases such as psoriasis. This inflammatory skin disorder is considered to be partly driven by several proteases and other mediators released from dermal mast cells. We are studying if apoptosis-inducing drugs may be applied to reduce the influence of mast cells in psoriatic skin. Preliminary experiments in collaboration with prof G. Pejler (Uppsala) indicate that such drugs will indeed reduce the number of dermal mast cells and the expression of pro-inflammatory mediators in cultured biopsies of lesional and non-lesional psoriatic skin. Our results support the idea that cutaneous mast cells contribute to the inflammatory process in psoriasis, and that lysosomotropic drugs should be evaluated as pro-apoptotic agents in mast cell-mediated dermatoses.

Immunologic mechanisms in idiopathic inflammatory skin diseases

Mohammad Alimohammadi

One of the major challenges in care of patients with skin disorders is to manage disease symptoms in a disease-specific manner. The majority of dermatologic disorders are today considered as idiopathic although in most of them, a role of the immune system can be observed. For example histological examination of most of skin disorders involve lymphocytic infiltration. Although, the underlying molecular reason for this immune action is rarely contemplated in the routine clinical work.

The overall purpose of this project is to elucidate and understand underlying disease mechanisms and determine biomarkers for diseases that may have autoimmune components. This could lead to better diagnosis and better treatment strategies for these patients. We collect tissue samples, including serum, PBMC and skin biopsies from clinically well characterized patients and use the samples. The collected samples are later examined for signs of autoimmune mechanisms using different autoantibody detection methods such as SEREX, candidate autoantigen approach, cytokine profiling, western blotting and T cell activation experiments.