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  • 1. Asumalahti, Kati
    et al.
    Ameen, Mahreen
    Suomela, Sari
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaelsson, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Evans, Julie
    Munro, Margo
    Veal, Colin
    Allen, Michael
    Leman, Joyce
    Burden, David A.
    Kirby, Brian
    Connolly, Maureen
    Griffiths, Christopher E. M.
    Trembath, Richard C.
    Kere, Juha
    Saarialho-Kere, Ulpho
    Barker, Jonathan N. W. N.
    Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis2003In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 120, no 4, p. 627-632Article in journal (Refereed)
    Abstract [en]

    The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other. We have genotyped the three psoriasis vulgaris susceptibility alleles of the PSORS1 locus in two clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis) to study whether PSORS1 is also involved in the pathogenesis of these variants. We also asked whether these two clinical subgroups could help us to distinguish the causative gene within the high-risk PSORS1 haplotype. The association of guttate psoriasis with the three PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the three candidate genes at this locus. Finally, no correlation with the age of onset for disease was observed. Our results show conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.

  • 2.
    Gillbro, J. M.
    et al.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    Merinville, E.
    Oriflame R&D Ltd, Bray, Co Wicklow, Ireland..
    Cattley, K.
    Oriflame R&D Ltd, Bray, Co Wicklow, Ireland..
    Al-Bader, T.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Nilsson, M.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    Mavon, A.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    In vivo topical application of acetyl aspartic acid increases fibrillin-1 and collagen IV deposition leading to a significant improvement of skin firmness2015In: International Journal of Cosmetic Science, ISSN 0142-5463, E-ISSN 1468-2494, Vol. 37, p. 41-46Article in journal (Refereed)
    Abstract [en]

    Synopsis ObjectiveAcetyl aspartic acid (A-A-A) was discovered through gene array analysis with corresponding Cmap analysis. We found that A-A-A increased keratinocyte regeneration, inhibited dermal matrix metalloprotease (MMP) expression and relieved fibroblast stiffness through reduction of the fibroblast stiffness marker F-actin. Dermal absorption studies showed successful delivery to both the epidermal and dermal regions, and in-use trial demonstrated that 1% A-A-A was well tolerated. In this study, the aim was to investigate whether A-A-A could stimulate the synthesis of extracellular matrix supporting proteins invivo and thereby improving the viscoelastic properties of human skin by conducting a dual histological and biophysical clinical study. MethodTwo separate double-blind vehicle-controlled invivo studies were conducted using a 1% A-A-A containing oil-in-water (o/w) emulsion. In the histological study, 16 female volunteers (>55years of age) exhibiting photodamaged skin on their forearm were included, investigating the effect of a 12-day treatment of A-A-A on collagen IV (COLIV) and fibrillin-1. In a subsequent pilot study, 0.1% retinol was used for comparison to A-A-A (1%). The biomechanical properties of the skin were assessed in a panel of 16 women (>45years of age) using the standard Cutometer MPA580 after topical application of the test products for 28days. The use of multiple suction enabled the assessment of F4, an area parameter specifically representing skin firmness. ResultsTwelve-day topical application of 1% A-A-A significantly increased COLIV and fibrillin with 13% and 6%, respectively, compared to vehicle. 1% A-A-A and 0.1% retinol were found to significantly reduce F4 after 28days of treatment by 15.8% and 14.7%, respectively, in the pilot Cutometer study. No significant difference was found between retinol and A-A-A. However, only A-A-A exhibited a significant effect vs. vehicle on skin firmness which indicated the incremental benefit of A-A-A as a skin-firming active ingredient. ConclusionIn this study, we showed the invivo efficacy of 1% A-A-A both on a protein level (fibrillin and collagen IV) and on a clinical end point, specifically skin firmness, providing proof that, acetyl aspartic acid has a strong potential as an anti-ageing cosmeceutical' ingredient answering the needs of our key consumer base. Resume ObjectifL'acide aspartique acetyle (A-A-A) a ete identifie en utilisant la technologie de puces a ADN combine a une analyse en connectivity mapping' (Cmap), pour ces potentielles proprietes anti-age. A-A-A a la capacite d'augmenter la regeneration cellulaire et d'inhiber l'expression des MMP, ainsi que reduire la rigidite des fibroblastes en depolymerisant le reseau d'actine. Les etudes d'absorption cutanee ont montre une tres bonne biodisponibilite tant dans l'epiderme que le derme et les etudes de securite on confirme une tres bonne tolerance cutanee de A-A-A. Dans cette etude, nous avons cherche a demontrer que A-A-A pouvait stimuler la synthese des proteines de la matrice extra-cellulaire ainsi qu'ameliorer les proprietes viscoelastiques de la peau humaine en procedant a une double etude clinique, par immunohistochimie et biophysique sur volontaires. MethodesLes deux etudes on ete realisees en double aveugle contre placebo avec une emulsion H/E contenant 1% A-A-A. L'etude histologique a ete realisee sur 16 femmes volontaires (>55ans) presentant des signes de photoveillissement sur l'avant-bras durant une periode de 12 jours sur l'expression du collagene IV (COLIV) et de la fibrilline-1. Dans la seconde etude, les proprietes biomecaniques de la peau ont ete evaluees dans un panel de 16 femmes (>45ans) utilisant le Cutometre MPA580 et en mesurant le parametre F4, valeur representant specifiquement la fermete de la peau, apres l'application topique de produits durant pour 28 jours. Pour cette etude A-A-A (1%) a ete compare, en plus du placebo, a une formulation contenant 0.1% de retinol. ResultatsApres 12 jours d'application topique de 1% A-A-A, nous avons pu demontre une augmentation significative de l'expression de COLIV et de la fibrilline respectivement 13% et 6% par rapport au placebo. L'application de 1% A-A-A et 0,1% de retinol ont permis de pour reduire significativement F4 apres 28 jours de traitement respectivement de 15.8% et 14.7%. Aucune difference significative n'a ete trouvee entre le retinol et A-A-A. Cependant, seul A-A-A presentait une ameloration significative sur la fermete de la peau, ce qui confime le benefice apporte par A-A-A comme actif stimulant le raffermissement de la peau. ConclusionDans cette etude, nous avons montre l'efficacite de 1% A-A-A a la fois invivo sur l'expression des proteines (fibrilline et collagene IV) et sur un parametre clinique specifiquement lie a la fermete de la peau. Ces deux etudes confirment que l'acide acetyl-aspartique a un fort potentiel en tant qu' agent anti-age pouvant aussi etre considere comme un ingredient cosmeceutique' repondant aux besoins des consommateurs en demande de produits cosmetiques a efficacite prouvee.

  • 3.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    The cutaneous non-neuronal cholinergic system and smoking related dermatoses: Studies of the psoriasis variant palmoplantar pustulosis2007In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 80, no 24-25, p. 2227-2234Article in journal (Refereed)
    Abstract [en]

    Palmoplantar pustulosis (PPP) is probably the inflammatory skin disease most strongly associated to smoking. The disease is common in middle-aged, smoking women, and is chronic, sometimes disabling and characterized by pustules, erythema and scaling on the soles and palms. It is often treatment-resistant. PPP patients have a co-morbidity with an increased risk of autoimmune thyroid disease, celiac disease/gluten intolerance, abnormal calcium homeostasis, diabetes type 2, and depression. The sweat gland apparatus is involved in the pathogenesis of PPP since a) the normal structure of the acrosyringium is abolished so the keratin pattern differs to that in normal palmar skin; b) granulocytes migrate outwards in the acrosyringium forming the pustule in the stratum corneum. Acetylcholine (ACh) is the main inducer of sweating. With immunohistochemistry the ACh synthesizing enzyme choline acetyltransferase (ChAT) and the ACh-degrading enzyme acetylcholinesterase (AChE) were found to be strongly expressed in the gland and duct as were the alpha-3 and alpha-7 nicotinic acetylcholine receptors (nAChRs). Smoking influenced the staining intensity of the enzymes and the alpha-3 nAChR in healthy subjects. In involved PPP skin there was a massive infiltration of granulocytes expressing ChAT and alpha-3 nAChR, and mast cells expressing AChE indicating a role for acetylcholine in inflammation. Cessation of smoking resulted in fewer pustules, and less scaling and erythema. The mechanisms for the effect of nicotine/smoking in PPP are still unknown but nicotine may lead to enhanced inflammation in consideration of the properties of the sweat duct and/or nicotine might facilitate autoimmune reactions.

  • 4.
    Hagforsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Michaëlsson, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Normal and PPP-affected palmoplantar sweat gland express neuroendocrine markers chromogranins and synaptophysin differently2010In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 302, no 9, p. 685-693Article in journal (Refereed)
    Abstract [en]

    Earlier findings indicate the acrosyringium as the target for the inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat gland apparatus seems to be an immune-competent structure that probably contributes to the defence of the skin. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ because it expresses cholineacetyl-transferase and acetylcholinesterase, nicotinic receptors, beta-adrenergic and angiotensin receptors.

    The aim of this study was to obtain further information about neuroendocrine properties of the sweat gland apparatus by examining the expression of common neuroendocrine markers synaptophysin and chromogranins A and B in healthy palmar skin and in PPP skin.

    Synaptophysin and chromogranins were expressed in the sweat glands and ducts with some variation in the pattern and intensity of the expression. In PPP skin the expression differed, being higher and lower, depending on the part of the sweat duct. Chromogranins were further expressed in the epidermis, endothelium and inflammatory cells, but its intensity was weaker in epidermis than in the sweat gland apparatus. In most cases, chromogranins in epidermis in involved PPP were weakly expressed compared to healthy controls. The presence of synaptophysin and chromogranins in palmoplantar skin may have marked neuroendocrine effects, and the palmoplantar skin is likely to have important neuroimmuno-endocrine properties. Moreover, the altered chromogranin expression in PPP skin might influence both the neuroendocrine and neuroimmunologic properties of palmoplantar skin in these patients. These results indicate important neuroendocrine properties of the palmoplantar skin.

  • 5.
    Hagforsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Michaëlsson, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Somatostatin receptors are strongly expresssed in palmoplantar sweat glands and ducts: studies of normal and palmoplantar pustulosis skin2011In: Clincal and Experimental Dermatology, ISSN 0307-6938, E-ISSN 1365-2230, Vol. 36, no 5, p. 521-527Article in journal (Refereed)
    Abstract [en]

    Background

    The acrosyringium is the target for inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat-gland apparatus seems to be an immunocompetent structure that probably contributes to skin defence. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ.

    Aim

    To obtain further information about the neuroendocrine properties of the sweat-gland apparatus by examining expression of the somatostatin receptors (SSTRs) 1-5 in healthy palmar skin and in PPP skin.

    Methods

    Biopsy specimens were taken from 25 patients with PPP and 25 healthy controls. Immunohistochemical analysis was used to investigate expression of SSTRs 1-5.

    Results

    SSTRs 1-5 were expressed in both epidermal and endothelial structures. The staining intensity of the sweat-gland apparatus was more pronounced than that of the epidermis. Expression differed significantly between lesional PPP and normal plantar skin, with increased expression of SSTRs 3 and 4 in ducts in epidermis, and decreased expression of SSTR 1 in ducts in both papillary and reticular dermis. In specimens with pronounced inflammation, numerous dendritic cells with strong expression of SSTRs 1.. 2 and 4 were seen, especially in the papillary dermis.

    Conclusions

    The presence of SSTRs in palmoplantar skin, and specifically at high density in the sweat glands and ducts, might be of particular importance in skin neuroimmunoendocrinology. Although the relevance of the changes in SSTR expression in PPP skin compared with normal skin is unclear, our hypothesis is that these differences might influence the function of both the neuroendocrine and neuroimmunological properties of palmoplantar skin, especially in the sweat-gland apparatus.

  • 6.
    Hagforsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lundgren, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Olofsson, Helena
    Petersson, Axel
    Lagumdzija, Alena
    Hedstrand, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaelsson, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Women with palmoplantar pustulosis have disturbed calcium homeostasis and a high prevalence of diabetes mellitus and psychiatric disorders: a case-control study2005In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 85, no 3, p. 225-232Article in journal (Refereed)
    Abstract [en]

    Palmoplantar pustulosis is characterized by pustule formation in the acrosyringium. Nearly 50% of palmoplantar pustulosis sera produce immunofluorescence of the palmar papillary endothelium from healthy subjects, but also of the endothelium of normal parathyroid gland. With a case-control design the levels of calcium and parathyroid hormone in serum were measured in 60 women with palmoplantar pustulosis and 154 randomly selected population-based control women. One-third of the controls had been smokers, whereas 95% of the cases were or had been smokers. Mean age-adjusted serum calcium was increased in the patients compared with the controls (2.43 vs 2.36 mmol/l; p<0.0001), whereas the parathyroid hormone concentration was suppressed (23.2 vs 31.1 ng/l; p<0.0001). The plasma levels of parathyroid hormone-related protein were normal in patients but there was a strong expression of this protein in the acrosyringium both in palmoplantar pustulosis and control skin. As even a marginal elevation of serum calcium is associated with an increased risk for diabetes, cardiovascular disease and psychiatric disease, we analysed the risk for these disorders in palmoplantar pustulosis patients compared with that in the control group. Both diabetes mellitus and psychiatric disorders were associated with palmoplantar pustulosis with an odds ratio of 8.7 (95% CI 3.3-22.8) and 5.6 (95% CI 2.2-14.4), respectively. Palmoplantar pustulosis is a complex disease with an increased risk for several non-dermatological disorders. The role of the mildly increased serum calcium for the high risk for diabetes and depression deserves to be studied.

  • 7.
    Hagforsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Paivandy, Aida
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Calounova, Gabriela
    Melo, Fabio R.
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ablation of human skin mast cells in situ by lysosomotropic agents2015In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 24, no 7, p. 516-521Article in journal (Refereed)
    Abstract [en]

    Mast cells are known to have a detrimental impact on numerous types of inflammatory skin diseases such as contact dermatitis, atopic eczema and cutaneous mastocytosis. Regimens that dampen skin mast cell-mediated activities can thus offer an attractive therapeutic option under such circumstances. As mast cells are known to secrete a large array of potentially pathogenic compounds, both from preformed stores in secretory lysosomes (granules) and after de novo synthesis, mere inhibition of degranulation or interference with individual mast cell mediators may not be sufficient to provide an effective blockade of harmful mast cell activities. An alternative strategy may therefore be to locally reduce skin mast cell numbers. Here, we explored the possibility of using lysosomotropic agents for this purpose, appreciating the fact that mast cell granules contain bioactive compounds prone to trigger apoptosis if released into the cytosolic compartment. Based on this principle, we show that incubation of human skin punch biopsies with the lysosomotropic agents siramesine or Leu-Leu methyl ester preferably ablated the mast cell population, without causing any gross adverse effects on the skin morphology. Subsequent analysis revealed that mast cells treated with lysosomotropic agents predominantly underwent apoptotic rather than necrotic cell death. In summary, this study raises the possibility of using lysosomotropic agents as a novel approach to targeting deleterious mast cell populations in cutaneous mastocytosis and other skin disorders negatively influenced by mast cells.

  • 8.
    Hagforsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Pihl-Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Calcium homeostasis and body composition in patients with palmoplantar pustulosis: a case-control study2012In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 166, no 1, p. 74-81Article in journal (Refereed)
    Abstract [en]

    Background

    Palmoplantar pustulosis (PPP) is a common disease strongly associated with smoking, autoimmune comorbidities and a deranged calcium homeostasis. It is unclear whether these changes in calcium homeostasis are a consequence of vitamin D status, abnormal dermal vitamin D synthesis or whether they are substantiated in effects on bone mineral density (BMD).

    Objectives

    To study the vitamin D status and BMD in patients with PPP.

    Methods

    In comparisons with two sets of controls (n = 101 for serum analyses and n = 5123 for BMD analyses), we therefore aimed to investigate whether PPP (59 cases) was associated with serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, whether patients with PPP had decreased BMD and finally if the dermal expression of 25-hydroxyvitamin D(3) -1α-hydroxylase (CYP27B1) and the vitamin D receptor (VDR) were affected in PPP skin lesions.

    Results

    We found no differences in mean serum 25-hydroxyvitamin D levels between cases and controls, whereas PPP cases displayed 17·8 pmol L(-1) lower (P = 0·04) values in 1,25-dihydroxyvitamin D. BMD at the hip, lumbar spine or of total body did not differ substantially between cases and controls. Finally, patients with PPP had lower dermal expression of CYP27B1 and VDR in affected skin lesions.

    Conclusions

    The increase in serum calcium levels and suppressed parathyroid hormone in patients with PPP were not attributable to derangements in vitamin D status and these patients did not have lower BMD.

  • 9.
    Hagforsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Sunnerberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hedstrand, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Psoriasis autoantigens in normal scalp skin: Identification by expression cloning2007In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 127, no 9, p. 2276-2280Article in journal (Refereed)
  • 10.
    Landegren, Nils
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Pourmousa Lindberg, Mina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skov, Jakob
    Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Eriksson, Daniel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Lisberg Toft-Bertelsen, Trine
    Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
    MacAulay, Nanna
    Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Räisänen-Sokolowski, Anne
    Helsinki Univ Hosp, Dept Pathol, Helsinki, Finland.; Univ Helsinki, Helsinki, Finland.
    Saha, Heikki
    Tampere Univ Hosp, Sch Med, Dept Med, Tampere, Finland.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Ohlsson, Sophie
    Lund Univ, Dept Nephrol, Lund, Sweden.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Husebye, Eystein S
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.; Univ Bergen, Dept Clin Sci, Bergen, Norway.; Haukeland Hosp, Dept Med, Bergen, Norway.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Anderson, Mark S
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Perheentupa, Jaakko
    Univ Helsinki, Hosp Children & Adolescents, Helsinki, Finland.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Fenton, Robert A
    Aarhus Univ, Dept Biomed, Interact Prot Epithelial Transport Ctr, Aarhus, Denmark.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, SE-17176 Stockholm, Sweden.
    Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.2016In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 27, no 10, p. 3220-3228Article in journal (Refereed)
    Abstract [en]

    Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.

  • 11.
    Lindqvist, Ulla
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Medicin.
    Kristjansson, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Pihl-Lundin, Inger
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Dermatologi o venereologi.
    Hagforsen, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Dermatologi o venereologi.
    Michaelsson, Gerd
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Dermatologi o venereologi.
    Patients with psoriatic arthritis have an increased number of lymphocytes in the duodenal mucosa in comparison with patients with psoriasis vulgaris.2006In: J RheumatolArticle in journal (Refereed)
  • 12.
    Michaëlsson, Gerd
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ahs, S.
    Hammarström, I.
    Pihl-Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gluten-free diet in psoriasis patients with antibodies to gliadin results in decreased expression of tissue transglutaminase and fewer Ki67+ cells in the dermis2003In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 83, no 6, p. 425-429Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that 16% of patients with psoriasis vulgaris have IgA and/or IgG antibodies to gliadin, but few have antibodies to endomysium. The increase in duodenal intraepithelial lymphocytes was mild. Still, highly significant clinical improvement was observed after 3 months on a gluten-free diet. This study surveys certain immunohistological aspects of involved and non-involved skin in 28 AGA-positive psoriasis patients before and after 3 months of a gluten-free diet. Staining was performed for CD4+ T lymphocytes, Langerhans' cells, endothelium, proliferating (Ki67) cells and tissue transglutaminase. In the entire group of patients, as well as in those on a gluten-free diet as the only treatment, Ki67 + cells in involved dermis were highly significantly decreased after the diet. There was a significant decrease in Ki67 + cells even in patients without increased intraepithelial lymphocytes. Tissue transglutaminase was highly overexpressed in involved skin in the papillary endothelium, and decreased by 50% after gluten-free diet. The possible role of tissue transglutaminase in the pathogenesis of psoriasis needs further investigation.

  • 13.
    Michaëlsson, Gerd
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dermatologi o Venereologi.
    Gustafsson, Karin
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dermatologi o venereologi.
    The psoriasis variant palmoplantar pustulosis can be improved after cessation of smoking2006In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 54, no 4, p. 737-738Article in journal (Refereed)
  • 14.
    Michaëlsson, Gerd
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kajermo, U.
    Michaëlsson, A.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Infliximab can precipitate as well as worsen palmoplantar pustulosis: possible linkage to the expression of tumour necrosis factor-alpha in the normal palmar eccrine sweat duct?2005In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 153, no 6, p. 1243-1244Article in journal (Refereed)
  • 15.
    Michaëlsson, Gerd
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kristjánsson, Gudjon A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pihl Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Palmoplantar pustulosis and gluten sensitivity: A study of serum antibodies against gliadin and tissue transglutaminase, the duodenal mucosa and effects of gluten-free diet2007In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 156, no 4, p. 659-666Article in journal (Refereed)
    Abstract [en]

    Background: Palmoplantar pustulosis (PPP) is a chronic inflammatory disease affecting mainly smoking women. Some patients also have psoriasis. A subgroup of patients with psoriasis has been shown to have silent gluten sensitivity with relevance for their psoriasis. Nothing is known about gluten sensitivity in PPP. Objectives: To find out whether any patients with PPP are gluten-sensitive and whether this might be relevant for the PPP activity. Patients and methods: One hundred and twenty-three patients (113 women) with PPP participated. Screening for IgA antibodies against gliadin and tissue transglutaminase (tTG) was performed, the duodenal mucosa in patients with and without these antibodies was studied and the effect of a gluten-free diet (GFD) was followed up. Results: Twenty-two patients (18%) had IgA antibodies against gliadin and nine of 94 (10%) against tTG. Twelve patients with antibodies and 11 without underwent gastro-duodenoscopy. Four displayed villous atrophy, whereas all other specimens were judged as essentially normal at routine staining. However, with immunohistochemistry, the numbers of CD3+ and CD8+ lymphocytes in the epithelium were found to be increased in patients with any type of antibody, although they were most numerous in those with both types of antibodies. Seven of 123 patients (6%) had coeliac disease (three previously diagnosed). Patients with antibodies who adhered to the GFD displayed total or nearly total clearance of the skin lesions and normalization of the antibody levels. Conclusions: Patients with PPP should be screened for antibodies against gliadin and tTG. Those with antibodies can be much improved on a GFD regardless of the degree of mucosal abnormalities.

  • 16.
    Murakami, Masamoto
    et al.
    Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Morhenn, Vera
    Division of Dermatology, University of California, San Diego, CA, USA.
    Ishida-Yamamoto, Akemi
    Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
    Iizuka, Hajime
    Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
    Patients with palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum2011In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 20, no 10, p. 845-847Article in journal (Refereed)
    Abstract [en]

    Recent findings about the pathogenesis of pustulosis palmaris et plantaris (PPP), also known as palmoplantar pustulosis, suggest that IL-17 expression in the acrosyringium as well as infiltration of IL-17 positive cells, e. g. Langerhans cells may play important roles. However, to date, it has not been established whether circulating IL-17 related cytokines are involved in PPP. We studied the circulating IL-17 related cytokines as well as the mRNA levels in lesional skin. IL-17 related cytokine mRNAs were increased in the PPP lesions compared with the control tissues (five patients vs five controls). The serum levels of TNF-alpha, IL-17, IL-22 and IFN-gamma also were significantly increased in PPP, but not IL-23 and IL-8 (48 patients vs 20 controls). Our findings document that not only the serum IL-17 but also tissue IL-17 are elevated in PPP and may be in the pathogenesis of this disorder.

  • 17. Ronnberg, Elin
    et al.
    Calounova, Gabriela
    Sutton, Vivien R.
    Trapani, Joseph A.
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Pejler, Gunnar
    Granzyme H Is a Novel Protease Expressed by Human Mast Cells2014In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 165, no 1, p. 68-74Article in journal (Refereed)
    Abstract [en]

    Background: Many of the functions attributed to mast cells depend on the various pro-inflammatory mediators that are secreted upon mast cell activation. These include a panel of mast cell-specific proteases. In addition, recent studies have indicated that murine mast cells also express granzyme D, a protease previously thought to be confined to cytotoxic lymphocytes. Here, we address the human relevance of the latter findings by investigating whether human mast cells express granzyme H, the granzyme that may represent the functional counterpart to murine granzyme D. Methods: Cord blood-derived mast cells, LAD2 cells and skin mast cells in situ were evaluated for their expression of granzymes using quantitative PCR, Western blot analysis and immunostaining. Mast cells were activated by either calcium ionophore stimulation or IgE receptor cross-linking. Results: Cord blood-derived mast cells and LAD2 cells were shown to express granzyme H and B mRNA, while granzyme A, K and M expression was undetectable. Mast cell activation by either calcium ionophore or IgE receptor cross-linking caused down-regulated expression of granzyme H. In contrast, granzyme B expression was up-regulated by the same stimuli. Granzyme H expression was also confirmed at the protein level, as shown by both Western blot analysis and confocal microscopy. Further, we show that granzyme H is expressed by human skin mast cells in situ. Conclusions: The present findings implicate granzyme H as a novel protease expressed by human mast cells and support earlier findings obtained in natural killer cells suggesting that granzymes B and H are reciprocally regulated.

  • 18.
    Swartling, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Naver, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Pihl-Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sweat gland morphology and periglandular innervation in essential palmar hyperhidrosis before and after treatment with intradermal botulinum toxin2004In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 51, no 5, p. 739-745Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Intradermal botulinum toxin (Btx) produces long-lasting relief of focal hyperhidrosis, but its mechanism of action is poorly understood.

    OBJECTIVE: To study the effect of Btx A on the size and innervation of sweat glands in patients with palmar hyperhidrosis.

    METHODS: Palmar skin biopsy was performed in 26 hyperhidrotic patients before scheduled Btx treatment and in 11 controls. Twelve of the patients also underwent biopsy 1 to 6 months after the Btx injections. Sweat gland morphology was investigated by light microscopy; the cross-sectional area of the secretory tubule and its lumen was measured by image analysis. Immunofluorescence (IF) with antibodies to the neural markers protein gene product 9.5 (PGP 9.5) and growth-associated protein 43 (GAP 43), and to vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP), was used to analyze the periglandular innervation.

    RESULTS: The gross morphology of the sweat glands was similar in patients and controls, with no significant differences in tubular and luminal areas between the groups. After Btx treatment, the tubular dimensions remained unchanged, but the lumen tended to be smaller ( P = .07). Around the glands, increased GAP 43 staining indicating sprouting was seen within 3 months after Btx treatment ( P = .016); whereas the PGP 9.5 staining was decreased in most specimens ( P = .09) indicating lack of functional nerve growth. No change in VIP or CGRP immunoreactivity was observed.

    CONCLUSIONS: The sweat glands appear structurally normal in hyperhidrotic patients before Btx therapy, whereas after therapy the luminal area of the gland is frequently diminished. The IF data GAP 43/PGP 9.5 suggest that Btx therapy induces long-standing functional denervation of the sweat glands, which might explain its anti-transpiratory efficacy.

1 - 18 of 18
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