Pathophysiologie der Psoriasis

Zusammenfassung

Erkenntnisse zur (Immun-)Pathogenese der Psoriasis haben einerseits kürzlich zur Einführung mehrerer Pathogenese-orientierter Therapeutika geführt; andererseits haben diese neuen Therapien auch der Psoriasisforschung einen beispiellosen Aufschwung beschert. Insbesondere die Rolle entzündlicher Mediatoren wie Zytokine und Chemokine, aber auch die Funktion von Adhäsionsmolekülen bei der Rekrutierung von Immunzellen wurden intensiv beforscht. Diese Facetten müssen jedoch, und das wird gerade durch neueste Arbeiten verdeutlicht, durch weitere Bausteine eines komplexen Mosaikes, welches auch epidermale und neuronale Faktoren beinhaltet, ergänzt werden. Die komplexen Zusammenhänge der Pathophysiologie der Psoriasis werden in dieser Übersicht diskutiert.

Abstract

On the one hand, new insights into the (immuno-)pathogenesis of psoriasis have recently resulted in the approval of several pathogenesis-oriented novel therapeutics. These new therapies, on the other hand, have greatly stimulated research into the pathogenesis of psoriasis. In particular, pro-inflammatory mediators such as cytokines and chemokines as well as adhesion molecules involved in recruitment of immune cells into the skin have been in the focus of psoriasis research. However, new results indicate that the pathogenic mosaic of psoriasis has to be complemented by other important factors, such as epithelial or neurological dysregulations. This review discusses aspects of the complex pathophysiology of psoriasis.

Literatur

• 1 Schön M P, Boehncke W H. Psoriasis.  N Engl J Med. 2005;  352 1899-1912
• 2 Gottlieb A B. Psoriasis: emerging therapeutic strategies.  Nat Rev Drug Discov. 2005;  4 19-34
• 3 Schön M P. Advances in psoriasis therapy.  Lancet. 2005;  366 1333-1335
• 4 Nickoloff B J. Keratinocytes regain momentum as instigators of cutaneous inflammation.  Trend Mol Med. 2006;  12 102-106
• 5 Christophers E. The immunopathology of psoriasis.  Int Arch Allergy Immunol. 1996;  110 199-206
• 6 Mueller W, Herrmann B. Cyclosporin A for psoriasis.  N Engl J Med. 1979;  301 555
• 7 Gottlieb J L, Gilleaudeau P, Johnson R, Estes L, Woodworth T G, Gottlieb A B, Krueger J G. Response of psoriasis to a lymphocyte-selective toxin (DAB389 IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.  Nature Med. 1995;  1 442-447
• 8 Ellis C N, Krueger G G, Group A CS. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes.  N Engl J Med. 2001;  345 248-255
• 9 Kupper T S. Immunologic targets in psoriasis.  New Engl J Med. 2003;  349 1987-1990
• 10 Lebwohl M, Tyring S K, Hamilton T K, Toth D, Glazer S, Tawfik N H, Walicke P, Dummer W, Wang X, Garovoy M R, Pariser D. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis.  New Engl J Med. 2003;  349 2004-2013
• 11 Nicolas J F, Chamchick N, Thivolet J, Wijdenes J, Morel P, Revillard J P. CD4 antibody treatment of severe psoriasis.  Lancet. 1991;  338 321
• 12 Prinz J, Braun-Falco O, Meurer M, Daddona P, Reiter C, Rieber P, Riethmuller G. Chimaeric CD4 monoclonal antibody in treatment of generalized pustular psoriasis.  Lancet. 1991;  338 320-321
• 13 Tomfohrde J, Silverman A, Barnes R, Fernandez-Vina M A, Young M, Lory D, Morris L, Wuepper K D, Stastny P, Menter A, Bowcock A. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.  Science. 1994;  264 1141-1145
• 14 Eedy D J, Burrows D, Bridges J M, Jones F GC. Clearance of severe psoriasis after allogeneic bone marrow transplantation.  Br Med J. 1990;  300 908
• 15 Gardembas-Pain M, Ifrah N, Foussard C, Boasson M, Saint Andre J P, Verret J L. Psoriasis after allogeneic bone marrow transplantation.  Arch Dermatol. 1990;  126 1523
• 16 Christophers E. Psoriasis - Epidemiology and clinical spectrum.  Clin Exp Dermatol. 2001;  26 314-320
• 17 Bour H, Puisieux I, Kouritsky P, Favrot M, Musette P, Nicolas J F. T-cell repertoire analysis in chronic plaque psoriasis suggests an antigen-specific immune response.  Hum Immunol. 1999;  60 665-676
• 18 Lin W J, Norris D A, Achziger M, Kotzin B L, Tomkinson B. Oligoclonal expansion of intraepidermal T cells in psoriasis skin lesions.  J Invest Dermatol. 2001;  117 1546-1553
• 19 Prinz J C, Vollmer S, Boehncke W H, Menssen A, Laisney I, Trommler P. Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris.  Eur J Immunol. 1999;  29 3360-3368
• 20 Boehncke W-H. Psoriasis and bacterial superantigens - formal or causal relation?.  Trends Microbiol.. 1996;  4 485-489
• 21 Vekony M A, Holder J E, Lee A J, Horrocks C, Eperon I C, Camp R D. Selective amplifications of T-cell receptor variable region species is demonstrable but not essential in early lesions of psoriasis vulgaris: analysis by anchored polymerase chain reaction and hypervariable region size spectratyping.  J Invest Dermatol. 1997;  109 5-13
• 22 Weisenseel P, Laumbacher B, Besgen P, Ludolph-Hauser D, Herzinger T, Röcken M, Wank R, Prinz J C. Streptococcal infection distinguishes different types of psoriasis.  J Med Genet. 2002;  39 767-768
• 23 Boehncke W-H, Dressel D, Zollner T M, Kaufmann R. Pulling the trigger on psoriasis.  Nature. 1996;  379 777
• 24 Gudmundsdottir A S, Sigmundsdottir H, Sigurgeirsson B, Good M F, Valdimarsson H, Jonsdottir I. Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis?.  Clin Exp Immunol. 1999;  117 580-586
• 25 Schön M P. Animal models of psoriasis - what can we learn from them?.  J Invest Dermatol. 1999;  112 405-410
• 26 Wrone-Smith T, Nickoloff B J. Dermal injection of immunocytes induces psoriasis.  J Clin Invest. 1996;  98 1878-1887
• 27 Boyman O, Hefti H P, Conrad C, Nickoloff B J, Suter M, Nestle F O. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor alpha.  J Exp Med. 2004;  199 731-736
• 28 Breban M, Fernandez-Sueiro J L, Richardson J A, Hadavand R R, Maika S D, Hammer R E, Taurog J D. T cells, but not thymic exposure to HLA-B27, are required for the inflammatory disease of HLA-B27 transgenic rats.  J Immunol. 1996;  156 794-803
• 29 Schön M P, Detmar M, Parker C M. Murine psoriasis-like disorder induced by naive CD4⁺ T-cells.  Nature Med. 1997;  3 183-188
• 30 Bos J D, de Rie M A, Teunissen M B, Piskin G. Psoriasis: dysregulation of innate immunity.  Br J Dermatol. 2005;  152 1098-1107
• 31 von den Driesch P. Is psoriasis a T-cell disease? Viewpoint 3.  Exp Dermatol. 2000;  9 367-377
• 32 Schön M, Denzer D, Kubitza R C, Ruzicka T, Schön M P. Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice.  J Invest Dermatol. 2000;  114 976-983
• 33 Zhu K, Mrowietz U. Enhancement of antibacterial superoxide-anion generation in human monocytes by fumaric acid esters.  Arch Dermatol Res. 2005;  297 170-176
• 34 Schaerli P, Britschgi M, Keller M, Steiner U C, Steinmann L S, Moser B, Pichler W J. Characterization of human T cells that regulate neutrophilic skin inflammation.  J Immunol. 2004;  173 2151-2158
• 35 Keller M, Spanou Z, Schaerli P, Britschgi M, Yawalkar N, Seitz M, Villiger P M, Pichler W J. T cell-regulated neutrophilic inflammation in autoinflammatory diseases.  J Immunol. 2005;  175 7678-7686
• 36 Nickoloff B J. The cytokine network of psoriasis.  Arch Dermatol. 1991;  127 871-884
• 37 Schön M P, Ruzicka T. Psoriasis: The plot thickens.  Nat Immunol. 2001;  2 91
• 38 Barker J NWN, Sarma V, Mitra R S, Dixit V M, Nickoloff B J. Marked synergism between tumor necrosis factor-alpha and interferon-gamma in regulation of keratinocyte-derived adhesion molecules and chemotactic factors.  J Clin Invest. 1990;  85 605-608
• 39 Murphy J E, Robert C, Kupper T S. Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity.  J Invest Dermatol. 2000;  114 602-608
• 40 Neuner P, Urbanski A, Trautinger F, Moller A, Kirnbauer R, Kapp A, Schopf E, Schwarz T, Luger T A. Increased IL-6 production by monocytes and keratinocytes in patients with psoriasis.  J Invest Dermatol. 1991;  97 27-33
• 41 Leonardi C L, Powers J L, Matheson R T, Goffe B S, Zitnik R, Wang A, Gottlieb A B,. T.e.p.s. group . Etanercept as monotherapy in patients with psoriasis.  N Engl J Med. 2003;  349 2014-2022
• 42 Reich K, Nestle F O, Papp K, Ortonne J P, Evans R, Guzzo C, Li S, Dooley L T, Griffiths C EM. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis.  Lancet. 2005;  366 1367-1374
• 43 Kuroda K, Sapadin A, Shoji T, Fleischmajer R, Lebwohl M. Altered expression of angiopoietins and Tie2 endothelium receptor in psoriasis.  J Invest Dermatol. 2001;  116 713-720
• 44 Detmar M, Brown L F, Claffey K P, Yeo K T, Kocher O, Jackman R W, Berse B, Dvorak H F. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis.  J Exp Med. 1994;  180 1141-1146
• 45 Michel G, Mirmohammadsadegh A, Olasz E, Jarzebska-Deussen B, Müschen A, Kemeny L, Abts H F, Ruzicka T. Demonstration and functional analysis of IL-10 receptors in human epidermal cells: decreased expression in psoriatic skin, down-modulation by IL-8, and up-regulation by an antipsoriatic glucocorticosteroid in normal cultured keratinocytes.  J Immunol. 1997;  159 6291-6297
• 46 Asadullah K, Sterry W, Stephanek K. IL-10 is a key cytokine in psoriasis. Proof of principle by IL-10 therapy: a new therapeutic approach.  J Clin Invest. 1998;  101 783-794
• 47 Ghoreschi K, Thomas P, Dugas M, Mailhammer R, van Eden W, van der Zee R, Biedermann T, Prinz J, Mack M, Mrowietz U, Christophers E, Schlöndorff D, Plewig G, Sander C A, Röcken M. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease.  Nature Med. 2003;  9 40-46
• 48 Ghoreschi K, Röcken M. Immune deviation strategies in the therapy of psoriasis.  Curr Drug Targets Inflamm Allergy. 2004;  3 193-198
• 49 Asadullah K, Volk H D, Sterry W. Novel immunotherapies for psoriasis.  Trends Immunol. 2002;  23 47-53
• 50 Homey B. Chemokines and chemokine receptors as targets in the therapy of psoriasis.  Curr Drug Targets Inflamm Allerg. 2004;  3 169-174
• 51 Campbell J J, Haraldsen G, Pan J, Rottman J, Qin S, Ponath P, Andrew D P, Warnke R, Ruffing N, Kassam N, Wu L, Butcher E C. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells.  Nature. 1999;  400 776-780
• 52 Homey B, Alenius H, Müller A, Soto H, Bowman E P, Yuan W, McEvoy L, Lauerma A I, Assmann T, Bünemann E, Lehto M, Wolff H, Yen D, Marxhausen H, To W, Sedgwick J, Ruzicka T, Lehmann P, Zlotnik A. CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.  Nature Med. 2002;  8 157-165
• 53 Goebeler M, Toksoy A, Spandau U, Engelhardt E, Bröcker E-B, Gillitzer R. The C-X-C chemokine Mig is highly expressed in the papillae of psoriatic lesions.  J Pathol. 1998;  184 89-95
• 54 Liao F, Rabin R L, Yannelli J R, Koniaris L G, Vanguri P, Farber J M. Human Mig chemokine: biochemical and functional characterization.  J Exp Med. 1995;  182 1301-1314
• 55 Raychaudhuri S P, Jiang W Y, Farber E M, Schall T J, Ruff M R, Pert C B. Upregulation of RANTES in psoriatic keratinocytes: a possible pathogenic mechanism for psoriasis.  Acta Derm Venereol. 1999;  79 9-11
• 56 Vestergaard C, Gesser B, Lohse N, Jensen S L, Sindet-Pedersen S, Thestrup-Pedersen K, Matsushima K, Larsen C G. Monocyte chemotactic and activating factor (MCAF/MCP-1) has an autoinductive effect in monocytes, a process regulated by IL-10.  J Dermatol Sci. 1997;  15 14-22
• 57 Schröder J M, Gregory H, Young J, Christophers E. Neutrophil-activating proteins in psoriasis.  J Invest Dermatol. 1992;  98 241-247
• 58 Schön M P, Zollner T M, Boehncke W H. The molecular basis of lymphocyte recruitment to the skin: Clues for pathogenesis and selective therapies of inflammatory disorders.  J Invest Dermatol. 2003;  121 951-962
• 59 Dewing S B. Remission of psoriasis associated with cutaneous nerve section.  Arch Dermatol. 1971;  104 220-221
• 60 Perlman H H. Remission of psoriasis vulgaris from the use of nerve-blocking agents.  Arch Dermatol. 1972;  105 128-129
• 61 Scholzen T E, Luger T A. Neutral endopeptidase and angiotensin-converting enzyme - key enzymes terminating the action of neuroendocrine mediators.  Exp Dermatol. 2004;  13s 22s-26s
• 62 Raychaudhuri S P, Raychaudhuri S K. Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis.  Prog Brain Res. 2004;  146 433-437
• 63 Steinhoff M, Ständer S, Seeliger S, Ansel J C, Schmelz M, Luger T A. Modern aspects of cutaneous neurogenic inflammation.  Arch Dermatol. 2003;  139 1479-1488
• 64 Raychaudhuri S P, Sanyal M, Weltman H, Kundu-Raychaudhuri S. K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: an in vivo study using the severe combined immunodeficient mouse-human skin model.  J Invest Dermatol. 2004;  122 812-819
• 65 Robert C, Kupper T S. Inflammatory skin diseases, T cells, and immune surveillance.  N Engl J Med. 1999;  341 1817-1828
• 66 Lebwohl M. Psoriasis.  Lancet. 2003;  361 1197-1204
• 67 Papp K, Bissonnette R, Krueger J G, Carey W, Gratton D, Gulliver W P, Lui H, Lynde C W, Magee A, Minier D, Ouellet J P, Patel P, Shapiro J, Shear N H, Kramer S, Walicke P, Bauer R, Dedrick R L, Kim S S, White M, Garovoy M R. The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody.  J Am Acad Dermatol. 2001;  45 665-674
• 68 Butcher E C, Picker L J. Lymphocyte homing and homeostasis.  Science. 1996;  272 60-66
• 69 Andrian U H von, Mackay C R. T-cell function and migration. Two sides of the same coin.  N Engl J Med. 2000;  343 1020-1034
• 70 Ley K. Functions of selectins.  Results Probl Cell Differ. 2001;  33 177-200
• 71 Fuhlbrigge R C, Kieffer J D, Armerding D, Kupper T S. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells.  Nature. 1997;  389 978-981
• 72 Bhushan M, Bleiker T O, Ballsdon A E, Allen M H, Sopwith M, Robinson M K, Clarke C, Weller R P, Graham-Brown R A, Keefe M, Barker J N, Griffiths C E. Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial.  Br J Dermatol. 2002;  146 824-831
• 73 Hardtke M, Friedrich M, Philipp S, Holzmann R, Mueller C, Soos N, Höflich C, Sabat R, Merk H, Sterry W, Mrowietz U. Anti-L-selectin therapy is not effective in psoriasis: a randomized trial (abstr.).  Arch Dermatol Res. 2005;  296 427
• 74 Boehncke W-H, Schön M P. Interfering with leukocyte rolling - a promising therapeutic approach in inflammatory skin disorders?.  Trends Pharmacol Sci. 2003;  24 49-52
• 75 Friedrich M, Bock D, Philipp S, Ludwig N, Sabat R, Wolk K, Schroeter-Maas S, Aydt E, Kang S, Dam T N, Zahlten R, Sterry W, Wolff G. Pan-selectin antagonism improves psoriasis manifestation in mice and man.  Arch Dermatol Res. 2006;  297 345-351
• 76 Schön M P, Drewniok C, Boehncke W H. Targeting selectin functions in the therapy of psoriasis.  Curr Drug Targets Inflamm Allerg. 2004;  3 163-168
• 77 Schön M P, Krahn T, Schön M, Rodriguez M-L, Antonicek H, Schultz J E, Ludwig R J, Zollner T M, Bischoff E, Bremm K-D, Schramm M, Henninger K, Kaufmann R, Gollnick H PM, Parker C M, Boehncke W-H. Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation.  Nature Med. 2002;  8 366-372
• 78 Ulbrich H, Eriksson E E, Lindbom L. Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease.  Trends Pharmacol Sci. 2003;  24 640-647
• 79 Hwang S T. Mechanisms of T cell homing to skin.  Adv Dermatol. 2001;  17 211-241
• 80 Ludwig R J, Zollner T M, Santoso S, Hardt K, Gille J, Baatz H, Johann P S, Pfeffer J, Radeke H H, Schön M P, Kaufmann R, Boehncke W H, Podda M. Junctional adhesion molecules (JAM)-B and -C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation.  J Invest Dermatol. 2005;  125 969-976
• 81 Nakada M T, Amin K, Christofidou-Solomidou M, O'Brien C D, Sun J, Gurubhagavatula I, Heavner G A, Taylor A H, Paddock C, Sun Q H, Zehnder J L, Newman P J, Albelda S M, DeLisser H M. Antibodies against the first Ig-like domain of human platelet endothelial cell adhesion molecule-1 (PECAM-1) that inhibit PECAM-1-dependent homophilic adhesion block in vivo neutrophil recruitment.  J Immunol. 2000;  164 452-462
• 82 Dustin M L, Singer K H, Springer T. Adhesion of T lymphoblasts to epidermal keratinocytes is regulated by interferon gamma and is mediated by intercellular adhesion molecule-1.  J Exp Med. 1988;  167 1323-1340
• 83 Griffiths C EM, Voorhees J J, Nickoloff B J. Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: Modulation by recombinant gamma interferon and tumor necrosis factor.  J Am Acad Dermatol. 1989;  20 617-629
• 84 Sterry W, Mielke V, Konter U, Kellner I, Boehncke W-H. Role of β1 integrins in epidermotropism of malignant T cells.  Am J Pathol. 1992;  141 855-860
• 85 Cepek K L, Shaw S K, Parker C M, Russell G J, Morrow J S, Rimm D L, Brenner M B. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alphaEbeta7 integrin.  Nature. 1994;  372 190-193
• 86 Pauls K, Schön M, Kubitza R C, Homey B, Wiesenborn A, Lehmann P, Ruzicka T, Parker C M, Schön M P. Role of integrin αE(CD103)β7 for tissue-specific epidermal localization of CD8+ T lymphocytes.  J Invest Dermatol. 2001;  117 569-575
• 87 Rottman J B, Smith T L, Ganley K G, Kikuchi T, Krueger J G. Potential role of the chemokine receptors CXCR3, CCR4, and the integrin aEb7 in the pathogenesis of psoriasis vulgaris.  Lab Invest. 2001;  81 335-347
• 88 Zenz R, Eferl R, Kenner L, Florin L, Hummerich L, Mehic D, Scheuch H, Angel P, Tschachler E, and Wagner EF. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.  Nature. 2005;  437 369-375
• 89 Sano S, Chan K S, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff B J, DiGiovanni J. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model.  Nat Med. 2004;  11 43-49
• 90 Holick M F. Is psoriasis a T cell disease? Commentary 6.  Exp Dermatol. 2000;  9 374-375
• 91 Holick M F, Chimeh F N, Ray S. Topical PTH (1 - 34) is a novel, safe and effective treatment for psoriasis: a randomized self-controlled trial and an open trial.  Br J Dermatol. 2003;  149 370-376
• 92 Schröder J M. Is psoriasis a T-cell disease? Viewpoint 2.  Exp Dermatol. 2000;  9 363-366
• 93 Nestle F O, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, Burg G, Liu Y J, Gilliet M. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.  J Exp Med. 2005;  202 135-143