Clinical Reviews in Allergy & Immunology

, Volume 33, Issue 1–2, pp 45–56 | Cite as

Immunopathogenesis of Psoriasis

  • Brian J. Nickoloff
  • Jian-Zhong Qin
  • Frank O. Nestle


Investigations into the cause and treatment of psoriasis remain at the forefront of basic and applied clinical research efforts around the world. The purpose for this review is to provide an up-to-date synopsis of recent progress in ten sections exploring the immunological and inflammatory basis for psoriasis. Given the breadth of this topic in investigative skin biology and frequent paradigm shifts, it should not be surprising that the bibliography contains more than 150 references; many of which have been published in the last 5 years. Whereas considerable progress has been made into the immunopathogenesis of psoriasis, many fundamentally important questions remain regarding the role of cells located in both epidermal and dermal compartments. Attempts to characterize various animal models of psoriasis, delineation of the mechanism of action for biological agents, and consideration of molecular links between skin inflammation and various extracutaneous comorbidities are likely to continue challenging investigators and clinicians for many years to come.


Psoriasis Immunopathogenesis Epidermal compartment Dermal compartment 



The authors would like to thank Ms. Lynn Walter for the valuable assistance in preparing the text and figure. This work was supported in part by NIH grant AR40065 (BJN, FON) and Wellcome Trust Grant (FON).


  1. 1.
    Nickoloff BJ, Nestle FO (2004) Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest 113:1664–1675PubMedGoogle Scholar
  2. 2.
    Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, Darst MA, Gao B, Boguniewicz M, Travers JB, Leung DY (2003) Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 171:3262–3269PubMedGoogle Scholar
  3. 3.
    Lebwohl M (2003) Psoriasis. Lancet 361:1197–1204PubMedGoogle Scholar
  4. 4.
    Nickoloff BJ, Bonish BK, Marble DJ, Schriedel K, DiPietro LA, Gordon KB, Lingen MW (2006) Lessons learned from psoriatic plaques concerning mechanisms of tissue repair, remodeling, and inflammation. J Investig Dermatol Symp Proc 11:16–29PubMedGoogle Scholar
  5. 5.
    Bowcock AM, Krueger JG (2005) Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol 5:699–711PubMedGoogle Scholar
  6. 6.
    Krueger JG, Bowcock A (2005) Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis 64(Suppl 2):ii30–ii36PubMedGoogle Scholar
  7. 7.
    Allen MH, Veal C, Faassen A, Powis SH, Vaughan RW, Trembath RC, Barker JN (1999) A non-HLA gene within the MHC in psoriasis. Lancet 353:1589–1590PubMedGoogle Scholar
  8. 8.
    Capon F, Munro M, Barker J, Trembath R (2002) Searching for the major histocompatibility complex psoriasis susceptibility gene. J Invest Dermatol 118:745–751PubMedGoogle Scholar
  9. 9.
    Elder JT (2006) PSORS1: linking genetics and immunology. J Invest Dermatol 126:1205–1206PubMedGoogle Scholar
  10. 10.
    Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch S, Weichenthal M, Abecasis GR, Lim HW, Christophers E, Voorhees JJ, Elder JT (2006) Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 78:827–851PubMedGoogle Scholar
  11. 11.
    Norrlind R (1955) The significance of infections in the origination of psoriasis. Acta Rheumatol Scand 1:135–144PubMedCrossRefGoogle Scholar
  12. 12.
    Baker BS, Ovigne JM, Fischetti VA, Powles A, Fry L (2003) Selective response of dermal Th-1 cells to 20–50 kDa streptococcal cell-wall proteins in chronic plaque psoriasis. Scand J Immunol 58:335–341PubMedGoogle Scholar
  13. 13.
    Brown DW, Baker BS, Ovigne JM, Hardman C, Powles AV, Fry L (2000) Skin CD4+ T cells produce interferon-gamma in vitro in response to streptococcal antigens in chronic plaque psoriasis. J Invest Dermatol 114:576–580PubMedGoogle Scholar
  14. 14.
    Diluvio L, Vollmer S, Besgen P, Ellwart JW, Chimenti S, Prinz JC (2006) Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris. J Immunol 176:7104–7111PubMedGoogle Scholar
  15. 15.
    Nickoloff BJ (1991) The cytokine network in psoriasis. Arch Dermatol 127:871–884PubMedGoogle Scholar
  16. 16.
    Nickoloff BJ, Karabin GD, Barker JN, Griffiths CE, Sarma V, Mitra RS, Elder JT, Kunkel SL, Dixit VM (1991) Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am J Pathol 138:129–140PubMedGoogle Scholar
  17. 17.
    Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138–146PubMedGoogle Scholar
  18. 18.
    Lew W, Bowcock AM, Krueger JG (2004) Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and “type 1” inflammatory gene expression. Trends Immunol 25:295–305PubMedGoogle Scholar
  19. 19.
    Zhou X, Krueger JG, Kao MC, Lee E, Du F, Menter A, Wong WH, Bowcock AM (2003) Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol Genomics 13:69–78PubMedGoogle Scholar
  20. 20.
    Gottlieb AB (2005) Psoriasis: emerging therapeutic strategies. Nat Rev Drug Discov 4:19–34PubMedGoogle Scholar
  21. 21.
    Krueger JG (2002) The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 46:1–23PubMedGoogle Scholar
  22. 22.
    Nash PT, Florin TH (2005) Tumour necrosis factor inhibitors. Med J Aust 183:205–208PubMedGoogle Scholar
  23. 23.
    Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG (1999) The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 113:752–759PubMedGoogle Scholar
  24. 24.
    Ferenczi K, Burack L, Pope M, Krueger JG, Austin LM (2000) CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry. J Autoimmun 14:63–78PubMedGoogle Scholar
  25. 25.
    Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, Meyer zum Buschenfelde KH, Fleischer B (1994) T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 102:145–149PubMedGoogle Scholar
  26. 26.
    Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ (1993) The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol 101:701–705PubMedGoogle Scholar
  27. 27.
    Bonish B, Jullien D, Dutronc Y, Huang BB, Modlin R, Spada FM, Porcelli SA, Nickoloff BJ (2000) Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-gamma production by NK-T cells. J Immunol 165:4076–4085PubMedGoogle Scholar
  28. 28.
    Gilhar A, Ullmann Y, Kerner H, Assy B, Shalaginov R, Serafimovich S, Kalish RS (2002) Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors. J Invest Dermatol 119:384–391PubMedGoogle Scholar
  29. 29.
    Nelson GW, Martin MP, Gladman D, Wade J, Trowsdale J, Carrington M (2004) Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol 173:4273–4276PubMedGoogle Scholar
  30. 30.
    Nickoloff BJ, Wrone-Smith T, Bonish B, Porcelli SA (1999) Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161. Arch Dermatol 135:546–552PubMedGoogle Scholar
  31. 31.
    Luszczek W, Manczak M, Cislo M, Nockowski P, Wisniewski A, Jasek M, Kusnierczyk P (2004) Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris. Hum Immunol 65:758–766PubMedGoogle Scholar
  32. 32.
    Holm SJ, Sakuraba K, Mallbris L, Wolk K, Stahle M, Sanchez FO (2005) Distinct HLA-C/KIR genotype profile associates with guttate psoriasis. J Invest Dermatol 125:721–730PubMedGoogle Scholar
  33. 33.
    Gilhar A, Yaniv R, Assy B, Serafimovich S, Ullmann Y, Kalish RS (2006) Fas pulls the trigger on psoriasis. Am J Pathol 168:170–175PubMedGoogle Scholar
  34. 34.
    Bos JD, de Rie MA, Teunissen MB, Piskin G (2005) Psoriasis: dysregulation of innate immunity. Br J Dermatol 152:1098–1107PubMedGoogle Scholar
  35. 35.
    Nickoloff BJ (1999) Skin innate immune system in psoriasis: friend or foe? J Clin Invest 104:1161–1164PubMedGoogle Scholar
  36. 36.
    Teunissen MB, Koomen CW, de Waal MR, Wierenga EA, Bos JD (1998) Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 111:645–649PubMedGoogle Scholar
  37. 37.
    Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A, Haugen H, Jelinek L, Kelly JD, Madden K, Maurer MF, Parrish-Novak J, Prunkard D, Sexson S, Sprecher C, Waggie K, West J, Whitmore TE, Yao L, Kuechle MK, Dale BA, Chandrasekher YA (2001) Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104:9–19PubMedGoogle Scholar
  38. 38.
    Romer J, Hasselager E, Norby PL, Steiniche T, Thorn CJ, Kragballe K (2003) Epidermal overexpression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with cyclosporine a or calcipotriol. J Invest Dermatol 121:1306–1311PubMedGoogle Scholar
  39. 39.
    Wei CC, Chen WY, Wang YC, Chen PJ, Lee JY, Wong TW, Chen WC, Wu JC, Chen GY, Chang MS, Lin YC (2005) Detection of IL-20 and its receptors on psoriatic skin. Clin Immunol 117:65–72PubMedGoogle Scholar
  40. 40.
    Villadsen LS, Schuurman J, Beurskens F, Dam TN, Dagnaes-Hansen F, Skov L, Rygaard J, Voorhorst-Ogink MM, Gerritsen AF, van Dijk MA, Parren PW, Baadsgaard O, van De Winkel JG (2003) Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest 112:1571–1580PubMedGoogle Scholar
  41. 41.
    Nickoloff BJ (2006) Keratinocytes regain momentum as instigators of cutaneous inflammation. Trends Mol Med 12:102–106PubMedGoogle Scholar
  42. 42.
    Griffiths CE (2004) T-cell-targeted biologicals for psoriasis. Curr Drug Targets Inflamm Allergy 3:157–161PubMedGoogle Scholar
  43. 43.
    Gottlieb AB, Lebwohl M, Shirin S, Sherr A, Gilleaudeau P, Singer G, Solodkina G, Grossman R, Gisoldi E, Phillips S, Neisler HM, Krueger JG (2000) Anti-CD4 monoclonal antibody treatment of moderate to severe psoriasis vulgaris: results of a pilot, multicenter, multiple-dose, placebo-controlled study. J Am Acad Dermatol 43:595–604PubMedGoogle Scholar
  44. 44.
    Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, Krueger JG (1995) Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1:442–447PubMedGoogle Scholar
  45. 45.
    Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S, Lebwohl MG, Guzzo CA, Jegasothy BV, Linsley PS, Krueger JG (2000) Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J Exp Med 192:681–694PubMedGoogle Scholar
  46. 46.
    Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 290:3073–3080PubMedGoogle Scholar
  47. 47.
    Dubertret L, Sterry W, Bos JD, Chimenti S, Shumack S, Larsen CG, Shear NH, Papp KA (2006) Clinical experience acquired with the efalizumab (Raptiva) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from a phase III international randomized, placebo-controlled trial. Br J Dermatol 155:170–181PubMedGoogle Scholar
  48. 48.
    Hwang HY, Bahk YY, Kim TG, Kim TY (2003) Identification of a commonly used CDR3 region of infiltrating T cells expressing Vbeta13 and Vbeta15 derived from psoriasis patients. J Invest Dermatol 120:359–364PubMedGoogle Scholar
  49. 49.
    Lin WJ, Norris DA, Achziger M, Kotzin BL, Tomkinson B (2001) Oligoclonal expansion of intraepidermal T cells in psoriasis skin lesions. J Invest Dermatol 117:1546–1553PubMedGoogle Scholar
  50. 50.
    Baker BS, Laman JD, Powles A, van der FL, Voerman JS, Melief MJ, Fry L (2006) Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin lesions. J Pathol 209:174–181PubMedGoogle Scholar
  51. 51.
    Johnston A, Gudjonsson JE, Sigmundsdottir H, Love TJ, Valdimarsson H (2004) Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8(+) T cells. Clin Exp Immunol 138:83–93PubMedGoogle Scholar
  52. 52.
    Leung DY, Travers JB, Giorno R, Norris DA, Skinner R, Aelion J, Kazemi LV, Kim MH, Trumble AE, Kotb M (1995) Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest 96:2106–2112PubMedGoogle Scholar
  53. 53.
    Travers JB, Hamid QA, Norris DA, Kuhn C, Giorno RC, Schlievert PM, Farmer ER, Leung DY (1999) Epidermal HLA-DR and the enhancement of cutaneous reactivity to superantigenic toxins in psoriasis. J Clin Invest 104:1181–1189PubMedGoogle Scholar
  54. 54.
    Valdimarsson H, Baker BS, Jonsdottir I, Powles A, Fry L (1995) Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens? Immunol Today 16:145–149PubMedGoogle Scholar
  55. 55.
    Nickoloff BJ, Wrone-Smith T (1999) Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis. Am J Pathol 155:145–158PubMedGoogle Scholar
  56. 56.
    Jones DA, Yawalkar N, Suh KY, Sadat S, Rich B, Kupper TS (2004) Identification of autoantigens in psoriatic plaques using expression cloning. J Invest Dermatol 123:93–100PubMedGoogle Scholar
  57. 57.
    Bos JD, Zonneveld I, Das PK, Krieg SR, van der Loos CM, Kapsenberg ML (1987) The skin immune system (SIS): distribution and immunophenotype of lymphocyte subpopulations in normal human skin. J Invest Dermatol 88:569–573PubMedGoogle Scholar
  58. 58.
    Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, Kupper TS (2006) The vast majority of CLA+ T cells are resident in normal skin. J Immunol 176:4431–4439PubMedGoogle Scholar
  59. 59.
    Curry JL, Qin JZ, Robinson J, Nickoloff BJ (2003) Reactivity of resident immunocytes in normal and prepsoriatic skin using an ex vivo skin-explant model system. Arch Pathol Lab Med 127:289–296PubMedGoogle Scholar
  60. 60.
    Dunn DA, Gadenne AS, Simha S, Lerner EA, Bigby M, Bleicher PA (1993) T-cell receptor V beta expression in normal human skin. Proc Natl Acad Sci U S A 90:1267–1271PubMedGoogle Scholar
  61. 61.
    Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO (2004) 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 199:731–736PubMedGoogle Scholar
  62. 62.
    Bhushan M, Cumberbatch M, Dearman RJ, Andrew SM, Kimber I, Griffiths CE (2002) Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing. Br J Dermatol 146:32–40PubMedGoogle Scholar
  63. 63.
    Schon MP, Zollner TM, Boehncke WH (2003) The molecular basis of lymphocyte recruitment to the skin: clues for pathogenesis and selective therapies of inflammatory disorders. J Invest Dermatol 121:951–962PubMedGoogle Scholar
  64. 64.
    Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK (2004) Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 200:79–87PubMedGoogle Scholar
  65. 65.
    Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748PubMedGoogle Scholar
  66. 66.
    Hunter CA (2005) New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 5:521–531PubMedGoogle Scholar
  67. 67.
    McKenzie BS, Kastelein RA, Cua DJ (2006) Understanding the IL-23–IL-17 immune pathway. Trends Immunol 27:17–23PubMedGoogle Scholar
  68. 68.
    Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ (2003) Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951–1957PubMedGoogle Scholar
  69. 69.
    Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310–1316PubMedGoogle Scholar
  70. 70.
    Iwakura Y, Ishigame H (2006) The IL-23/IL-17 axis in inflammation. J Clin Invest 116:1218–1222PubMedGoogle Scholar
  71. 71.
    Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467–476PubMedGoogle Scholar
  72. 72.
    Kauffman CL, Aria N, Toichi E, McCormick TS, Cooper KD, Gottlieb AB, Everitt DE, Frederick B, Zhu Y, Graham MA, Pendley CE, Mascelli MA (2004) A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol 123:1037–1044PubMedGoogle Scholar
  73. 73.
    Nestle FO, Conrad C (2004) The IL-12 family member p40 chain as a master switch and novel therapeutic target in psoriasis. J Invest Dermatol 123:xiv–xxvPubMedGoogle Scholar
  74. 74.
    Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG (2004) Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 199:125–130PubMedGoogle Scholar
  75. 75.
    Piskin G, Sylva-Steenland RM, Bos JD, Teunissen MB (2006) In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 176:1908–1915PubMedGoogle Scholar
  76. 76.
    Leung DY, Gately M, Trumble A, Ferguson-Darnell B, Schlievert PM, Picker LJ (1995) Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production. J Exp Med 181:747–753PubMedGoogle Scholar
  77. 77.
    Sigmundsdottir H, Gudjonsson JE, Valdimarsson H (2003) Interleukin-12 alone can not enhance the expression of the cutaneous lymphocyte associated antigen (CLA) by superantigen-stimulated T lymphocytes. Clin Exp Immunol 132:430–435PubMedGoogle Scholar
  78. 78.
    Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R (2003) Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem 278:17036–17043PubMedGoogle Scholar
  79. 79.
    Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G (2000) Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol 115:81–87PubMedGoogle Scholar
  80. 80.
    Kanda N, Koike S, Watanabe S (2005) IL-17 suppresses TNF-alpha-induced CCL27 production through induction of COX-2 in human keratinocytes. J Allergy Clin Immunol 116:1144–1150PubMedGoogle Scholar
  81. 81.
    Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, van Eden W, van der ZR, Biedermann T, Prinz J, Mack M, Mrowietz U, Christophers E, Schlondorff D, Plewig G, Sander CA, Rocken M (2003) Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med 9:40–46PubMedGoogle Scholar
  82. 82.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedGoogle Scholar
  83. 83.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234PubMedGoogle Scholar
  84. 84.
    Tato CM, O’Shea JJ (2006) Immunology: what does it mean to be just 17? Nature 441:166–168PubMedGoogle Scholar
  85. 85.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189PubMedGoogle Scholar
  86. 86.
    Nestle FO, Turka LA, Nickoloff BJ (1994) Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines. J Clin Invest 94:202–209PubMedGoogle Scholar
  87. 87.
    Haftek M, Faure M, Schmitt D, Thivolet J (1983) Langerhans cells in skin from patients with psoriasis: quantitative and qualitative study of T6 and HLA-DR antigen-expressing cells and changes with aromatic retinoid administration. J Invest Dermatol 81:10–14PubMedGoogle Scholar
  88. 88.
    Gordon KB, Bonish BK, Patel T, Leonardi CL, Nickoloff BJ (2005) The tumour necrosis factor-alpha inhibitor adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques. Br J Dermatol 153:945–953PubMedGoogle Scholar
  89. 89.
    Mizumoto N, Kumamoto T, Robson SC, Sevigny J, Matsue H, Enjyoji K, Takashima A (2002) CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med 8:358–365PubMedGoogle Scholar
  90. 90.
    Cumberbatch M, Singh M, Dearman RJ, Young HS, Kimber I, Griffiths CE (2006) Impaired Langerhans cell migration in psoriasis. J Exp Med 203:953–960PubMedGoogle Scholar
  91. 91.
    Cumberbatch M, Griffiths CE, Tucker SC, Dearman RJ, Kimber I (1999) Tumour necrosis factor-alpha induces Langerhans cell migration in humans. Br J Dermatol 141:192–200PubMedGoogle Scholar
  92. 92.
    Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, Weissman IL, Cyster JG, Engleman EG (2002) Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 3:1135–1141PubMedGoogle Scholar
  93. 93.
    Wollenberg A, Kraft S, Hanau D, Bieber T (1996) Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol 106:446–453PubMedGoogle Scholar
  94. 94.
    Jawdat DM, Rowden G, Marshall JS (2006) Mast cells have a pivotal role in TNF-independent lymph node hypertrophy and the mobilization of Langerhans cells in response to bacterial peptidoglycan. J Immunol 177:1755–1762PubMedGoogle Scholar
  95. 95.
    Cerio R, Griffiths CE, Cooper KD, Nickoloff BJ, Headington JT (1989) Characterization of factor XIIIa positive dermal dendritic cells in normal and inflamed skin. Br J Dermatol 121:421–431PubMedGoogle Scholar
  96. 96.
    Nestle FO, Zheng XG, Thompson CB, Turka LA, Nickoloff BJ (1993) Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J Immunol 151:6535–6545PubMedGoogle Scholar
  97. 97.
    Koga T, Duan H, Urabe K, Furue M (2002) In situ localization of CD83-positive dendritic cells in psoriatic lesions. Dermatology 204:100–103PubMedGoogle Scholar
  98. 98.
    Wang F, Lee E, Lowes MA, Haider AS, Fuentes-Duculan J, Abello MV, Chamian F, Cardinale I, Krueger JG (2006) Prominent production of IL-20 by CD68(+)/CD11c(+) myeloid-derived cells in psoriasis: gene regulation and cellular effects. J Invest Dermatol 126:1590–1599PubMedGoogle Scholar
  99. 99.
    Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin SL, Nussbaum R, Novitskaya I, Carbonaro H, Cardinale I, Kikuchi T, Gilleaudeau P, Sullivan-Whalen M, Wittkowski KM, Papp K, Garovoy M, Dummer W, Steinman RM, Krueger JG (2005) Increase in TNF-{alpha} and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc Natl Acad Sci U S A 102:19057–19062PubMedGoogle Scholar
  100. 100.
    Wollenberg A, Wagner M, Gunther S, Towarowski A, Tuma E, Moderer M, Rothenfusser S, Wetzel S, Endres S, Hartmann G (2002) Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 119:1096–1102PubMedGoogle Scholar
  101. 101.
    Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG (2003) TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19:59–70PubMedGoogle Scholar
  102. 102.
    Gilliet M, Conrad C, Geiges M, Cozzio A, Thurlimann W, Burg G, Nestle FO, Dummer R (2004) Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch Dermatol 140:1490–1495PubMedGoogle Scholar
  103. 103.
    Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, Burg G, Liu YJ, Gilliet M (2005) Plasmacytoid predendritic cells initiate psoriasis through interferon-{alpha} production. J Exp Med 202:135–143PubMedGoogle Scholar
  104. 104.
    Nestle FO, Gilliet M (2005) Defining upstream elements of psoriasis pathogenesis: an emerging role for interferon alpha. J Invest Dermatol 125:xiv–xxvPubMedGoogle Scholar
  105. 105.
    Djemadji-Oudjiel N, Goerdt S, Kodelja V, Schmuth M, Orfanos CE (1996) Immunohistochemical identification of type II alternatively activated dendritic macrophages (RM 3/1+3, MS-1+/−, 25F9−) in psoriatic dermis. Arch Dermatol Res 288:757–764PubMedGoogle Scholar
  106. 106.
    Nickoloff BJ (2000) Characterization of lymphocyte-dependent angiogenesis using a SCID mouse: human skin model of psoriasis. J Investig Dermatol Symp Proc 5:67–73PubMedGoogle Scholar
  107. 107.
    van den Oord JJ, Wolf-Peeters C (1994) Epithelium-lining macrophages in psoriasis. Br J Dermatol 130:589–594PubMedGoogle Scholar
  108. 108.
    Vestergaard C, Just H, Baumgartner NJ, Thestrup-Pedersen K, Deleuran M (2004) Expression of CCR2 on monocytes and macrophages in chronically inflamed skin in atopic dermatitis and psoriasis. Acta Derm Venereol 84:353–358PubMedGoogle Scholar
  109. 109.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686PubMedGoogle Scholar
  110. 110.
    Karin M, Lawrence T, Nizet V (2006) Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124:823–835PubMedGoogle Scholar
  111. 111.
    Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442:39–44PubMedGoogle Scholar
  112. 112.
    Osterlund A, Popa R, Nikkila T, Scheynius A, Engstrand L (1997) Intracellular reservoir of Streptococcus pyogenes in vivo: a possible explanation for recurrent pharyngotonsillitis. Laryngoscope 107:640–647PubMedGoogle Scholar
  113. 113.
    Baker BS, Brown DW, Fischetti VA, Ovigne JM, Porter W, Powles A, Fry L (2001) Skin T cell proliferative response to M protein and other cell wall and membrane proteins of group A streptococci in chronic plaque psoriasis. Clin Exp Immunol 124:516–521PubMedGoogle Scholar
  114. 114.
    Thepen T, van Vuuren AJ, Kiekens RC, Damen CA, Vooijs WC, van De Winkel JG (2000) Resolution of cutaneous inflammation after local elimination of macrophages. Nat Biotechnol 18:48–51PubMedGoogle Scholar
  115. 115.
    Gilroy DW, Lawrence T, Perretti M, Rossi AG (2004) Inflammatory resolution: new opportunities for drug discovery. Nat Rev Drug Discov 3:401–416PubMedGoogle Scholar
  116. 116.
    Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771PubMedGoogle Scholar
  117. 117.
    Wilbanks GA, Mammolenti M, Streilein JW (1992) Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta. Eur J Immunol 22:165–173PubMedGoogle Scholar
  118. 118.
    Lin HH, Faunce DE, Stacey M, Terajewicz A, Nakamura T, Zhang-Hoover J, Kerley M, Mucenski ML, Gordon S, Stein-Streilein J (2005) The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance. J Exp Med 201:1615–1625PubMedGoogle Scholar
  119. 119.
    Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMedGoogle Scholar
  120. 120.
    Toda A, Piccirillo CA (2006) Development and function of naturally occurring CD4+CD25+ regulatory T cells. J Leukoc BiolGoogle Scholar
  121. 121.
    Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ (2005) Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 174:1783–1786PubMedGoogle Scholar
  122. 122.
    Annacker O, Asseman C, Read S, Powrie F (2003) Interleukin-10 in the regulation of T cell-induced colitis. J Autoimmun 20:277–279PubMedGoogle Scholar
  123. 123.
    Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, Strober W (2004) TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 172:834–842PubMedGoogle Scholar
  124. 124.
    Almeida AR, Legrand N, Papiernik M, Freitas AA (2002) Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 169:4850–4860PubMedGoogle Scholar
  125. 125.
    Annacker O, Burlen-Defranoux O, Pimenta-Araujo R, Cumano A, Bandeira A (2000) Regulatory CD4 T cells control the size of the peripheral activated/memory CD4 T cell compartment. J Immunol 164:3573–3580PubMedGoogle Scholar
  126. 126.
    Thornton AM, Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287–296PubMedGoogle Scholar
  127. 127.
    Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA (2001) A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol 166:7282–7289PubMedGoogle Scholar
  128. 128.
    Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, McCormick TS, Cooper KD (2005) Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 174:164–173PubMedGoogle Scholar
  129. 129.
    Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106:3490–3497PubMedGoogle Scholar
  130. 130.
    Nathan C (2002) Points of control in inflammation. Nature 420:846–852PubMedGoogle Scholar
  131. 131.
    Serhan CN, Savill J (2005) Resolution of inflammation: the beginning programs the end. Nat Immunol 6:1191–1197PubMedGoogle Scholar
  132. 132.
    Zenz R, Eferl R, Kenner L, Florin L, Hummerich L, Mehic D, Scheuch H, Angel P, Tschachler E, Wagner EF (2005) Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437:369–375PubMedGoogle Scholar
  133. 133.
    Gudjonsson JE, Elder JT (2006) Mouse models: psoriasis: an epidermal disease after all? Eur J Hum Genet 14:2–4PubMedGoogle Scholar
  134. 134.
    Haider AS, Duculan J, Whynot JA, Krueger JG (2006) Increased JunB mRNA and protein expression in psoriasis vulgaris lesions. J Invest Dermatol 126:912–914PubMedGoogle Scholar
  135. 135.
    Pasparakis M, Courtois G, Hafner M, Schmidt-Supprian M, Nenci A, Toksoy A, Krampert M, Goebeler M, Gillitzer R, Israel A, Krieg T, Rajewsky K, Haase I (2002) TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417:861–866PubMedGoogle Scholar
  136. 136.
    Kess D, Peters T, Zamek J, Wickenhauser C, Tawadros S, Loser K, Varga G, Grabbe S, Nischt R, Sunderkotter C, Muller W, Krieg T, Scharffetter-Kochanek K (2003) CD4+ T cell-associated pathophysiology critically depends on CD18 gene dose effects in a murine model of psoriasis. J Immunol 171:5697–5706PubMedGoogle Scholar
  137. 137.
    Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff BJ, DiGiovanni J (2005) Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med 11:43–49PubMedGoogle Scholar
  138. 138.
    Voskas D, Jones N, Van Slyke P, Sturk C, Chang W, Haninec A, Babichev YO, Tran J, Master Z, Chen S, Ward N, Cruz M, Jones J, Kerbel RS, Jothy S, Dagnino L, Arbiser J, Klement G, Dumont DJ (2005) A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice. Am J Pathol 166:843–855PubMedGoogle Scholar
  139. 139.
    Jamieson T, Cook DN, Nibbs RJ, Rot A, Nixon C, McLean P, Alcami A, Lira SA, Wiekowski M, Graham GJ (2005) The chemokine receptor D6 limits the inflammatory response in vivo. Nat Immunol 6:403–411PubMedGoogle Scholar
  140. 140.
    Nickoloff BJ (2006) Psoriatic animal model validation index. J Invest Dermatol 126:59Google Scholar
  141. 141.
    Christophers E (2001) Psoriasis—epidemiology and clinical spectrum. Clin Exp Dermatol 26:314–320PubMedGoogle Scholar
  142. 142.
    Ho P, Bruce IN, Silman A, Symmons D, Newman B, Young H, Griffiths CE, John S, Worthington J, Barton A (2005) Evidence for common genetic control in pathways of inflammation for Crohn’s disease and psoriatic arthritis. Arthritis Rheum 52:3596–3602PubMedGoogle Scholar
  143. 143.
    Henseler T, Christophers E (1995) Disease concomitance in psoriasis. J Am Acad Dermatol 32:982–986PubMedGoogle Scholar
  144. 144.
    Rogler G (2004) Update in inflammatory bowel disease pathogenesis. Curr Opin Gastroenterol 20:311–317PubMedGoogle Scholar
  145. 145.
    Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, Sharma K, Silverstein RL (2000) Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest 105:1049–1056PubMedCrossRefGoogle Scholar
  146. 146.
    Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104:503–516PubMedGoogle Scholar
  147. 147.
    Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198PubMedGoogle Scholar
  148. 148.
    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336PubMedGoogle Scholar
  149. 149.
    Illman J, Corringham R, Robinson D Jr, Davis HM, Rossi JF, Cella D, Trikha M (2005) Are inflammatory cytokines the common link between cancer-associated cachexia and depression? J Support Oncol 3:37–50PubMedGoogle Scholar
  150. 150.
    Simen BB, Duman CH, Simen AA, Duman RS (2006) TNFalpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol Psychiatry 59:775–785PubMedGoogle Scholar
  151. 151.
    Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, Cella D, Krishnan R (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 367:29–35PubMedGoogle Scholar
  152. 152.
    Cua DJ, Kastelein RA (2006) TGF-beta, a ‘double agent’ in the immune pathology war. Nat Immunol 7:557–559PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Brian J. Nickoloff
    • 1
    • 2
  • Jian-Zhong Qin
    • 1
  • Frank O. Nestle
    • 3
  1. 1.Department of PathologyLoyola University Medical CenterMaywoodUSA
  2. 2.Oncology InstituteCardinal Bernardin Cancer Center, Loyola University Medical CenterMaywoodUSA
  3. 3.St. John’s Institute of Dermatology, Division of Genetics and Molecular MedicineKings College London School of MedicineLondonUK

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