Skip to main content

Advertisement

Log in

Interactions of the Immune System with Skin and Bone Tissue in Psoriatic Arthritis: A Comprehensive Review

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Cutaneous psoriasis (e.g., psoriasis vulgaris (PsV)) and psoriatic arthritis (PsA) are complex heterogeneous diseases thought to have similar pathophysiology. The soluble and cellular mediators of these closely related diseases are being elucidated through genetic approaches such as genome-wide association studies (GWAS), as well as animal and molecular models. Novel therapeutics targeting these mediators (IL-12, IL-23, IL-17, IL-17 receptor, TNF) are effective in treating both the skin and joint manifestations of psoriasis, reaffirming the shared pathophysiology of PsV and PsA. However, the molecular and cellular interactions between skin and joint disease have not been well characterized. Clearly, PsV and PsA are highly variable in terms of their clinical manifestations, and this heterogeneity can partially be explained by differences in HLA-associations (HLA-Cw*0602 versus HLA-B*27, for example). In addition, there are numerous other genetic susceptibility loci (LCE3, CARD14, NOS2, NFKBIA, PSMA6, ERAP1, TRAF3IP2, IL12RB2, IL23R, IL12B, TNIP1, TNFAIP3, TYK2) and geoepidemiologic factors that contribute to the wide variability seen in psoriasis. Herein, we review the complex interplay between the genetic, cellular, ethnic, and geographic mediators of psoriasis, focusing on the shared mechanisms of PsV and PsA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Moll JMH, Wright V (1973) Psoriatic arthritis. Semin Arthritis Rheum 3(1):55–78. doi:10.1016/0049-0172(73)90035-8

    Article  CAS  PubMed  Google Scholar 

  2. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 64(suppl 2):ii14–ii17. doi:10.1136/ard.2004.032482

    PubMed  PubMed Central  Google Scholar 

  3. Camisa C (2008) 3 Histopathology of psoriasis. Handbook of Psoriasis:36

  4. Elder DE (2014) Lever’s histopathology of the skin. Lippincott Williams & Wilkins

  5. Trozak DJ (1994) Histologic grading system for psoriasis vulgaris. Int J Dermatol 33(5):380–381. doi:10.1111/j.1365-4362.1994.tb01073.x

    Article  CAS  PubMed  Google Scholar 

  6. Johnson MA, Armstrong A (2013) Clinical and histologic diagnostic guidelines for psoriasis: a critical review. Clin Rev Allergy Immunol 44(2):166–172. doi:10.1007/s12016-012-8305-3

    Article  PubMed  Google Scholar 

  7. Zachariae H (2003) Prevalence of joint disease in patients with psoriasis. Am J Clin Dermatol 4(7):441–447. doi:10.2165/00128071-200304070-00001

    Article  PubMed  Google Scholar 

  8. Gudjonsson JE, Johnston A, Sigmundsdottir H, Valdimarsson H (2004) Immunopathogenic mechanisms in psoriasis. Clin Exp Immunol 135(1):1–8. doi:10.1111/j.1365-2249.2004.02310.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Apps R, Qi Y, Carlson JM, Chen H, Gao X, Thomas R, Yuki Y, Del Prete GQ, Goulder P, Brumme ZL, Brumme CJ, John M, Mallal S, Nelson G, Bosch R, Heckerman D, Stein JL, Soderberg KA, Moody MA, Denny TN, Zeng X, Fang J, Moffett A, Lifson JD, Goedert JJ, Buchbinder S, Kirk GD, Fellay J, McLaren P, Deeks SG, Pereyra F, Walker B, Michael NL, Weintrob A, Wolinsky S, Liao W, Carrington M (2013) Influence of HLA-C expression level on HIV control. Science (New York, NY) 340(6128):87–91. doi:10.1126/science.1232685

    Article  CAS  Google Scholar 

  10. Mallon E, Newson R, Bunker CB (1999) HLA-Cw6 and the genetic predisposition to psoriasis: a meta-analysis of published serologic studies. J Investig Dermatol 113(4):693–695. doi:10.1046/j.1523-1747.1999.00724.x

    Article  CAS  PubMed  Google Scholar 

  11. Gudjonsson JE, Karason A, Antonsdottir A, Runarsdottir EH, Hauksson VB, Upmanyu R, Gulcher J, Stefansson K, Valdimarsson H (2003) Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2 · 5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes. Br J Dermatol 148(2):233–235. doi:10.1046/j.1365-2133.2003.05115.x

    Article  CAS  PubMed  Google Scholar 

  12. Cibulova A, Zajacova M, Fojtikova M, Stolfa J, Sedova L, Cejkova P, Lippert J, Arenberger P, Cerna M (2013) The HLA-Cw*06 allele and −1149 G/T polymorphism of extrapituitary promoter of PRL gene as a possible common genetic predisposing factors to psoriasis vulgaris and psoriatic arthritis in Czech population. Rheumatol Int 33(4):913–919. doi:10.1007/s00296-012-2472-7

    Article  CAS  PubMed  Google Scholar 

  13. Enerbäck C, Nilsson S, Enlund F, Inerot A, Samuelsson L, Wahlström J, Swanbeck G, Martinsson T (2000) Stronger association with HLA-Cw6 than with corneodesmosin (S-gene) polymorphisms in Swedish psoriasis patients. Arch Dermatol Res 292(11):525–530. doi:10.1007/s004030000175

    Article  PubMed  Google Scholar 

  14. Ikäheimo I, Tiilikainen A, Karvonen J, Silvennoinen-Kassinen S (1996) HLA risk haplotype Cw6, DR7, DQA1*0201 and HLA-Cw6 with reference to the clinical picture of psoriasis vulgaris. Arch Dermatol Res 288(7):363–365. doi:10.1007/BF02507104

    Article  PubMed  Google Scholar 

  15. Gudjonsson JE, Karason A, Runarsdottir EH, Antonsdottir AA, Hauksson VB, Jonsson HH, Gulcher J, Stefansson K, Valdimarsson H (2006) Distinct clinical differences between HLA-Cw[ast]0602 positive and negative psoriasis patients - an analysis of 1019 HLA-C- and HLA-B-typed patients. J Invest Dermatol 126(4):740–745

    Article  CAS  PubMed  Google Scholar 

  16. Queiro R, Torre JC, González S, López-Larrea C, Tinturé T, López-Lagunas I (2003) HLA antigens may influence the age of onset of psoriasis and psoriatic arthritis. J Rheumatol 30(3):505–507

    PubMed  Google Scholar 

  17. Gujonsson JE, Karason A, Antonsdottir AA, Runarsdottir EH, Gulcher JR, Stefansson K, Valdimarsson H (2002) HLA-Cw6-Positive and HLA-Cw6-Negative Patients with Psoriasis Vulgaris have Distinct Clinical Features. J Invest Dermatol 118(2):362–365

  18. Winchester R, Minevich G, Steshenko V, Kirby B, Kane D, Greenberg DA, FitzGerald O (2012) HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype. Arthritis Rheum 64(4):1134–1144

    Article  CAS  PubMed  Google Scholar 

  19. Rammensee HG, Bachmann J, Emmerich NPN, Bachor OA, Stevanović S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50(3–4):213–219. doi:10.1007/s002510050595

    Article  CAS  PubMed  Google Scholar 

  20. Marsh SGE, Parham P, Barber LD (1999) The HLA factsbook. Academic Press

  21. Benjamin R, Parham P (1990) Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today 11:137–142

    Article  CAS  PubMed  Google Scholar 

  22. Sobao Y, Tsuchiya N, Takiguchi M, Tokunaga K (1999) Overlapping peptide-binding specificities of HLA-B27 and B39. Arthritis Rheum 42:175–181

    Article  CAS  PubMed  Google Scholar 

  23. López-Larrea C, Torre Alonso JC, Rodriguez Perez A, Coto E (1990) HLA antigens in psoriatic arthritis subtypes of a Spanish population. Ann Rheum Dis 49(5):318–319

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gladman DD, Anhorn KA, Schachter RK, Mervart H (1986) HLA antigens in psoriatic arthritis. J Rheumatol 13(3):586–592

    CAS  PubMed  Google Scholar 

  25. Salvarani C, Macchioni PL, Zizzi F, Mantovani W, Rossi F, Baricchi R, Ghirelli L, Frizziero L, Portioli I (1988) Clinical subgroups and HLA antigens in Italian patients with psoriatic arthritis. Clin Exp Rheumatol 7(4):391–396

    Google Scholar 

  26. McHugh NJ, Laurent MR, Treadwell BL, Tweed JM, Dagger J (1987) Psoriatic arthritis: clinical subgroups and histocompatibility antigens. Ann Rheum Dis 46(3):184–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Queiro R, Morante I, Cabezas I, Acasuso B (2015) HLA-B27 and psoriatic disease: a modern view of an old relationship. Rheumatology. doi:10.1093/rheumatology/kev296

    PubMed  Google Scholar 

  28. Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, Wise C, Miner A, Malloy MJ, Pullinger CR, Kane JP, Saccone S, Worthington J, Bruce I, Kwok PY, Menter A, Krueger J, Barton A, Saccone NL, Bowcock AM (2008) A Genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 4(4):e1000041. doi:10.1371/journal.pgen.1000041

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A (1996) Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (“epidermal differentiation complex”) on human chromosome 1q21. J Investig Dermatol 106(5):989–992

    Article  CAS  PubMed  Google Scholar 

  30. Shen C, Gao J, Yin X, Sheng Y, Sun L, Cui Y, Zhang X (2015) Association of the late cornified envelope-3 genes with psoriasis and psoriatic arthritis: a systematic review. J Genet Genomics 42(2):49–56. doi:10.1016/j.jgg.2015.01.001

    Article  PubMed  Google Scholar 

  31. de Cid R, Riveira-Munoz E, Zeeuwen PLJM, Robarge J, Liao W, Dannhauser EN, Giardina E, Stuart PE, Nair R, Helms C, Escaramís G, Ballana E, Martín-Ezquerra G, den Heijer M, Kamsteeg M, Joosten I, Eichler EE, Lázaro C, Pujol RM, Armengol L, Abecasis G, Elder JT, Novelli G, Armour JAL, Kwok P, Bowcock A, Schalkwijk J, Estivill X (2009) Deletion of the late cornified envelope (LCE) 3B and 3C genes as a susceptibility factor for psoriasis. Nat Genet 41(2):211–215. doi:10.1038/ng.313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Jordan CT, Cao L, Roberson EDO, Pierson KC, Yang C-F, Joyce CE, Ryan C, Duan S, Helms CA, Liu Y (2012) PSORS2 is due to mutations in CARD14. Am J Hum Genet 90(5):784–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jacques P, McGonagle D (2014) The role of mechanical stress in the pathogenesis of spondyloarthritis and how to combat it. Best Pract Res Clin Rheumatol 28(5):703–710. doi:10.1016/j.berh.2014.10.009

    Article  PubMed  Google Scholar 

  34. Bertin J, Wang L, Guo Y, Jacobson MD, Poyet J-L, Srinivasula SM, Merriam S, DiStefano PS, Alnemri ES (2001) CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-κB. J Biol Chem 276(15):11877–11882. doi:10.1074/jbc.M010512200

    Article  CAS  PubMed  Google Scholar 

  35. Hammond ME, Lapointe GR, Feucht PH, Hilt S, Gallegos CA, Gordon CA, Giedlin MA, Mullenbach G, Tekamp-Olson P (1995) IL-8 induces neutrophil chemotaxis predominantly via type I IL-8 receptors. J Immunol 155(3):1428–1433

    CAS  PubMed  Google Scholar 

  36. Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Takeshita S, Wagner EF, Noda M, Matsuo K, Xing L, Boyce BF (2007) NF-κB p50 and p52 regulate receptor activator of NF-κB Ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem 282(25):18245–18253. doi:10.1074/jbc.M610701200

    Article  CAS  PubMed  Google Scholar 

  37. Iotsova V, Caamaño J, Loy J, Yang Y, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-κB1 and NF-κB2. Nat Med 3(11):1285–1289

    Article  CAS  PubMed  Google Scholar 

  38. Stuart PE, Nair RP, Ellinghaus E, Ding J, Tejasvi T, Gudjonsson JE, Li Y, Weidinger S, Eberlein B, Gieger C, Wichmann HE, Kunz M, Ike R, Krueger GG, Bowcock AM, Mroweitz U, Lim HW, Voorhees JJ, Abecasis GR, Weichenthal M, Franke A, Rahman P, Gladman DD, Elder JT (2010) Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet 42(11):1000–1004. doi:10.1038/ng.693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Melchiorri C, Meliconi R, Frizziero L, Silvestri T, Pulsatelli L, Mazzetti I, Borzì RM, Uguccioni M, Facchini A (1998) Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum 41(12):2165–2174

    Article  CAS  PubMed  Google Scholar 

  40. Stefanovic-Racic M, Stadler J, Evans CH (1993) Nitric oxide and arthritis. Arthritis Rheum 36(8):1036–1044. doi:10.1002/art.1780360803

    Article  CAS  PubMed  Google Scholar 

  41. Zaba LC, Krueger JG, Lowes MA (2009) Resident and “inflammatory” dendritic cells in human skin. J Investig Dermatol 129(2):302–308. doi:10.1038/jid.2008.225

    Article  CAS  PubMed  Google Scholar 

  42. Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin S-L, 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-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc Natl Acad Sci U S A 102(52):19057–19062. doi:10.1073/pnas.0509736102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Michael K (1999) How NF-kB is activated: the role of the IkB kinase (IKK) complex. Oncogene 18:6867–6874

    Article  CAS  Google Scholar 

  44. Ramirez VP, Gurevich I, Aneskievich BJ (2012) Emerging roles for TNIP1 in regulating post-receptor signaling. Cytokine Growth Factor Rev 23(3):109–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, Formisano S, Vito P, Leonardi A (2006) ABIN-1 binds to NEMO/IKKγ and co-operates with A20 in inhibiting NF-κB. J Biol Chem 281(27):18482–18488

    Article  CAS  PubMed  Google Scholar 

  46. Patel F, Marusina AI, Duong C, Adamopoulos IE, Maverakis E (2013) NKG2C, HLA-E and their association with psoriasis. Exp Dermatol 22(12):797–799. doi:10.1111/exd.12280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Reveille JD, Sims A-M, Danoy P, Evans DM, Leo P, Pointon JJ, Jin R, Zhou X, Bradbury LA, Appleton LH, Davis JC, Diekman L, Doan T, Dowling A, Duan R, Duncan EL, Farrar C, Hadler J, Harvey D, Karaderi T, Mogg R, Pomeroy E, Pryce K, Taylor J, Savage L, Deloukas P, Kumanduri V, Peltonen L, Ring SM, Whittaker P, Glazov E, Thomas GP, Maksymowych WP, Inman RD, Ward MM, Stone MA, Weisman MH, Wordsworth BP, Brown MA (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42(2):123–127. doi:10.1038/ng.513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Harden JL, Krueger JG, Bowcock AM (2015) The immunogenetics of psoriasis: a comprehensive review. J Autoimmun 64:66–73. doi:10.1016/j.jaut.2015.07.008

    Article  CAS  PubMed  Google Scholar 

  49. Chandran V (2013) The genetics of psoriasis and psoriatic arthritis. Clin Rev Allergy Immunol 44(2):149–156

    Article  CAS  PubMed  Google Scholar 

  50. Chen L, Ridley A, Hammitzsch A, Al-Mossawi MH, Bunting H, Georgiadis D, Chan A, Kollnberger S, Bowness P (2015) Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis. Ann Rheum Dis. doi:10.1136/annrheumdis-2014-206996

    Google Scholar 

  51. Khare SD, Hansen J, Luthra HS, David CS (1996) HLA-B27 heavy chains contribute to spontaneous inflammatory disease in B27/human beta2-microglobulin (beta2m) double transgenic mice with disrupted mouse beta2m. J Clin Investig 98(12):2746–2755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Martayan A, Fiscella M, Setini A, Ciccarelli G, Gambari R, Feriotto G, Beretta A, Siccardi AG, Appella E, Giacomini P (1997) Conformation and surface expression of free HLA-CW1 heavy chains in the absence of β2-microglobulin. Hum Immunol 53(1):23–33. doi:10.1016/S0198-8859(96)00256-X

    Article  CAS  PubMed  Google Scholar 

  53. Payeli SK, Kollnberger S, Marroquin Belaunzaran O, Thiel M, McHugh K, Giles J, Shaw J, Kleber S, Ridley A, Wong‐Baeza I (2012) Inhibiting HLA-B27 homodimer-driven immune cell inflammation in spondylarthritis. Arthritis Rheum 64(10):3139–3149

    Article  CAS  PubMed  Google Scholar 

  54. Bowness P, Ridley A, Shaw J, Chan AT, Baeza IW, Fleming M, Cummings F, McMichael A, Kollnberger S (2011) Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in Ankylosing Spondylitis. J Immunol (Baltimore, Md: 1950) 186(4):2672–2680. doi:10.4049/jimmunol.1002653

    Article  CAS  Google Scholar 

  55. Zhao H, Wang D, Fu D, Xue L (2015) Predicting the potential ankylosing spondylitis-related genes utilizing bioinformatics approaches. Rheumatol Int 35(6):973–979. doi:10.1007/s00296-014-3178-9

    Article  PubMed  CAS  Google Scholar 

  56. 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 Investig Dermatol 101(5):701–705

    Article  CAS  PubMed  Google Scholar 

  57. Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L, Szeliga W, Wang Y, Liu Y, Welling TH, Elder JT, Zou W (2008) Induction of IL-17+ T cell trafficking and development by IFN-γ: mechanism and pathological relevance in psoriasis. J Immunol 181(7):4733–4741. doi:10.4049/jimmunol.181.7.4733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Raychaudhuri S, Raychaudhuri S, Genovese M (2012) IL-17 receptor and its functional significance in psoriatic arthritis. Mol Cell Biochem 359(1–2):419–429. doi:10.1007/s11010-011-1036-6

    Article  CAS  PubMed  Google Scholar 

  59. Tonel G, Conrad C, Laggner U, Di Meglio P, Grys K, McClanahan TK, Blumenschein WM, Qin J-Z, Xin H, Oldham E, Kastelein R, Nickoloff BJ, Nestle FO (2010) Cutting edge: a critical functional role for IL-23 in psoriasis. J Immunol (Baltimore, Md: 1950) 185(10):5688–5691. doi:10.4049/jimmunol.1001538

    Article  CAS  Google Scholar 

  60. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron J-C, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8(9):950–957, http://www.nature.com/ni/journal/v8/n9/suppinfo/ni1497_S1.html

    Article  CAS  PubMed  Google Scholar 

  61. Nograles KE, Zaba LC, Guttman E, Fuentes-Duculan J, Suarez-Farinas M, Cardinale I, Khatcherian A, Gonzalez J, Pierson KC, White TR, Pensabene C, Coats I, Novitskaya I, Lowes MA, Krueger JG (2008) Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 159(5):1092–1102. doi:10.1111/j.1365-2133.2008.08769.x

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Mitra A, Raychaudhuri SK, Raychaudhuri SP (2012) Functional role of IL-22 in psoriatic arthritis. Arthritis Res Ther 14(2):R65. doi:10.1186/ar3781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liang SC, Tan X-Y, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203(10):2271–2279. doi:10.1084/jem.20061308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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(7090):235–238, http://www.nature.com/nature/journal/v441/n7090/suppinfo/nature04753_S1.html

    Article  CAS  PubMed  Google Scholar 

  65. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24(6):677–688. doi:10.1016/j.immuni.2006.06.002

    Article  CAS  PubMed  Google Scholar 

  66. Aggarwal S, Ghilardi N, Xie M-H, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T Cell activation state characterized by the production of interleukin-17. J Biol Chem 278(3):1910–1914. doi:10.1074/jbc.M207577200

    Article  CAS  PubMed  Google Scholar 

  67. 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 TH17 lineage. Nature 441(7090):231–234, http://www.nature.com/nature/journal/v441/n7090/suppinfo/nature04754_S1.html

    Article  CAS  PubMed  Google Scholar 

  68. Gagliani N, Vesely MCA, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA (2015) Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523(7559):221–225. doi:10.1038/nature14452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Adamopoulos IE, Suzuki E, Chao C-C, Gorman DAN, Adda S, Maverakis E, Zarbalis K, Geissler R, Asio A, Blumenschein WM, McClanahan T, De Waal Malefyt R, Gershwin ME, Bowman EP (2015) IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis. Ann Rheum Dis 74(6):1284–1292. doi:10.1136/annrheumdis-2013-204782

    Article  PubMed  Google Scholar 

  70. Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, Lucian L, Geissler R, Brodie S, Kimball AB, Gorman DM, Smith K, de Waal Malefyt R, Kastelein RA, McClanahan TK, Bowman EP (2006) IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2–dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 203(12):2577–2587. doi:10.1084/jem.20060244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, Gorman DM, Bowman EP, McClanahan TK, Yearley JH, Eberl G, Buckley CD, Kastelein RA, Pierce RH, LaFace DM, Cua DJ (2012) IL-23 induces spondyloarthropathy by acting on ROR-[gamma]t + CD3 + CD4-CD8- entheseal resident T cells. Nat Med 18(7):1069–1076. http://www.nature.com/nm/journal/v18/n7/abs/nm.2817.html - supplementary-information

  72. Adamopoulos IE, Tessmer M, Chao C-C, Adda S, Gorman D, Petro M, Chou C-C, Pierce RH, Yao W, Lane NE, Laface D, Bowman EP (2011) IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. J Immunol (Baltimore, Md: 1950) 187(2):951–959. doi:10.4049/jimmunol.1003986

    Article  CAS  Google Scholar 

  73. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H (2006) Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203(12):2673–2682. doi:10.1084/jem.20061775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wu DJ, Dixit N, Nguyen T, Suzuki E, Shin HS, Davis J, Maverakis E, Adamopoulos IE (2014) A Novel In Vivo Gene Transfer Technique and In Vitro Cell Based Assays for the Study of Bone Loss in Musculoskeletal Disorders. J Vis Exp: JoVE (88). doi:10.3791/51810

  75. Adamopoulos IE, Chao C-C, Geissler R, Laface D, Blumenschein W, Iwakura Y, McClanahan T, Bowman EP (2010) Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors. Arthritis Res Ther 12(1):R29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Sivamani R, Goodarzi H, Garcia M, Raychaudhuri S, Wehrli L, Ono Y, Maverakis E (2013) Biologic therapies in the treatment of psoriasis: a comprehensive evidence-based basic science and clinical review and a practical guide to tuberculosis monitoring. Clin Rev Allergy Immunol 44(2):121–140. doi:10.1007/s12016-012-8301-7

    Article  CAS  PubMed  Google Scholar 

  77. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB, Investigators PS (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371(9625):1665–1674

    Article  CAS  PubMed  Google Scholar 

  78. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo C, Hsu M-C, Wang Y, Li S (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371(9625):1675–1684

    Article  CAS  PubMed  Google Scholar 

  79. Torres T, Faria R (2015) Ustekinumab: The “New Kid on the Block” in the Treatment of Psoriatic Arthritis. Drug Dev Res 76(8):428–431

  80. Thaçi D, Blauvelt A, Reich K, Tsai T-F, Vanaclocha F, Kingo K, Ziv M, Pinter A, Hugot S, You R, Milutinovic M (2015) Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol 73(3):400–409. doi:10.1016/j.jaad.2015.05.013

    Article  PubMed  CAS  Google Scholar 

  81. Gottlieb AB, Langley RG, Philipp S, Sigurgeirsson B, Blauvelt A, Martin R, Papavassilis C, Mpofu S (2015) secukinumab improves physical function in subjects with plaque psoriasis and psoriatic arthritis: results from two randomized, phase 3 trials. J Drugs Dermatol: JDD 14(8):821–833

    PubMed  Google Scholar 

  82. McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, van der Heijde D, Landewé R, Conaghan PG, Gottlieb AB, Richards H, Pricop L, Ligozio G, Patekar M, Mpofu S (2015) Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386(9999):1137–1146. doi:10.1016/S0140-6736(15)61134-5

    Article  CAS  PubMed  Google Scholar 

  83. Schmidt C (2015) Suicidal thoughts end Amgen’s blockbuster aspirations for psoriasis drug. Nat Biotechnol 33(9):894–895

    Article  CAS  PubMed  Google Scholar 

  84. Harper EG, Guo C, Rizzo H, Lillis JV, Kurtz SE, Skorcheva I, Purdy D, Fitch E, Iordanov M, Blauvelt A (2009) Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Investig Dermatol 129(9):2175–2183. doi:10.1038/jid.2009.65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Homey B, Dieu-Nosjean M-C, Wiesenborn A, Massacrier C, Pin J-J, Oldham E, Catron D, Buchanan ME, Müller A, de Waal Malefyt R, Deng G, Orozco R, Ruzicka T, Lehmann P, Lebecque S, Caux C, Zlotnik A (2000) Up-regulation of macrophage inflammatory protein-3α/CCL20 and CC chemokine receptor 6 in psoriasis. J Immunol 164(12):6621–6632. doi:10.4049/jimmunol.164.12.6621

    Article  CAS  PubMed  Google Scholar 

  86. Harper EG, Guo C, Rizzo H, Lillis JV, Kurtz SE, Skorcheva I, Purdy D, Fitch E, Iordanov M, Blauvelt A (2009) Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Investig Dermatol 129(9):2175–2183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hedrick MN, Lonsdorf AS, Shirakawa A-K, Lee C-CR, Liao F, Singh SP, Zhang HH, Grinberg A, Love PE, Hwang ST (2009) CCR6 is required for IL-23–induced psoriasis-like inflammation in mice. J Clin Invest 119(8):2317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hedrick MN, Lonsdorf AS, Hwang ST, Farber JM (2010) CCR6 as a possible therapeutic target in psoriasis. Expert Opin Ther Targets 14(9):911–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Celis R, Planell N, Fernández-Sueiro JL, Sanmartí R, Ramírez J, González-Álvaro I, Pablos JL, Cañete JD (2012) Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. Arthritis Res Ther 14(2):R93. doi:10.1186/ar3817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mrabet D, Laadhar L, Sahli H, Zouari B, Haouet S, Makni S, Sellami S (2013) Synovial fluid and serum levels of IL-17, IL-23, and CCL-20 in rheumatoid arthritis and psoriatic arthritis: a Tunisian cross-sectional study. Rheumatol Int 33(1):265–266. doi:10.1007/s00296-011-2231-1

    Article  PubMed  Google Scholar 

  91. Wolk K, Sabat R (2006) Interleukin-22: A novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev 17(5):367–380. doi:10.1016/j.cytogfr.2006.09.001

    Article  CAS  PubMed  Google Scholar 

  92. Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R (2004) IL-22 increases the innate immunity of tissues. Immunity 21(2):241–254. doi:10.1016/j.immuni.2004.07.007

    Article  CAS  PubMed  Google Scholar 

  93. Wolk K, Witte E, Reineke U, Witte K, Friedrich M, Sterry W, Asadullah K, Volk HD, Sabat R (2004) Is there an interaction between interleukin-10 and interleukin-22? Genes Immun 6(1):8–18

    Google Scholar 

  94. Wolk K, Witte E, Wallace E, Döcke W-D, Kunz S, Asadullah K, Volk H-D, Sterry W, Sabat R (2006) IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 36(5):1309–1323. doi:10.1002/eji.200535503

    Article  CAS  PubMed  Google Scholar 

  95. Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, Vom Baur E, Witte K, Warszawska K, Philipp S (2009) IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not. J Mol Med 87(5):523–536

    Article  CAS  PubMed  Google Scholar 

  96. Rømer J, Hasselager E, Nørby PL, Steiniche T, Clausen JT, 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 Investig Dermatol 121(6):1306–1311

    Article  PubMed  Google Scholar 

  97. Kunz S, Wolk K, Witte E, Witte K, Doecke WD, Volk HD, Sterry W, Asadullah K, Sabat R (2006) Interleukin (IL)‐19, IL‐20 and IL‐24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp Dermatol 15(12):991–1004

    Article  CAS  PubMed  Google Scholar 

  98. Geboes L, Dumoutier L, Kelchtermans H, Schurgers E, Mitera T, Renauld J-C, Matthys P (2009) Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum 60(2):390–395. doi:10.1002/art.24220

    Article  CAS  PubMed  Google Scholar 

  99. Nakae S, Iwakura Y, Suto H, Galli SJ (2007) Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. J Leukoc Biol 81(5):1258–1268. doi:10.1189/jlb.1006610

    Article  CAS  PubMed  Google Scholar 

  100. Nash PT, Florin THJ (2005) Tumour necrosis factor inhibitors. Med J Aust 183(4):205

    PubMed  Google Scholar 

  101. 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-α. J Exp Med 199(5):731–736. doi:10.1084/jem.20031482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A (2000) Tumor necrosis factor-α induces differentiation of and bone resorption by osteoclasts. J Biol Chem 275(7):4858–4864. doi:10.1074/jbc.275.7.4858

    Article  CAS  PubMed  Google Scholar 

  103. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T (2000) Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the Odf/Rankl–rank interaction. J Exp Med 191(2):275–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Olivieri I, D’Angelo S, Palazzi C, Padula A (2014) Advances in the management of psoriatic arthritis. Nat Rev Rheumatol 10(9):531–542

    Article  CAS  PubMed  Google Scholar 

  105. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189. doi:10.1016/j.immuni.2006.01.001

    Article  CAS  PubMed  Google Scholar 

  106. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang Y-H, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6(11):1133–1141, http://www.nature.com/ni/journal/v6/n11/suppinfo/ni1261_S1.html

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6(11):1123–1132, http://www.nature.com/ni/journal/v6/n11/suppinfo/ni1254_S1.html

    Article  CAS  PubMed  Google Scholar 

  108. 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(12):1951–1957. doi:10.1084/jem.20030896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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(6924):744–748, http://www.nature.com/nature/journal/v421/n6924/suppinfo/nature01355_S1.html

    Article  CAS  PubMed  Google Scholar 

  110. Gran B, Zhang G-X, Yu S, Li J, Chen X-H, Ventura ES, Kamoun M, Rostami A (2002) IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol 169(12):7104–7110. doi:10.4049/jimmunol.169.12.7104

    Article  CAS  PubMed  Google Scholar 

  111. Cargill M, Schrodi Steven J, Chang M, Garcia Veronica E, Brandon R, Callis Kristina P, Matsunami N, Ardlie Kristin G, Civello D, Catanese Joseph J, Leong Diane U, Panko Jackie M, McAllister Linda B, Hansen Christopher B, Papenfuss J, Prescott Stephen M, White Thomas J, Leppert Mark F, Krueger Gerald G, Begovich Ann B (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80(2):273–390

    Article  CAS  PubMed  Google Scholar 

  112. Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S, Schwarz T, Penninger JM, Beissert S (2006) Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med 12(12):1372–1379, http://www.nature.com/nm/journal/v12/n12/suppinfo/nm1518_S1.html

    Article  CAS  PubMed  Google Scholar 

  113. Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, McCormick TS, Cooper KD (2005) Dysfunctional blood and target tissue CD4(+)CD25(high) regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 174(1):164–173

  114. Toberer F, Sykora J, Göttel D, Ruland V, Hartschuh W, Enk A, Luger TA, Beissert S, Loser K, Joos S, Krammer PH, Kuhn A (2011) Tissue microarray analysis of RANKL in cutaneous lupus erythematosus and psoriasis. Exp Dermatol 20(7):600–602. doi:10.1111/j.1600-0625.2011.01303.x

    Article  CAS  PubMed  Google Scholar 

  115. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423(6937):337–342

    Article  CAS  PubMed  Google Scholar 

  116. Zachariae H, Zachariae R, Blomqvist K, Davidsson S, Molin L, Mork C, Sigurgeirsson B (2002) Quality of life and prevalence of arthritis reported by 5,795 members of the Nordic Psoriasis Associations. Acta Derm Venereol 82(2):108–113

    Article  PubMed  Google Scholar 

  117. Gudjonsson JE, Elder JT (2007) Psoriasis: epidemiology. Clin Dermatol 25(6):535–546. doi:10.1016/j.clindermatol.2007.08.007

    Article  PubMed  Google Scholar 

  118. Lomholt G, Anna LA (1963) Psoriasis. Prevalence, Spontaneous Course, and Genetics. A Census Study on the Prevalence of Skin Diseases on the Faroe Islands.(Translated by Anna la Cour.) [A Thesis]. Copenhagen

  119. Brandrupl F, Green A (1975) The prevalence of psoriasis in Denmark. Allergy 1 (136)

  120. Gelfand JM, Stern RS, Nijsten T, Feldman SR, Thomas J, Kist J, Rolstad T, Margolis DJ (2005) The prevalence of psoriasis in African Americans: results from a population-based study. J Am Acad Dermatol 52(1):23–26

    Article  PubMed  Google Scholar 

  121. Shbeeb M, Uramoto KM, Gibson LE, O’Fallon WM, Gabriel SE (2000) The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982–1991. J Rheumatol 27(5):1247–1250

    CAS  PubMed  Google Scholar 

  122. Kaipiainen-SeppÄNen O (1996) Incidence of psoriatic arthritis in finland. Rheumatology 35(12):1289–1291. doi:10.1093/rheumatology/35.12.1289

    Article  Google Scholar 

  123. Kubota K, Kamijima Y, Sato T, Ooba N, Koide D, Iizuka H, Nakagawa H (2015) Epidemiology of psoriasis and palmoplantar pustulosis: a nationwide study using the Japanese national claims database. BMJ Open 5(1):e006450. doi:10.1136/bmjopen-2014-006450

    Article  PubMed  PubMed Central  Google Scholar 

  124. Alamanos Y, Voulgari PV, Drosos AA (2008) Incidence and prevalence of psoriatic arthritis: a systematic review. J Rheumatol 35(7):1354–1358

    PubMed  Google Scholar 

  125. Convit J (1962) Investigation of the incidence of psoriasis among Latin American Indians. In: Proceedings of the 13th Congress on Dermatology. p 196

  126. Farber EM, Nall L (1998) Epidemiology: natural history and genetics. Basic Clin Dermatol 16:107–158

    Google Scholar 

  127. Chandran V, Raychaudhuri SP (2010) Geoepidemiology and environmental factors of psoriasis and psoriatic arthritis. J Autoimmun 34(3):J314–J321. doi:10.1016/j.jaut.2009.12.001

    Article  CAS  PubMed  Google Scholar 

  128. Docampo E, Giardina E, Riveira‐Muñoz E, de Cid R, Escaramís G, Perricone C, Fernández‐Sueiro JL, Maymó J, González‐Gay MA, Blanco FJ (2011) Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: a study in Spanish and Italian populations and meta‐analysis. Arthritis Rheum 63(7):1860–1865

    Article  CAS  PubMed  Google Scholar 

  129. Hüffmeier U, Bergboer JGM, Becker T, Armour JA, Traupe H, Estivill X, Riveira-Munoz E, Mössner R, Reich K, Kurrat W (2010) Replication of LCE3C–LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. J Investig Dermatol 130(4):979–984

    Article  PubMed  CAS  Google Scholar 

  130. Chiraz BS, Myriam A, Ines Z, Catherine J, Fatma B, Ilhem C, Raoudha T, Hela Z, Hela F, Elyes B (2014) Deletion of late cornified envelope genes, LCE3C_LCE3B-del, is not associated with psoriatic arthritis in Tunisian patients. Mol Biol Rep 41(6):4141–4146

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Emanual Maverakis.

Ethics declarations

Funding Sources

This work was supported by the Burroughs Wellcome Fund and NIH 1 DP2 OD008752.

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sukhov, A., Adamopoulos, I.E. & Maverakis, E. Interactions of the Immune System with Skin and Bone Tissue in Psoriatic Arthritis: A Comprehensive Review. Clinic Rev Allerg Immunol 51, 87–99 (2016). https://doi.org/10.1007/s12016-016-8529-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-016-8529-8

Keywords

Navigation