1,098
Views
32
CrossRef citations to date
0
Altmetric
Review

The adaptive immune system in atopic dermatitis and implications on therapy

, &
Pages 787-796 | Received 12 Jan 2016, Accepted 09 Mar 2016, Published online: 28 Mar 2016

References

  • Werfel T, Schwerk N, Hansen G, et al. The diagnosis and graded therapy of atopic dermatitis. Dtsch Arztebl Int. 2014;111(29–30):509–520.
  • Ring J, Mohrenschlager M, Weidinger S. Molecular genetics of atopic eczema. Chem Immunol Allergy. 2012;96:24–29.
  • Czarnowicki T, Malajian D, Shemer A, et al. Skin-homing and systemic T-cell subsets show higher activation in atopic dermatitis versus psoriasis. J Allergy Clin Immunol. 2015;136(1):208–211.
  • Breuer K, Heratizadeh A, Wulf A, et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy. 2004;34(5):817–824.
  • Heratizadeh A, Wichmann K, Werfel T. Food allergy and atopic dermatitis: how are they connected? Curr Allergy Asthma Rep. 2011;11(4):284–291.
  • Reekers R, Busche M, Wittmann M, et al. Birch pollen-related foods trigger atopic dermatitis in patients with specific cutaneous T-cell responses to birch pollen antigens. J Allergy Clin Immunol. 1999;104(2 Pt 1):466–472.
  • Custovic A, Sonntag HJ, Buchan IE, et al. Evolution pathways of IgE responses to grass and mite allergens throughout childhood. J Allergy Clin Immunol. 2015;136(6):1645–1652.e8.
  • Turjanmaa K, Darsow U, Niggemann B, et al. EAACI/GA(2)LEN position paper: present status of the atopy patch test. Allergy. 2006;61(12):1377–1384.
  • Darsow U, Laifaoui J, Kerschenlohr K, et al. The prevalence of positive reactions in the atopy patch test with aeroallergens and food allergens in subjects with atopic eczema: a European multicenter study. Allergy. 2004;59(12):1318–1325.
  • Tupker RA, De Monchy JG, Coenraads PJ, et al. Induction of atopic dermatitis by inhalation of house dust mite. J Allergy Clin Immunol. 1996;97(5):1064–1070.
  • Werfel T, Heratizadeh A, Aberer W, et al. S2k guideline on diagnosis and treatment of atopic dermatitis – short version. J Dtsch Dermatol Ges. 2016;14(1):92–105.
  • Banerjee S, Resch Y, Chen KW, et al. Der p 11 is a major allergen for house dust mite-allergic patients suffering from atopic dermatitis. J Invest Dermatol. 2015;135(1):102–109.
  • Weghofer M, Thomas WR, Kronqvist M, et al. Variability of IgE reactivity profiles among European mite allergic patients. Eur J Clin Invest. 2008;38(12):959–965.
  • Batard T, Baron-Bodo V, Martelet A, et al. Patterns of IgE sensitization in house dust mite-allergic patients: implications for allergen immunotherapy. Allergy. 2015;71(2):220–229.
  • Dumez ME, Herman J, Campizi V, et al. Orchestration of an uncommon maturation cascade of the house dust mite protease allergen quartet. Front Immunol. 2014;5:138.
  • Szalai K, Kopp T, Lukschal A, et al. Establishing an allergic eczema model employing recombinant house dust mite allergens Der p 1 and Der p 2 in BALB/c mice. Exp Dermatol. 2012;21(11):842–846.
  • Landheer J, Giovannone B, Sadekova S, et al. TSLP is differentially regulated by vitamin D3 and cytokines in human skin. Immun Inflamm Dis. 2015;3(1):32–43.
  • Novak N, Bieber T, Hoffmann M, et al. Efficacy and safety of subcutaneous allergen-specific immunotherapy with depigmented polymerized mite extract in atopic dermatitis. J Allergy Clin Immunol. 2012;130(4):925–931e924.
  • Roesner LM, Heratizadeh A, Begemann G, et al. Der p1 and Der p2-specific T cells display a Th2, Th17, and Th2/Th17 phenotype in atopic dermatitis. J Invest Dermatol. 2015;135(9):2324–2327.
  • Akdis M, Verhagen J, Taylor A, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med. 2004;199(11):1567–1575.
  • Cosmi L, Maggi L, Santarlasci V, et al. Identification of a novel subset of human circulating memory CD4(+) T cells that produce both IL-17A and IL-4. J Allergy Clin Immunol. 2010;125(1):222–230 e221–224.
  • Wang YH, Voo KS, Liu B, et al. A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med. 2010;207(11):2479–2491.
  • Wambre E, Bonvalet M, Bodo VB, et al. Distinct characteristics of seasonal (Bet v 1) vs. perennial (Der p 1/Der p 2) allergen-specific CD4(+) T cell responses. Clin Exp Allergy. 2011;41(2):192–203.
  • Hammad H, Chieppa M, Perros F, et al. House dust mite allergen induces asthma via toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15(4):410–416.
  • Reynolds JM, Pappu BP, Peng J, et al. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010;32(5):692–702.
  • Barrett NA, Rahman OM, Fernandez JM, et al. Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes. J Exp Med. 2011;208(3):593–604.
  • Parsons MW, Li L, Wallace AM, et al. Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. J Immunol. 2014;192(4):1361–1371.
  • Kramer U, Weidinger S, Darsow U, et al. Seasonality in symptom severity influenced by temperature or grass pollen: results of a panel study in children with eczema. J Invest Dermatol. 2005;124(3):514–523.
  • Darsow U, Ring J. [Atopy patch testing with aeroallergens and food]. Hautarzt. 2005;56(12):1133–1140.
  • Werfel T, Heratizadeh A, Niebuhr M, et al. Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge chamber. J Allergy Clin Immunol. 2015;136(1):96–103e109.
  • Jinnestal CL, Belfrage E, Back O, et al. Skin barrier impairment correlates with cutaneous Staphylococcus aureus colonization and sensitization to skin-associated microbial antigens in adult patients with atopic dermatitis. Int J Dermatol. 2014;53(1):27–33.
  • Till SJ, Francis JN, Nouri-Aria K, et al. Mechanisms of immunotherapy. J Allergy Clin Immunol. 2004;113(6):1025–1034; quiz 1035.
  • Mobs C, Ipsen H, Mayer L, et al. Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies. J Allergy Clin Immunol. 2012;130(5):1108–1116 e1106.
  • Wambre E, DeLong JH, James EA, et al. Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J Allergy Clin Immunol. 2012;129(2):544–551, 551 e541–547.
  • Archila LD, DeLong JH, Wambre E, et al. Grass-specific CD4(+) T-cells exhibit varying degrees of cross-reactivity, implications for allergen-specific immunotherapy. Clin Exp Allergy. 2014;44(7):986–998.
  • Till SJ, Raynsford EJ, Reynolds CJ, et al. Peptide-induced immune regulation by a promiscuous and immunodominant CD4T-cell epitope of Timothy grass pollen: a role of Cbl-b and Itch in regulation. Thorax. 2014;69(4):335–345.
  • Wambre E, Delong JH, James EA, et al. Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J Allergy Clin Immunol. 2014;133(3):872–879e877.
  • Van Overtvelt L, Wambre E, Maillere B, et al. Assessment of Bet v 1-specific CD4+ T cell responses in allergic and nonallergic individuals using MHC class II peptide tetramers. J Immunol. 2008;180(7):4514–4522.
  • Mobs C, Slotosch C, Loffler H, et al. Birch pollen immunotherapy leads to differential induction of regulatory T cells and delayed helper T cell immune deviation. J Immunol. 2010;184(4):2194–2203.
  • Roesner LM, Floess S, Witte T, et al. Foxp3 regulatory T cells are expanded in severe atopic dermatitis patients. Allergy. 2015;70(12):1656–1660.
  • Baron U, Floess S, Wieczorek G, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol. 2007;37(9):2378–2389.
  • Hinz D, Bauer M, Roder S, et al. Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year. Allergy. 2012;67(3):380–389.
  • Schaub B, Liu J, Hoppler S, et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol. 2009;123(4):774–782e775.
  • Noh J, Noh G, Kim HS, et al. Allergen-specific responses of CD19(+)CD5(+)Foxp3(+) regulatory B cells (Bregs) and CD4(+)Foxp3(+) regulatory T cell (Tregs) in immune tolerance of cow milk allergy of late eczematous reactions. Cell Immunol. 2012;274(1–2):109–114.
  • Lee JH, Noh J, Noh G, et al. Allergen-specific transforming growth factor-beta-producing CD19+CD5+ regulatory B-cell (Br3) responses in human late eczematous allergic reactions to cow’s milk. J Interferon Cytokine Res. 2011;31(5):441–449.
  • Bremmer SF, Simpson EL. Dust mite avoidance for the primary prevention of atopic dermatitis: A systematic review and meta-analysis. Pediatr Allergy Immunol. 2015;26(7):646–654.
  • Campana R, Moritz K, Marth K, et al. Frequent occurrence of T cell-mediated late reactions revealed by atopy patch testing with hypoallergenic rBet v 1 fragments. J Allergy Clin Immunol. 2015;137(2):601–609.e8.
  • Focke-Tejkl M, Weber M, Niespodziana K, et al. Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy. J Allergy Clin Immunol. 2015;135(5):1207–1207 e1201–1211.
  • Niederberger V, Marth K, Eckl-Dorna J, et al. Skin test evaluation of a novel peptide carrier-based vaccine, BM32, in grass pollen-allergic patients. J Allergy Clin Immunol. 2015;136(4):1101–1103 e1108.
  • Heil PM, Maurer D, Klein B, et al. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course – a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges. 2010;8(12):990–998.
  • Werfel T, Biedermann T. Current novel approaches in systemic therapy of atopic dermatitis: specific inhibition of cutaneous Th2 polarized inflammation and itch. Curr Opin Allergy Clin Immunol. 2015;15(5):446–452.
  • Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130–139.
  • Howell MD, Parker ML, Mustelin T, et al. Past, present, and future for biologic intervention in atopic dermatitis. Allergy. 2015;70(8):887–896.
  • Zhang Z, Xiao C, Gibson AM, et al. EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis. J Immunol. 2014;192(3):859–866.
  • Wichmann K, Uter W, Weiss J, et al. Isolation of alpha-toxin-producing Staphylococcus aureus from the skin of highly sensitized adult patients with severe atopic dermatitis. Br J Dermatol. 2009;161(2):300–305.
  • Breuer K, Wittmann M, Bosche B, et al. Severe atopic dermatitis is associated with sensitization to staphylococcal enterotoxin B (SEB). Allergy. 2000;55(6):551–555.
  • Breuer K, Wittmann M, Kempe K, et al. Alpha-toxin is produced by skin colonizing Staphylococcus aureus and induces a T helper type 1 response in atopic dermatitis. Clin Exp Allergy. 2005;35(8):1088–1095.
  • Nograles KE, Zaba LC, Shemer A, et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009;123(6):1244–1252e1242.
  • Sonkoly E, Muller A, Lauerma AI, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117(2):411–417.
  • Nakajima S, Kitoh A, Egawa G, et al. IL-17A as an inducer for Th2 immune responses in murine atopic dermatitis models. J Invest Dermatol. 2014;134(8):2122–2130.
  • Reginald K, Westritschnig K, Werfel T, et al. Immunoglobulin E antibody reactivity to bacterial antigens in atopic dermatitis patients. Clin Exp Allergy. 2011;41(3):357–369.
  • Biedermann T, Skabytska Y, Kaesler S, et al. Regulation of T cell immunity in atopic dermatitis by microbes: the Yin and Yang of cutaneous inflammation. Front Immunol. 2015;6:353.
  • Kong HH, Oh J, Deming C, et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012;22(5):850–859.
  • Tauber M, Balica S, Hsu CY, et al. Staphylococcus aureus density on lesional and nonlesional skin is strongly associated with disease severity in atopic dermatitis. J Allergy Clin Immunol. 2015. Nov 7;pii: S0091-6749(15)01367-6. [Epub ahead of print]
  • Laborel-Preneron E, Bianchi P, Boralevi F, et al. Effects of the Staphylococcus aureus and Staphylococcus epidermidis Secretomes Isolated from the skin microbiota of atopic children on CD4+ T cell activation. PLoS One. 2015;10(10):e0141067.
  • Kobayashi T, Glatz M, Horiuchi K, et al. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis. Immunity. 2015;42(4):756–766.
  • Roberts SO. Pityrosporum orbiculare: incidence and distribution on clinically normal skin. Br J Dermatol. 1969;81(4):264–269.
  • Gaitanis G, Velegraki A, Mayser P, et al. Skin diseases associated with Malassezia yeasts: facts and controversies. Clin Dermatol. 2013;31(4):455–463.
  • Balaji H, Heratizadeh A, Wichmann K, et al. Malassezia sympodialis thioredoxin-specific T cells are highly cross-reactive to human thioredoxin in atopic dermatitis. J Allergy Clin Immunol. 2011;128(1):92–99e94.
  • Casagrande BF, Fluckiger S, Linder MT, et al. Sensitization to the yeast Malassezia sympodialis is specific for extrinsic and intrinsic atopic eczema. J Invest Dermatol. 2006;126(11):2414–2421.
  • Glatz M, Buchner M, von Bartenwerffer W, et al. Malassezia spp.-specific immunoglobulin E level is a marker for severity of atopic dermatitis in adults. Acta Derm Venereol. 2015;95(2):191–196.
  • Devos SA, van der Valk PG. The relevance of skin prick tests for Pityrosporum ovale in patients with head and neck dermatitis. Allergy. 2000;55(11):1056–1058.
  • Lintu P, Savolainen J, Kortekangas-Savolainen O, et al. Systemic ketoconazole is an effective treatment of atopic dermatitis with IgE-mediated hypersensitivity to yeasts. Allergy. 2001;56(6):512–517.
  • Mayser P, Kupfer J, Nemetz D, et al. Treatment of head and neck dermatitis with ciclopiroxolamine cream–results of a double-blind, placebo-controlled study. Skin Pharmacol Physiol. 2006;19(3):153–158.
  • Hradetzky S, Werfel T, Rosner LM. Autoallergy in atopic dermatitis. Allergo J Int. 2015;24(1):16–22.
  • Schmid-Grendelmeier P, Fluckiger S, Disch R, et al. IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis. J Allergy Clin Immunol. 2005;115(5):1068–1075.
  • Tang TS, Bieber T, Williams HC. Does “autoreactivity” play a role in atopic dermatitis? J Allergy Clin Immunol. 2012;129(5):1209–1215e1202.
  • Valenta R, Seiberler S, Natter S, et al. Autoallergy: a pathogenetic factor in atopic dermatitis? J Allergy Clin Immunol. 2000;105(3):432–437.
  • Mittermann I, Reininger R, Zimmermann M, et al. The IgE-reactive autoantigen Hom s 2 induces damage of respiratory epithelial cells and keratinocytes via induction of IFN-gamma. J Invest Dermatol. 2008;128(6):1451–1459.
  • Heratizadeh A, Mittermann I, Balaji H, et al. The role of T-cell reactivity towards the autoantigen alpha-NAC in atopic dermatitis. Br J Dermatol. 2011;164(2):316–324.
  • Roesner LM. Meeting abstracts P001. Exp Dermatol. 2013;22(3):e1–e55.
  • Hradetzky S, Roesner LM, Heratizadeh A, et al. Differential cytokine induction by the human skin-associated autoallergen thioredoxin in sensitized patients with atopic dermatitis and healthy control subjects. J Allergy Clin Immunol. 2015;135(5):1378–1380 e1371–1375.
  • Hradetzky S, Balaji H, Roesner LM, et al. The human skin-associated autoantigen alpha-NAC activates monocytes and dendritic cells via TLR-2 and primes an IL-12-dependent Th1 response. J Invest Dermatol. 2013;133(9):2289–2292.
  • Hradetzky S, Roesner LM, Balaji H, et al. Cytokine effects induced by the human autoallergen alpha-NAC. J Invest Dermatol. 2014;134(6):1570–1578.
  • Yosipovitch G, Papoiu AD. What causes itch in atopic dermatitis? Curr Allergy Asthma Rep. 2008;8(4):306–311.
  • Mollanazar NK, Smith PK, Yosipovitch G. Mediators of chronic pruritus in atopic dermatitis: getting the itch out? Clin Rev Allergy Immunol. 2015. [Epub ahead of print].
  • Wilson SR, The L, Batia LM, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155(2):285–295.
  • Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3(7):673–680.
  • Le TA, Takai T, Vu AT, et al. Flagellin induces the expression of thymic stromal lymphopoietin in human keratinocytes via toll-like receptor 5. Int Arch Allergy Immunol. 2011;155(1):31–37.
  • Xie Y, Takai T, Chen X, et al. Long TSLP transcript expression and release of TSLP induced by TLR ligands and cytokines in human keratinocytes. J Dermatol Sci. 2012;66(3):233–237.
  • Moniaga CS, Jeong SK, Egawa G, et al. Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice. Am J Pathol. 2013;182(3):841–851.
  • Ryu WI, Lee H, Kim JH, et al. IL-33 induces Egr-1-dependent TSLP expression via the MAPK pathways in human keratinocytes. Exp Dermatol. 2015;24(11):857–863.
  • Allakhverdi Z, Comeau MR, Jessup HK, et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med. 2007;204(2):253–258.
  • Nakajima S, Igyarto BZ, Honda T, et al. Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J Allergy Clin Immunol. 2012;129(4):1048–1055 e1046.
  • Raap U, Weissmantel S, Gehring M, et al. IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol. 2012;23(3):285–288.
  • Heise R, Neis MM, Marquardt Y, et al. IL-31 receptor alpha expression in epidermal keratinocytes is modulated by cell differentiation and interferon gamma. J Invest Dermatol. 2009;129(1):240–243.
  • Cornelissen C, Marquardt Y, Czaja K, et al. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 2012;129(2):426–433, 433 e421–428.
  • Kato A, Fujii E, Watanabe T, et al. Distribution of IL-31 and its receptor expressing cells in skin of atopic dermatitis. J Dermatol Sci. 2014;74(3):229–235.
  • Cevikbas F, Wang X, Akiyama T, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014;133(2):448–460.
  • Bilsborough J, Leung DY, Maurer M, et al. IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol. 2006;117(2):418–425.
  • Szegedi K, Kremer AE, Kezic S, et al. Increased frequencies of IL-31-producing T cells are found in chronic atopic dermatitis skin. Exp Dermatol. 2012;21(6):431–436.
  • Stott B, Lavender P, Lehmann S, et al. Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation. J Allergy Clin Immunol. 2013;132(2):446–454 e445.
  • Niebuhr M, Mamerow D, Heratizadeh A, et al. Staphylococcal alpha-toxin induces a higher T cell proliferation and interleukin-31 in atopic dermatitis. Int Arch Allergy Immunol. 2011;156(4):412–415.
  • Hwang JS, Kim GC, Park E, et al. NFAT1 and JunB cooperatively regulate IL-31 gene expression in CD4+ T cells in health and disease. J Immunol. 2015;194(4):1963–1974.
  • Bieber T, Vick K, Folster-Holst R, et al. Efficacy and safety of methylprednisolone aceponate ointment 0.1% compared to tacrolimus 0.03% in children and adolescents with an acute flare of severe atopic dermatitis. Allergy. 2007;62(2):184–189.
  • Luger T, Boguniewicz M, Carr W, et al. Pimecrolimus in atopic dermatitis: consensus on safety and the need to allow use in infants. Pediatr Allergy Immunol. 2015;26(4):306–315.
  • Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis) part I. J Eur Acad Dermatol Venereol. 2012;26(8):1045–1060.
  • Boralevi F, Saint Aroman M, Delarue A, et al. Long-term emollient therapy improves xerosis in children with atopic dermatitis. J Eur Acad Dermatol Venereol. 2014;28(11):1456–1462.
  • Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic dermatitis) part II. J Eur Acad Dermatol Venereol. 2012;26(9):1176–1193.
  • Thurmond RL. The histamine H4 receptor: from orphan to the clinic. Front Pharmacol. 2015;6:65.
  • Murata Y, Song M, Kikuchi H, et al. Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis. J Dermatol. 2015;42(2):129–139.
  • Nemoto O, Furue M, Nakagawa H, et al. The first trial of CIM331, a humanized anti-human IL-31 receptor A antibody, for healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomised, double-blind, placebo-controlled study. Br J Dermatol. 2015;174(2):296–304.
  • Staab D, Diepgen TL, Fartasch M, et al. Age related, structured educational programmes for the management of atopic dermatitis in children and adolescents: multicentre, randomised controlled trial. BMJ. 2006;332(7547):933–938.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.