TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis
Curdin Conrad, Jeremy Di Domizio, Alessio Mylonas, Cyrine Belkhodja, Olivier Demaria, Alexander A Navarini, Anne-Karine Lapointe, Lars E French, Maxime Vernez, Michel Gilliet, Curdin Conrad, Jeremy Di Domizio, Alessio Mylonas, Cyrine Belkhodja, Olivier Demaria, Alexander A Navarini, Anne-Karine Lapointe, Lars E French, Maxime Vernez, Michel Gilliet
Abstract
Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2-5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.
Conflict of interest statement
The authors declare no competing financial interests.
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References
- Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985;229:869–871. doi: 10.1126/science.3895437.
- Beutler B, Cerami A. The biology of cachectin/TNF–a primary mediator of the host response. Annu. Rev. Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205.
- Kneilling M, et al. Direct crosstalk between mast cell-TNF and TNFR1-expressing endothelia mediates local tissue inflammation. Blood. 2009;114:1696–1706. doi: 10.1182/blood-2008-11-187682.
- Vassalli P. The pathophysiology of tumor necrosis factors. Annu. Rev. Immunol. 1992;10:411–452. doi: 10.1146/annurev.iy.10.040192.002211.
- Di Giovine FS, Nuki G, Duff GW. Tumour necrosis factor in synovial exudates. Ann. Rheum. Dis. 1988;47:768–772. doi: 10.1136/ard.47.9.768.
- Breese EJ, et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology. 1994;106:1455–1466. doi: 10.1016/0016-5085(94)90398-0.
- Kristensen M, et al. Localization of tumour necrosis factor-alpha (TNF-alpha) and its receptors in normal and psoriatic skin: epidermal cells express the 55-kD but not the 75-kD TNF receptor. Clin. Exp. Immunol. 1993;94:354–362. doi: 10.1111/j.1365-2249.1993.tb03457.x.
- Moreland LW, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 1997;337:141–147. doi: 10.1056/NEJM199707173370301.
- Leonardi CL, et al. Etanercept as monotherapy in patients with psoriasis. N. Engl. J. Med. 2003;349:2014–2022. doi: 10.1056/NEJMoa030409.
- Rutgeerts P, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 2005;353:2462–2476. doi: 10.1056/NEJMoa050516.
- Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat. Rev. Rheumatol. 2009;5:578–582. doi: 10.1038/nrrheum.2009.181.
- Bongartz T, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275–2285. doi: 10.1001/jama.295.19.2275.
- Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann. Rheum. Dis. 2013;72:517–524. doi: 10.1136/annrheumdis-2011-201244.
- Baeten D, et al. Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease? Ann. Rheum. Dis. 2003;62:829–834. doi: 10.1136/ard.62.9.829.
- Sfikakis PP, Iliopoulos A, Elezoglou A, Kittas C, Stratigos A. Psoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction. Arthritis Rheum. 2005;52:2513–2518. doi: 10.1002/art.21233.
- Cohen JD, et al. Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series. J. Rheumatol. 2007;34:380–385.
- de Gannes GC, et al. Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients with rheumatologic conditions. Arch. Dermatol. 2007;143:223–231.
- Brown G, et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis: systematic review of clinical features, histopathological findings, and management experience. J. Am. Acad. Dermatol. 2017;76:334–341. doi: 10.1016/j.jaad.2016.08.012.
- Nestle FO, Kaplan DH, Barker J. Psoriasis. N. Engl. J. Med. 2009;361:496–509. doi: 10.1056/NEJMra0804595.
- Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370:263–271. doi: 10.1016/S0140-6736(07)61128-3.
- Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of psoriasis. Annu. Rev. Immunol. 2014;32:227–255. doi: 10.1146/annurev-immunol-032713-120225.
- Gottlieb SL, et al. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat. Med. 1995;1:442–447. doi: 10.1038/nm0595-442.
- Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N. Engl. J. Med. 2001;345:248–255. doi: 10.1056/NEJM200107263450403.
- Lebwohl M, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N. Engl. J. Med. 2003;349:2004–2013. doi: 10.1056/NEJMoa030002.
- Abrams JR, et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J. Clin. Invest. 1999;103:1243–1252. doi: 10.1172/JCI5857.
- Nair RP, et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 2006;78:827–851. doi: 10.1086/503821.
- Boyman O, et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J. Exp. Med. 2004;199:731–736. doi: 10.1084/jem.20031482.
- Conrad C, et al. Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat. Med. 2007;13:836–842. doi: 10.1038/nm1605.
- Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces psoriasis. J. Clin. Invest. 1996;98:1878–1887. doi: 10.1172/JCI118989.
- Prinz JC, et al. Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris. Eur. J. Immunol. 1999;29:3360–3368. doi: 10.1002/(SICI)1521-4141(199910)29:10<3360::AID-IMMU3360>;2-G.
- Vollmer S, Menssen A, Prinz JC. Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris. J. Invest. Dermatol. 2001;117:1296–1301. doi: 10.1046/j.0022-202x.2001.01494.x.
- Sigmundsdottir H, et al. Circulating T cells of patients with active psoriasis respond to streptococcal M-peptides sharing sequences with human epidermal keratins. Scand. J. Immunol. 1997;45:688–697. doi: 10.1046/j.1365-3083.1997.d01-438.x.
- Lande R, et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat. Commun. 2014;5:5621. doi: 10.1038/ncomms6621.
- Arakawa A, et al. Melanocyte antigen triggers autoimmunity in human psoriasis. J. Exp. Med. 2015;212:2203–2212. doi: 10.1084/jem.20151093.
- Nestle FO, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J. Exp. Med. 2005;202:135–143. doi: 10.1084/jem.20050500.
- Di Meglio P, et al. Targeting CD8 (+) T cells prevents psoriasis development. J. Allergy Clin. Immunol. 2016;138:274–276. doi: 10.1016/j.jaci.2015.10.046.
- Ashurst PJ. Relapsing pustular eruptions of the hands and feet. Br. J. Dermatol. 1964;76:169–180. doi: 10.1111/j.1365-2133.1964.tb14502.x.
- Enfors W, Molin L. Pustulosis palmaris et plantaris. A follow-up study of a ten-year material. Acta Derm. Venereol. 1971;51:289–294.
- Seneschal J, et al. Cytokine imbalance with increased production of interferon-alpha in psoriasiform eruptions associated with antitumour necrosis factor-alpha treatments. Br. J. Dermatol. 2009;161:1081–1088. doi: 10.1111/j.1365-2133.2009.09329.x.
- Lande R, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 2011;3:73ra19. doi: 10.1126/scitranslmed.3001180.
- Lande R, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564–569. doi: 10.1038/nature06116.
- Kadowaki N, Antonenko S, Lau JY, Liu YJ. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J. Exp. Med. 2000;192:219–226. doi: 10.1084/jem.192.2.219.
- Gregorio J, et al. Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J. Exp. Med. 2010;207:2921–2930. doi: 10.1084/jem.20101102.
- Vanbervliet B, et al. The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. J. Exp. Med. 2003;198:823–830. doi: 10.1084/jem.20020437.
- Meller S, et al. Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum. 2005;52:1504–1516. doi: 10.1002/art.21034.
- Conrad C, Meller S, Gilliet M. Plasmacytoid dendritic cells in the skin: to sense or not to sense nucleic acids. Semin. Immunol. 2009;21:101–109. doi: 10.1016/j.smim.2009.01.004.
- Cai Y, et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity. 2011;35:596–610. doi: 10.1016/j.immuni.2011.08.001.
- Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc. Natl Acad. Sci. USA. 2005;102:3372–3377. doi: 10.1073/pnas.0408506102.
- Bengtsson AA, et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus. 2000;9:664–671. doi: 10.1191/096120300674499064.
- Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 2001;294:1540–1543. doi: 10.1126/science.1064890.
- Soumelis V, Liu YJ. From plasmacytoid to dendritic cell: morphological and functional switches during plasmacytoid pre-dendritic cell differentiation. Eur. J. Immunol. 2006;36:2286–2292. doi: 10.1002/eji.200636026.
- Tsoi LC, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat. Genet. 2012;44:1341–1348. doi: 10.1038/ng.2467.
- Tsoi LC, et al. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci. Nat. Commun. 2015;6:7001. doi: 10.1038/ncomms8001.
- van der Fits L, van der Wel LI, Laman JD, Prens EP, Verschuren MC. In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered. J. Invest. Dermatol. 2004;122:51–60. doi: 10.1046/j.0022-202X.2003.22113.x.
- Boniface K, et al. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J. Immunol. 2005;174:3695–3702. doi: 10.4049/jimmunol.174.6.3695.
- Wolk K, et al. IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J. Mol. Med (Berl.) 2009;87:523–536. doi: 10.1007/s00109-009-0457-0.
- Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity. 2009;31:15–23. doi: 10.1016/j.immuni.2009.06.008.
- Mashiko S, et al. Human mast cells are major IL-22 producers in patients with psoriasis and atopic dermatitis. J. Allergy Clin. Immunol. 2015;136:351–359. doi: 10.1016/j.jaci.2015.01.033.
- Chen F, et al. mTOR mediates IL-23 induction of neutrophil IL-17 and IL-22 production. J. Immunol. 2016;196:4390–4399. doi: 10.4049/jimmunol.1501541.
- Lang KS, et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat. Med. 2005;11:138–145. doi: 10.1038/nm1176.
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