Doi:10.1016/j.jaut.2005.09.025

Immunopathogenesis of psoriasis: Recent insights on the role Department of Dermatology 1 and Unite' INSERM U697, Hoˆpital Saint-Louis, Paris, France Received 24 May 2005; revised 24 May 2005; accepted 14 September 2005 Psoriasis is a frequent chronic inflammatory disorder involving mostly skin and joints. Its characteristic features in the skin consist of in- flammatory changes in both dermis and epidermis, with abnormal keratinocytic differentiation and proliferation. In recent years, an importantset of knowledge has been provided by works addressing the immunopathogenic mechanisms of the disease. Indeed, recent advances in theknowledge of mechanisms linking innate and adaptive immunity have led to reconsideration of the roles of key players in the pathogenesisof the disease. This review will focus on results from studies performed in vitro and in vivo in patients with psoriasis, and on lessons from re-cently designed animal models which are considered as the most relevant with respect to the human disease. Even more important, these insightsprovide a rational basis for the design of new therapeutic strategies aiming at the deletion or the down regulation of activated T cells, or at thesuppression of pathogenic cytokines such as TNF-a. Some of these new biotherapeutic tools have been successfully used in vivo in clinical trials,providing a confirmation of such concepts.
Ó 2005 Elsevier Ltd. All rights reserved.
Keywords: Psoriasis; T lymphocyte; Keratinocyte; TNFa 1. The role of adaptive immunity in psoriasis cytokines and to enhance the proliferation of psoriatic kerati-nocytes, but not of keratinocytes from non-psoriatic individu- Several lines of evidence obtained in vitro or in vivo sup- als. These studies revealed an important pathogenic role port the key contribution of T cells to the psoriatic phenotype, for T-cell-derived cytokines, mostly interferon-g. These re- including the hyperproliferation of epidermal cells. First, both sults have been further confirmed by the development of ani- CD4C and CD8C T cells have respectively been shown to pre- mal models of psoriasis, mostly immunodeficient mice bearing dominantly colonize dermis and epidermis in lesional skin the SCID mutation, engrafted with human psoriatic skin, from patients with psoriasis, and these subsets are present in which demonstrated that the transfer of CD4C T lymphocytes early stages of plaque formation The pathogenicity of ef- from patients with psoriasis was mandatory for the induction fector CD4C T cells infiltrating skin lesions is now widely ac- and the maintenance of epidermal psoriatic changes Fi- cepted. This notion relies first on results from in vitro studies nally, the therapeutic efficacy of immunosuppressive drugs which showed that lesional skin-derived CD4C T cell lines such as cyclosporin humanized anti-CD4 or more re- were characterized by their ability to secrete mostly TH1 cently, LFA3-Ig chimeric molecules or humanized anti-CD11a monoclonal antibodies is dependent on the majorpathogenic role of CD4C helper T lymphocytes. Recently, * Institut de Recherche sur la Peau, Unite' INSERM U697, Pavillon Bazin, knowledge concerning mechanisms of T-cell expansion has Hopital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris cedex 10, been provided by several studies investigating the diversity France. Tel.: C33 1 42 49 98 17; fax: C33 1 53 72 20 51.
of the T-cell repertoire of the skin infiltrate in comparison 0896-8411/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jaut.2005.09.025 H. Bachelez / Journal of Autoimmunity 25 (2005) 69e73 with peripheral blood. These studies, based on TCRVb CDR3 receptors This model allows the development of psoriatic length and sequence analysis, showed evidence of a restricted lesions without any transfer of exogenous CD4C T cells. Se- diversity of the skin infiltrate, without topographic discrepan- quential studies showed evidence for a local proliferation of cies in a given patient, and the long term persistence of resident T cells without any detectable recirculation in the pe- expanded clonotypes. Interestingly, the study investi- ripheral blood. The relevance of this latter model with respect gating T-cell repertoire in lesional skin from two monozygotic to the human disease also relies on the evidence for local pro- twins with psoriasis revealed common clonotypes, suggesting duction of TNF-a and its critical role in the conversion of pre- the recognition of common antigens. Nevertheless, results psoriatic skin to psoriatic lesions, as treatment of these mice from most studies do not support the existence of public epit- with infliximab or ethanercept, two TNF-blocking agents, pre- opes targeted by lesional skin-infiltrating lymphocytes, and the vent the formation of plaques In this model, it is likely nature of antigens targeted by these T-cells remains elusive, that quantitatively, the main cellular subset involved in the even though some works suggest that bacterial superantigens production of TNF is the antigen presenting cell (APC) subset.
might be a triggering factor in some cases.
To conclude on the contribution of effector T cells in psoriasis, On the other hand, little direct evidence for the pathogenic it is likely that at least a significant proportion of T-cell clono- role of CD8C T cells in psoriasis has been reported so far, so types which persist over the long term are resident T lympho- that the role of this subset in human disease remains elusive.
cytes which are capable of undergoing local activation and In situ immunophenotypic studies have shown that CD8C T proliferation without requiring cutaneous lymphocyte associ- lymphocytes are predominant among the epidermal infiltrate, ated antigen (CLA)-dependent homing However, this hy- whereas the majority of dermal lymphocytes exhibit a pothesis does not rule out the recruitment of memory T cells CD4C T cell phenotype. Moreover, epidermal CD8C T cells, from the CLAC pool after their differentiation in regional like dermal T-cells, display a restricted repertoire, suggesting again that an antigen-specific immune response drives the Recently, several studies have focused on the role of a re- skin expansion of the subset. Likewise, the hypothesis cently described subset of T cells called regulatory T cells of a contribution of CD8C T lymphocytes to the pathogenesis (Tregs) This subset, characterized by high levels of of psoriasis is reinforced by findings in forms of the disease CD25 expression, a chain of the interleukin-2 receptor, and occurring in individuals infected with the human immunodefi- a high level of mRNA expression of a transcription factor be- ciency virus. In this model, even though the incidence and longing to the forkhead/winged helix family, is called foxp3 severity of HIV-related psoriasis has been lowered by the wide . It has been shown that CD4CCD25high cells, the so- usage of highly active antiretroviral therapy, the parallel wors- called naturally occurring Tregs, are involved in the control ening courses of skin symptoms and of quantitative and qual- of CD4C and CD8C effectors at the periphery, which include itative alterations affecting CD4C T cells, and the striking autoreactive T cells escaping from thymic deletion, since their predominance of CD8C T lymphocytes both in dermis and absence due to mutations of the Foxp3 gene is responsible for epidermis argue against the exclusive deleterious role of TH1 multiple autoimmune manifestations both in mouse and in hu- cells Furthermore, we recently found evidence in HIV- mans, notably skin inflammatory changes Naturally oc- associated psoriasis that T lymphocytes are predominantly curring Tregs exert their function through both contact- and CD8C cytotoxic T cells displaying an oligoclonal T-cell cytokine-dependent mechanisms, mostly through the produc- receptor pattern, with persistence of some clonotypes in the tion of IL-10 and TGF-b, and are involved in the tolerance long term (Kemula M. et al., manuscript in preparation).
to self and tumor-associated antigens, and in the regulation Analysis of T-cell repertoire in both skin and peripheral blood of immune response to pathogens. A recent study in- by using complementary determining region 3 (CDR3) length vestigated the presence and the functionality of Tregs in the polymorphism suggests that a dysregulated CD8 cytotoxic skin and in the peripheral blood of patients with plaque-type T-cell response towards skin autoantigens underlies psoriasis psoriasis. The results indicate that Tregs are present at the site of lesions, and suggest that their regulatory function Altogether, studies investigating the T-cell repertoire based would be altered when compared to that of peripheral Tregs on TCRVb CDR3 length and sequence analysis reveal the re- from healthy individuals. Similar findings have been re- stricted diversity of T cells infiltrating psoriatic skin lesions ported in patients with rheumatoid arthritis, and it remains both in the epidermis and in the dermis, suggesting that the ac- to be determined whether this reflects a transient hypofunc- tivation of both CD4C and CD8C cells in skin lesions are trig- tionality which might be observed in many inflammatory gered at least partly through antigen-driven mechanisms. So chronic disorders, or an intrinsequal abnormality of the Treg far, the self or non-self nature or the identity of epitopes tar- population. In the case of RA, functional alterations of Tregs geted by CD4C and CD8C T cells colonizing skin lesions reversed during remission induced by TNF-blocking agents, of plaque-type psoriasis remains unelucidated.
suggesting that mechanisms related to this cytokine are in- The pathogenic role of T cells has also been demonstrated in a mouse model of psoriasis, which relies on the graft of hu- Although the mechanisms controlling T cells with regulatory man symptomless psoriatic skin onto AGR 129 mice, which is function in vivo remain elusive, innovative therapeutic tools characterized by an invalidation of the recombination-activat- have been shown to enhance the function of the subset. A hu- ing gene 2, and by a deficiency in type I and type II interferon manized anti-CD3 monoclonal antibody (mAb) with two H. Bachelez / Journal of Autoimmunity 25 (2005) 69e73 alanine substitutions at residues critical for binding to Fc recep- keratinocyte function are associated with a psoriatic pheno- tor (FcR) has reduced the mitogenicity of OKT3 and favored the type, including the local expansion of CD4C and CD8C T production of IL-10. Clinical trials in patients with type cells Moreover, the constitutive expression of Stat3 in 1 diabetes provided evidence of a clinical benefit which paral- keratinocytes is associated with epidermal overreactivity in re- leled the induction of CD4C CD45ROC IL10C T cells, some sponse to physical stimulation, a feature typical of human pso- of which produce TGFb In the context of psoriasis, a re- riasis called Koebner's phenomenon. Finally, the authors cent open-labeled study conducted in patients with psoriatic ar- showed that CD4C T lymphocytes are critically involved in thritis suggest that hOKT3g1(Ala-Ala) induced clinical this phenomenon, and that inducing a downregulation of Stat3 signaling in vivo provides improvement of the skin con-dition in this transgenic mouse model Thus, it remains 2. The role of cytokines belonging to the interleukin-12 possible that constitutive abnormalities of keratinocytes would family as a link between innate and adaptive immunity lead to striking perturbations of keratinocyte-T lymphocyte in-teractions, and consequently to an uncontrolled inflammatory Recently, several studies have focused on the role of cyto- reaction with consistent recruitment of activated T cells.
kines belonging to the interleukin-12 (IL-12) family. Interleu-kin-12 is a heterodimeric cytokine which has been shown to 4. Clinical applications: immunotherapeutic strategies induce and favor the differentiation of naive CD4C and CD8C T cells into cells preferentially producing IFN-g andIL-2, and is thus involved in Th1-mediated immune responses The increasing knowledge about mechanisms allowing the Recently, the role of IL-12 in inflammatory T-cell medi- control of skin immune responses, mostly pathways linking in- ated disorders has been reconsidered in light of the character- nate and adaptive immunity and those involved in the control ization of new dimeric cytokines belonging to the same of activated effector T cells at the periphery, provides a rational family, and regulating IFN-g production by T cells. In this basis for immunotherapy of skin diseases using T-cell-directed field, several recent studies have focused on IL-23, which is therapies. Thus, clinical studies reporting the short-term, par- composed of the association of p40 with a p19 subunit, confer- tial benefit of anti-CD4 monoclonal antibodies (mAbs) in pa- ring specific functions to this cytokine which differ from those tients with psoriasis can be explained by the non-univocal role of IL-12, with evidence of enhanced cutaneous immune of CD4 T helper-type 1 cells in the pathogenesis of the dis- responses as shown in a transgenic mouse model resulting ease, and by the contribution of other lymphocyte subsets, from the skin-directed overexpression of p40 Interestingly, mostly cytotoxic T lymphocytes (CTLs), to skin inflammation.
it has recently been shown that IL-23 and not IL-12 is On the other hand, the anti-CD11a mAb efalizumab, which in- predominantly expressed in lesional psoriatic skin. These terferes with LFA-1/ICAM-1 interactions, provides some ben- findings raised a new therapeutic strategy relying on the use of efit in psoriatic patients. Finally, the properties of IL-10 and anti-p40 neutralizing Abs. Results from a phase I study in IL-4 to reverse the TH1 polarization of T lymphocytes have patients with psoriasis showed that a single administration of been used to induce a shift from a IFN-g-producing (TH1) an anti-p40 mAb induced striking clinical responses, with a to a IL-4-producing pattern in vivo, with evidence of clinical remission of lesions which was correlated with a reduction of responses Finally, the conclusions from animal mod- els stressing the key pathogenic role of TNF-a lead to the ther-apeutic use of monoclonal antibodies (infliximab) or chimeric 3. Lessons from recently developed animal models of receptors (etanercept) in order to neutralize the proinflamma- These past few years, the design of several genetically en- gineered murine models provided phenotypes more or less reminiscent of the human psoriatic disease The modelsaddressing the contribution of T cells as key effectors have al- While the hypothesis of the pathogenicity of T-cells in pso- ready been discussed. Among recently designed murine mod- riasis has now been validated, the specificity of T cell effectors els, some consisted of the targeted expression of a transgene in and the mechanisms underlying their uncontrolled activation keratinocytes and addressed the consequences of the primary are far from being fully understood. However, it is striking keratinocytic event on cutaneous inflammatory and immune that recent immunogenetic studies led to the characterization responses. Such a model, recently reported by Sano et al., is of two candidate genes, SLC9A3R1 and NAT9, which partici- based on the overexpression in keratinocytes of Stat3 trans- pate in the regulation of the immunological synapse at the in- gene, a member of the signal transducers and activators of terface between T cells and APC. The hypothesis that transcription under the command of the keratin 5 promoter these polymorphisms might be involved in tolerance breaking The rationale of the model is based on the finding that in psoriasis is very appealing, and will be discussed in another Stat3 is overexpressed by keratinocytes in lesional psoriatic paper in this issue. On the other hand, the central role of TNF- skin, but not in other inflammatory skin diseases such as atopic a, which is produced following activation of many receptors of dermatitis or in prurigo. In this transgenic model, alterations in innate immunity, raised the alternative scenario of a disease H. Bachelez / Journal of Autoimmunity 25 (2005) 69e73 related to innate autoimmunity However, the wide range receptor Vb 3 and/or Vb 13.1 genes. Proc Natl Acad Sci USA 1994; of pathways linking innate and adaptive immunity is blurring [17] Badger J. HIV and psoriasis. Clin Rev Allergy Immunol 1996;14: this distinction, and it is also likely that different mechanisms lead to a common psoriatic phenotype. Indeed, we are just en- [18] Munoz-Perez MA, Rodriguez-Pichardo A, Camacho F, Colmenero MA.
tering the new era opened up by the design of biotherapeutic Dermatological findings correlated with CD4 lymphocyte counts in a tools in inflammatory diseases, and there is no doubt that ad- prospective 3 year study of 1161 patients with human immunodeficiency ditional knowledge, both from bench and bedside, will help to virus disease predominantly acquired through intravenous drug abuse.
Br J Dermatol 1998;139:33 further elucidate the molecular and cellular mechanisms un- [19] Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO. Spon- derlying the chronicity of psoriatic inflammation.
taneous development of psoriasis in a new animal model shows an essen-tial role for resident T cells and tumor necrosis factor-a. J Exp Med2004;199:731e6.
[20] Nickoloff BJ, Nestle FO. Recent insights into the pathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest 2004; [21] Sakaguchi S. Foxp3-expressing CD25CCD4Cregulatory T cells in [1] Baker BS, Fry L. The immunology of psoriasis. Br J Dermatol 1992; immunological tolerance to self and non-self. Nat Immunol 2005;6: [2] Bata-Csorgo Z, Hammerberg C, Voorhees JJ, Cooper KD. Kinetics and [22] Coffer PJ, Burgering BMT. Forkhead-box transcription factors and their regulation of human keratinocyte stem cell growth in short-term primary role in the immune system. Nat Rev Immunol 2004;4:889e99.
ex vivo culture. Cooperative growth factors from psoriatic lesional T [23] Nieves DS, Phipps R, Pollock SJ, Ochs HD, Zhu Q, Scott GA, et al.
lymphocytes stimulate proliferation among psoriatic uninvolved, but Dermatologic and immunologic findings in the immune dysregulation, not normal, stem keratinocytes. J Clin Invest 1995;95:317e27.
polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol [3] Nestle FO, Turka LA, Nickoloff BJ. Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of [24] Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Th1 type cytokines. J Clin Invest 1994;94:202e9.
et al. Foxp3 expressing CD4CCD25(high) regulatory T cells are over- [4] Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces represented in human metastatic melanoma lymph nodes and inhibit psoriasis. J Clin Invest 1996;98:1878e87.
the function of infiltrating T cells. J Immunol 2004;173:1444e53.
[5] Nickoloff BJ, Wrone-Smith T. Injection of pre-psoriatic skin with CD4C [25] Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S, Stevens SR, T cells induces psoriasis. Am J Pathol 1999;155:145e58.
et al. Dysfunctional blood and target tissue CD4CCD25high regulatory [6] Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, T cells in psoriasis: mechanism underlying unrestrained pathogenic Goldschmidt WF, et al. Methotrexate versus cyclosporine in moderate- effector T cell proliferation. J Immunol 2005;174:164e73.
to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658e65.
[26] Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, [7] Bachelez H, Flageul B, Dubertret L, Fraitag S, Grossman R, Brousse N, et al. Compromised function of regulatory T cells in rheumatoid arthritis et al. Treatment of recalcitrant plaque psoriasis with a humanized non- and reversal by anti-TNFa therapy. J Exp Med 2004;200:277e85.
depleting antibody to CD4. J Autoimmun 1998;11:53e62.
[27] Herold KC, Burton JB, Francois F, Poumian-Ruiz E, Glandt M, [8] Ellis CN, Krueger GG, Alefacept Clinical Study Group. Treatment of Bluestone JA. Activation of human T cells by FcR nonbinding anti- chronic plaque psoriasis by selective targeting of memory effector T lym- CD3 mAb, hOKT3gamma1(Ala-Ala). J Clin Invest 2003;111:409e18.
phocytes. N Engl J Med 2001;345:248e55.
[28] Utset TO, Auger JA, Peace D, Zivin RA, Xu D, Jolliffe L, et al. Modified [9] Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial.
et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis.
[29] Brombacher F, Kastelein RA, Aber G. Novel IL-12 family members shed [10] Menssen A, Trommler P, Vollmer S, Schendel D, Albert E, Gu¨rtler L, light on the orchestration of Th1 responses. Trends Immunol 2003; et al. Evidence for an antigen-specific cellular immune response in skin lesions of patients with psoriasis vulgaris. J Immunol 1995;155: [30] Kopp T, Lenz P, Bello-Fernandez C, Kastelein RA, Kupper TS, Stingl G.
IL-23 production by cosecretion of endogenous p19 and transgenic p40 [11] Moss P, Charmley P, Mulvihill E, Ziegler S, Raugi GJ, Kern D, et al. The in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous im- repertoire of T cell antigen receptor beta-chain variable regions associat- ed with psoriasis vulgaris. J Invest Dermatol 1997;109:14e9.
[31] Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, [12] Vekony MA, Holder JE, Lee AJ, Horrocks C, Eperon IC, Camp RDR.
et al. Increased expression of interleukin-23 p19 and p40 in lesional skin Selective amplification of T-cell receptor variable region species is de- of patients with psoriasis. J Exp Med 2004;199:125e30.
monstrable but not essential in early lesions of psoriasis vulgaris: analy- [32] Kaufman CL, Aria N, Toichi E, McCormick TS, Cooper KD, sis by anchored polymerase chain reaction and hypervariable region size Gottlieb AB, et al. A phase I study evaluating the safety, pharmacokinet- spectratyping. J Invest Dermatol 1997;109:5e13.
ics, and clinical response of a human IL-12 p40 antibody in subjects with [13] Vollmer S, Menssen A, Prinz JC. Dominant lesional T cell receptor rear- plaque psoriasis. J Invest Dermatol 2004;123:1037e44.
rangements persist in relapsing psoriasis but are absent from nonlesional [33] Scho¨n MP. Animal models of psoriasis - What can we learn from them? skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris. J Invest Dermatol 2001;117:1296e301.
[34] Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, et al.
[14] Prinz JC, Vollmer S, Boehncke WH, Menssen A, Laisney I, Trommler P.
Stat3 links activated keratinocytes and immunocytes required for devel- Selection of conserved TCR VDJ rearrangements in chronic psoriatic opment of psoriasis in a novel transgenic mouse model. Nat Med plaques indicates a common antigen in psoriasis vulgaris. Eur J Immunol [35] Asadullah K, Sterry W, Stephanek K, Jasulatis D, Leupold M, Audring H, [15] Leung DY, Travers JB, Giorno R, Norris DA, Skinner R, Aelion J, et al.
et al. IL-10 is a key cytokine in psoriasis. Proof of principle by IL-10 ther- Evidence for a streptococcal superantigen-driven process in acute guttate apy: a new therapeutic approach. J Clin Invest 1998;101:783e94.
psoriasis. J Clin Invest 1995;96:2106e12.
[36] Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, van Eden W, [16] Chang JC, Smith LR, Froning KJ, Schwabe BJ, Laxer JA, Cralli LL, et al. Interleukin-4 therapy of psoriasis induces Th2 responses and im- et al. CD8C T cells in psoriatic lesions preferentially use T-cell proves human autoimmune disease. Nat Med 2003;9:40e6.
H. Bachelez / Journal of Autoimmunity 25 (2005) 69e73 [37] Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, [39] Helms C, Cao L, Krueger JG, Wijsman EM, Chamian F, Gordon D, Gottlieb AB. Efficacy and safety of infliximab monotherapy for pla- et al. A putative RUNX1 binding site variant between SLC9A3R1 que-type psoriasis: a randomised trial. Lancet 2001;357:1842e7.
and NAT9 is associated with susceptibility to psoriasis. Nat Genet [38] Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J [40] Beutler B. Inferences, questions and possibilities in Toll-like receptor

Source: http://img697.imageshack.us/img697/82/psoriase1.pdf