Stat3 &other target proteins in psoriasis by yousry a mawla

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Stat3 &other target proteins in psoriasis by yousry a mawla

  1. 1. STAT 3 and Other TargetSTAT 3 and Other Target Proteins :New Concepts inProteins :New Concepts in PsoriasisPsoriasis Pathogenesis&TherapyPathogenesis&Therapy M.YOUSRY ABDEL-MAWLA,MDM.YOUSRY ABDEL-MAWLA,MD Zagazig Faculty of Medicine,EgyptZagazig Faculty of Medicine,Egypt..
  2. 2. SignalSignal transducerstransducers andand activatorsactivators ofof transcriptiontranscription)) Stat) FamilyStat) Family StatsStats areare latentlatent inin thethe cytoplasmcytoplasm untiluntil theythey areare activatedactivated byby extracellularextracellular signalingsignaling ligandsligands,, includingincluding cytokinescytokines,, growthgrowth factorsfactors andand hormones.hormones. Binding of these extracellular ligands toBinding of these extracellular ligands to the specific receptors leads to activation ofthe specific receptors leads to activation of variousvarious Tyrosine kinases (TKs).Tyrosine kinases (TKs). They include JAKs, receptor TKs, and non-They include JAKs, receptor TKs, and non- receptor TKs such as Src and ABL, whichreceptor TKs such as Src and ABL, which can directly phosphorylate Stat proteins incan directly phosphorylate Stat proteins in the absence of ligand-induced receptorthe absence of ligand-induced receptor signalingsignaling
  3. 3. Cytokines and growth factors that activate STAT proteins
  4. 4. Structure of STAT3 protein.Structure of STAT3 protein. Similar to other members of the STAT family,Similar to other members of the STAT family, STAT3 is comprised of six domains: N-STAT3 is comprised of six domains: N- terminal domain, coiled-coil domain, DNAterminal domain, coiled-coil domain, DNA binding domain, linker domain, SH2 domainbinding domain, linker domain, SH2 domain and Tran activation domain.and Tran activation domain.
  5. 5. STAT3 ActivationSTAT3 Activation Stat3 is activated by cytokines of the IL-6Stat3 is activated by cytokines of the IL-6 family such as IL-6, IL-11, leukemia inhibitoryfamily such as IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factorfactor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M and cardiotropin I .(CNTF), oncostatin M and cardiotropin I . Stat3 is the major signal transducerStat3 is the major signal transducer downstream of gp130-like receptorsdownstream of gp130-like receptors .. Other extracellular signaling ligands suchOther extracellular signaling ligands such as IL-10 family members, epidermal growthas IL-10 family members, epidermal growth factor (EGF), platelet derived growth factorfactor (EGF), platelet derived growth factor (PDGF), hepa- tocyte growth factor (HGF),(PDGF), hepa- tocyte growth factor (HGF), granulocyte colony- stimulating factor (G-granulocyte colony- stimulating factor (G- CSF) and leptin have also known toCSF) and leptin have also known to activate Stat3.activate Stat3.
  6. 6. Mechanism of Stat3 signalingMechanism of Stat3 signaling Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such asDifferent tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3 through activation of intermediary kineases of the SRC and JAK families. Cytokinesthrough activation of intermediary kineases of the SRC and JAK families. Cytokines such as IL-6 family members bind to gp130, a common receptor subunit, thereby JAKsuch as IL-6 family members bind to gp130, a common receptor subunit, thereby JAK families and subsequent Stat3 are activated. Non-receptor TKs such as SRCfamilies and subsequent Stat3 are activated. Non-receptor TKs such as SRC and ABL can directly phophorylate Stat3 in the absence of ligand-dependentand ABL can directly phophorylate Stat3 in the absence of ligand-dependent receptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins formreceptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins form dimers, enter the nucleus and bind DNA to activate transcription of the target genesdimers, enter the nucleus and bind DNA to activate transcription of the target genes
  7. 7. Regulation of the STAT3 signalRegulation of the STAT3 signal transduction pathwaytransduction pathway Cytokine-binding induces receptor oligomerization thatCytokine-binding induces receptor oligomerization that facilitates cross-phosphorylation and activation of receptor-facilitates cross-phosphorylation and activation of receptor- associated JAK kinases.associated JAK kinases. Recruitment of STAT3 proteins to the activated receptorRecruitment of STAT3 proteins to the activated receptor complex results in their activation, dimerization andcomplex results in their activation, dimerization and translocation into the nucleustranslocation into the nucleus In the nucleus they to induce the expression of cytokine-In the nucleus they to induce the expression of cytokine- responsive genes including, SOCS3 and to a lesser extent,responsive genes including, SOCS3 and to a lesser extent, SOCS1. SOCS proteins inhibit or terminate JAK/STAT signalsSOCS1. SOCS proteins inhibit or terminate JAK/STAT signals by binding to tyrosine-phosphorylated JAKs and/or cytokineby binding to tyrosine-phosphorylated JAKs and/or cytokine receptors and targeting them for degradation.receptors and targeting them for degradation. The STAT3signal can also be attenuated by PIAS3, a member ofThe STAT3signal can also be attenuated by PIAS3, a member of the protein inhibitors of activated STATs (PIAS) family ofthe protein inhibitors of activated STATs (PIAS) family of proteins. PIAS3 binds selectively to activated STAT3 dimersproteins. PIAS3 binds selectively to activated STAT3 dimers and blocks their ability to activate gene transcription.and blocks their ability to activate gene transcription.
  8. 8. Regulation of the STAT3 signalRegulation of the STAT3 signal transduction pathwaytransduction pathway
  9. 9. Regulation of intracellular Stat3Regulation of intracellular Stat3 signallingsignalling..
  10. 10. JAK/Stat pathway activation and inhibition.JAK/Stat pathway activation and inhibition. Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left)Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left) leading to sequential cell response.leading to sequential cell response. The signaling process can be inhibited (right) byThe signaling process can be inhibited (right) by (1)(1) JAK degradation throughJAK degradation through ubiquitin-proteasome system (Ub), (ubiquitin-proteasome system (Ub), (2)2) dephosphorylate in cytoplasmic PTP1Bdephosphorylate in cytoplasmic PTP1B oror (3)(3) nuclear phosphatase (NPTP), or (nuclear phosphatase (NPTP), or (4)4) by blocking theby blocking the StatStat dimer formationdimer formation Deng et al.,Deng et al., Current Cancer Drug TargetsCurrent Cancer Drug Targets, 2007, 7, 2007, 7,, 91-10791-107
  11. 11. Small Molecule Inhibitors of Stat3Small Molecule Inhibitors of Stat3 Signaling PathwaySignaling Pathway Compelling evidence from mechanistic studies with antisense, RNACompelling evidence from mechanistic studies with antisense, RNA interference (RNAi), peptides, and small molecular inhibitors indicateinterference (RNAi), peptides, and small molecular inhibitors indicate that blocking Stat3 signaling can lead to successful suppression ofthat blocking Stat3 signaling can lead to successful suppression of tumor cell growth and apoptosis.tumor cell growth and apoptosis. Thus, Stat3 is an attractive molecular target for the development ofThus, Stat3 is an attractive molecular target for the development of novel therapeutics.novel therapeutics. These small molecular inhibitors, are divided into five classes ofThese small molecular inhibitors, are divided into five classes of compounds.compounds. They includeThey include (1) Natural products and derivatives, such as curcumin,(1) Natural products and derivatives, such as curcumin, resveratrol and others.resveratrol and others. (2) Tyrphostins.(2) Tyrphostins. (3) Patinum-containing complexes.(3) Patinum-containing complexes. (5) Azaspiranes.(5) Azaspiranes. Some compounds may have multiple targets including Stat3 protein.Some compounds may have multiple targets including Stat3 protein. Stat3 targeted small molecules will be beneficial for databaseStat3 targeted small molecules will be beneficial for database development and template design for future drug developmentdevelopment and template design for future drug development (( Deng,Deng, etal.,etal., Current Cancer Drug TargetsCurrent Cancer Drug Targets, 2007, 7, 2007, 7,, 91-10791-107))
  12. 12. Effects of STAT3 Deficiency onEffects of STAT3 Deficiency on Cellular FunctionCellular Function Stuart et al.TStuart et al.The Journal of Immunology,he Journal of Immunology, 2009, 182: 21–282009, 182: 21–28
  13. 13. PsoriasisPsoriasis Psoriasis is a chronic inflammatory skinPsoriasis is a chronic inflammatory skin disease characterized by excessivedisease characterized by excessive proliferation, abnormal differentiation ofproliferation, abnormal differentiation of epidermal keratino- cytes, vascularepidermal keratino- cytes, vascular proliferation, and leukocyte infiltration inproliferation, and leukocyte infiltration in the dermis and epidermis .the dermis and epidermis . It has been considered that psoriasisIt has been considered that psoriasis results from complex, aberrantresults from complex, aberrant relationships between the skin andrelationships between the skin and immune systemimmune system as well as geneticas well as genetic predisposition and environmental factorspredisposition and environmental factors
  14. 14. PsoriasisPsoriasis
  15. 15. Combined data on psoriasis susceptibility loci ND:not determinedND:not determined ((Pietrzak etal Folia Histochem Cytobiol. 2008:46(1): 12 (11-21)
  16. 16. Psoriasis Clinical PresentationPsoriasis Clinical Presentation
  17. 17. Clinical Manifestations ofClinical Manifestations of PsoriasisPsoriasis
  18. 18. Histopathology of PsoriasisHistopathology of Psoriasis Histology of healthy (A) and psoriatic (B) skin. Psoriatic skin shows epidermalHistology of healthy (A) and psoriatic (B) skin. Psoriatic skin shows epidermal acantohosis, elongation of rete ridges (indicated by arrows) with reciprocalacantohosis, elongation of rete ridges (indicated by arrows) with reciprocal elongation of intervening dermal papillae and inflammatory infiltrate (40Xelongation of intervening dermal papillae and inflammatory infiltrate (40X magnificationmagnification).).
  19. 19. Stress Effects & PsoriasisStress Effects & Psoriasis PathogenesisPathogenesis
  20. 20. Shared mechanisms betweenShared mechanisms between psoriasis &cardiovascular systempsoriasis &cardiovascular system In the lymph node, antigen-presenting cells (APCs) activate naive T-cells to increase expression of leukocyte- function-associated antigen-1 (LFA-1). Activated T-cells migrate to blood vessel and adhere to endothelium (and macrophages in case of atherosclerosis). After extravasation mediated by LFA-1 and intercellular adhesion molecule-1 (ICAM-1) or CD2 and LFA-3, they interact with dendritic cells and macrophages and keratinocytes in psoriasis but smooth muscle cells in atherosclerosis. These re-activated T-cells and macrophages secrete chemokines and cytokines that contribute to the inflammatory environment, resulting in the formation of psoriatic plaque or atherosclerotic plaque.
  21. 21. Shared mechanisms betweenShared mechanisms between psoriasis &cardiovascular systempsoriasis &cardiovascular system
  22. 22. Antigen-presenting cells (APCs) activate naive T cells within the lymph node to increase expression of leucocyte-function- associated antigen-1 (LFA-1); 2. Activated T cells migrate to blood vessel. Activated T cells adhere to endothelium;. Activated T cells and macrophages collect on endothelium;. Extravasation occurs mediated by LFA-1 and intercellular adhesion molecule-1 (ICAM-1); 5. Activated T cell interacts with macrophages, dendritic cells and smooth muscle cells ⁄ keratinocytes;. Re-activated T cells and macrophages secrete chemokines and cytokines that contribute to the inflammatory environment, resulting in the formation of (a) psoriatic plaque, or (b) atherosclerotic plaque;. Macrophages are transformed into lipid-laden foam cells by uptake of oxidized LDL; .. Formation of ‘fatty streaks’ in the subendothelium and, eventually, atherosclerotic plaques.
  23. 23. Shared mechanisms betweenShared mechanisms between psoriasis &cardiovascular systempsoriasis &cardiovascular system
  24. 24. Immunopathology of PsoriasisImmunopathology of Psoriasis Psoriasis is initiated and maintained through a multifaceted interplayPsoriasis is initiated and maintained through a multifaceted interplay between keratinocytes, blood vessels, gene expression, and thebetween keratinocytes, blood vessels, gene expression, and the immune system.immune system. The development of psoriatic plaque begins with antigen recognitionThe development of psoriatic plaque begins with antigen recognition and uptake by antigen-presenting cells (APC)and uptake by antigen-presenting cells (APC) In psoriasis the dendritic cells (DC) are the most common type ofIn psoriasis the dendritic cells (DC) are the most common type of antigen-presenting cells.antigen-presenting cells. Antigens are presented on the DC surface usually as MHC class IIAntigens are presented on the DC surface usually as MHC class II molecules, which can be recognized by T cell receptor ofmolecules, which can be recognized by T cell receptor of CD4+ TCD4+ T cells.cells. In addition DCs can present antigens on MHC class I molecules,In addition DCs can present antigens on MHC class I molecules, which lead to the activation ofwhich lead to the activation of CD8+ TCD8+ T cells. DCs also enhance thecells. DCs also enhance the production of adhesion and co-stimulatory molecules to facilitate itsproduction of adhesion and co-stimulatory molecules to facilitate its interaction with T cells (interaction with T cells (Sabat et al. 2007 Exp Dermatol 16:779-Sabat et al. 2007 Exp Dermatol 16:779- 798.798.).).
  25. 25. Immunopathology of PsoriasisImmunopathology of Psoriasis NaiveNaive T (CD4+ )cellsT (CD4+ )cells have to go through maturation in lymphatichave to go through maturation in lymphatic tissues.tissues. CD4+ TCD4+ T cells have a strong affinity to MHC II-peptide complex and theycells have a strong affinity to MHC II-peptide complex and they stick together by forming an immunological synapsis.stick together by forming an immunological synapsis. Interaction between ICAM-1, produced by DCs, and LFA-1, from TInteraction between ICAM-1, produced by DCs, and LFA-1, from T cells, is one of the most important in order to facilitate the DC-T cellcells, is one of the most important in order to facilitate the DC-T cell interaction.interaction. Naive T cellsNaive T cells can mature either tocan mature either to Th1, Th2, Th17Th1, Th2, Th17 or regulatory T cellsor regulatory T cells and subtype is guided by the selection of a soluble mediator presentand subtype is guided by the selection of a soluble mediator present during the activation of naive T cells. After the activation,during the activation of naive T cells. After the activation, T cellsT cells express cutaneous lymphocyte-associated antigen (express cutaneous lymphocyte-associated antigen (CLACLA), which), which directsdirects T cellsT cells to inflamed skin.to inflamed skin. P- and E-selectins expressed by endothelial cells are also importantP- and E-selectins expressed by endothelial cells are also important for T cell skin homing (for T cell skin homing (Sabat et al. 2007 Exp Dermatol 16:779-798.Sabat et al. 2007 Exp Dermatol 16:779-798.).).
  26. 26. Immunopathology of PsoriasisImmunopathology of Psoriasis In inflamed skin,In inflamed skin, T cellsT cells enter the tissue and participate in theenter the tissue and participate in the inflammation reaction.inflammation reaction. Interaction between P- and E- selectins and CLA, as well as otherInteraction between P- and E- selectins and CLA, as well as other selectin ligands, facilitate leukocytes rolling along the blood vesselselectin ligands, facilitate leukocytes rolling along the blood vessel wall as they decrease the rolling velocity.wall as they decrease the rolling velocity. Expressions of P- and E-selectins are upregulated in psoriatic skin,Expressions of P- and E-selectins are upregulated in psoriatic skin, possibly stiffening the inflammation observed in psoriatic plaque.possibly stiffening the inflammation observed in psoriatic plaque. T cellsT cells recognize chemokines secreted by the endothelial cells,recognize chemokines secreted by the endothelial cells, become active and a tight adhesion, facilitated by integrinsbecome active and a tight adhesion, facilitated by integrins produced byproduced by T cellsT cells and their ligands expressed by endothelial cells,and their ligands expressed by endothelial cells, is formed between the cells.is formed between the cells. The most important molecule in skin homing is LFA-1 binding toThe most important molecule in skin homing is LFA-1 binding to ICAM-2. T cells probably enter the endothelial wall through poresICAM-2. T cells probably enter the endothelial wall through pores formed between endothelial cells in an integrin-dependent processformed between endothelial cells in an integrin-dependent process called diapedesiscalled diapedesis ((Sabat et al. 2007 Exp Dermatol 16:779-798.Sabat et al. 2007 Exp Dermatol 16:779-798.).).
  27. 27. Immunopathology of PsoriasisImmunopathology of Psoriasis In the skinIn the skin T cellsT cells are reactivated by different kinds of APCs, whichare reactivated by different kinds of APCs, which also include keratinocytes. Interferon- (IFN-), produced by APCs,also include keratinocytes. Interferon- (IFN-), produced by APCs, has an important role inhas an important role in T cellT cell reactivation and proliferation.reactivation and proliferation. T cellsT cells in psoriatic skin have prolonged and increased IFN-in psoriatic skin have prolonged and increased IFN- response when compared to healthy skin. Interferon- enhances INF-response when compared to healthy skin. Interferon- enhances INF- expression inexpression in T cellsT cells.. Also cytokines produced by APCs, especiallyAlso cytokines produced by APCs, especially IL-23IL-23 andand IL-6IL-6, have, have an important role in reactivation.an important role in reactivation. After reactivationAfter reactivation T cellsT cells express a variety of cytokines.express a variety of cytokines. T cell response leads to the activation of keratinocytes and theT cell response leads to the activation of keratinocytes and the activation is carried out byactivation is carried out by Th17Th17 and different cytokines produced byand different cytokines produced by macrophages, DCs and keratinocytes themselves.macrophages, DCs and keratinocytes themselves. Keratinocyte activation leads to their increased proliferation andKeratinocyte activation leads to their increased proliferation and alterations in the maturation process.alterations in the maturation process. Activated keratinocytes produce a vast variety of mediators, whichActivated keratinocytes produce a vast variety of mediators, which further promote immigration of inflammatory cells and inducefurther promote immigration of inflammatory cells and induce angiogenesis, thus enhancing phenomena relevant for theangiogenesis, thus enhancing phenomena relevant for the pathogenesis of psoriasis (pathogenesis of psoriasis (Sabat et al. 2007 Exp DermatolSabat et al. 2007 Exp Dermatol 16:779-798 &.16:779-798 &. Boehncke et alBoehncke et al JEADV 2010, 24 Suppl. 5, 2–24JEADV 2010, 24 Suppl. 5, 2–24))..
  28. 28. One previous psoriasis model demonstrated that overexpression ofOne previous psoriasis model demonstrated that overexpression of the angiopoietin receptorthe angiopoietin receptor Tie2Tie2 in endothelial cells and keratinocytesin endothelial cells and keratinocytes led to the development of a psoriasiform phenotype.led to the development of a psoriasiform phenotype. Two new mouse models have been engineered wherebyTwo new mouse models have been engineered whereby Tie2Tie2 expression is confined to either endothelial cells or keratinocytes.expression is confined to either endothelial cells or keratinocytes. Both lines of mice have significant increases in dermal vasculature butBoth lines of mice have significant increases in dermal vasculature but only the KC-only the KC-Tie2-Tie2-overexpressing mice developed a cutaneousoverexpressing mice developed a cutaneous psoriasiform phenotype.psoriasiform phenotype. These mice spontaneously developed characteristic hallmarks ofThese mice spontaneously developed characteristic hallmarks of human psoriasis, including extensive acanthosis, increases in dermalhuman psoriasis, including extensive acanthosis, increases in dermal CD4+ T cells, infiltrating epidermal CD8+ T cells, dermal dendritic cellsCD4+ T cells, infiltrating epidermal CD8+ T cells, dermal dendritic cells and macrophages, and increased expression of cytokines andand macrophages, and increased expression of cytokines and chemokines associated with psoriasis, including interferon- , tumorchemokines associated with psoriasis, including interferon- , tumor necrosis factor- , and interleukins 1 , 6, 12, 22, 23, and 17. Host-necrosis factor- , and interleukins 1 , 6, 12, 22, 23, and 17. Host- defense molecules, cathelicidin, β-defensin, and S100A8/A9, were alsodefense molecules, cathelicidin, β-defensin, and S100A8/A9, were also up-regulated in the hyperproliferative skin.up-regulated in the hyperproliferative skin. Therefore, confiningTherefore, confining Tie2Tie2 overexpression solely to keratinocytesoverexpression solely to keratinocytes results in a mouse model that meets the clinical, histological,results in a mouse model that meets the clinical, histological, immunophenotypic, biochemical, and pharmacological criteriaimmunophenotypic, biochemical, and pharmacological criteria required for an animal model of human psoriasis (required for an animal model of human psoriasis (Wolfram et al,Wolfram et al,AmericanAmerican Journal of Pathology.Journal of Pathology. 2009 174:1443-1458 )2009 174:1443-1458 )..
  29. 29. Following a trigger or stimulus, dendritic cells and T cells are activated, leading to the formationFollowing a trigger or stimulus, dendritic cells and T cells are activated, leading to the formation of an ‘immunological synapse’ that enhances theirof an ‘immunological synapse’ that enhances their interactions.interactions. This ‘immunologic synapse’ results in the release of cytokines, chemokines and growthThis ‘immunologic synapse’ results in the release of cytokines, chemokines and growth factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis.factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis. Within the chronic psoriatic plaque, a vicious cycle of continuous T cell and dendritic cellWithin the chronic psoriatic plaque, a vicious cycle of continuous T cell and dendritic cell activation is envisionedactivation is envisioned ((Nickoloff & Nestle :Nickoloff & Nestle : J Clin Invest 2004; 113: 1664–1675.).J Clin Invest 2004; 113: 1664–1675.).
  30. 30. Immunopathology of PsoriasisImmunopathology of Psoriasis((((Nickoloff &Nickoloff & Nestle : J Clin Invest 2004; 113: 1664–1675.).Nestle : J Clin Invest 2004; 113: 1664–1675.).
  31. 31. Plasmacytoid predendritic cells (PDCs) & Psoriasis Pathogenesis Psoriasis is a chronic inflammatory skin disease that results from thePsoriasis is a chronic inflammatory skin disease that results from the complex interplay between T cells, dendritic cells (DCs) andcomplex interplay between T cells, dendritic cells (DCs) and keratinocyteskeratinocytes.. Plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)- –producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN- early during disease formation. In a xenograft model of human psoriasis, blocking IFN- signaling or inhibiting the ability of PDCs to produce IFN- prevented the T cell–dependent development of psoriasis. Furthermore, IFN- reconstitution experiments demonstrated that PDC-derived IFN- is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN- represent potential early targets for the treatment of psoriasis (Nestle, et al 2005 JEM. 202, July 4:135–143).
  32. 32. PDCs are increased in the normal-appearingPDCs are increased in the normal-appearing prepsoriatic skin of psoriasis patientsprepsoriatic skin of psoriasis patients compared with the skin of healthy controls .compared with the skin of healthy controls . This accumulation represents a conditioningThis accumulation represents a conditioning factor for future flares of the disease.factor for future flares of the disease. Through their ability to secrete IFN-Through their ability to secrete IFN- δδ inin response to innate activation signals, PDCsresponse to innate activation signals, PDCs in prepsoriatic skin determine the onset ofin prepsoriatic skin determine the onset of local autoimmune inflammation leading tolocal autoimmune inflammation leading to disease formation.disease formation. Because injury to the skin is a well knownBecause injury to the skin is a well known elicitation factor for psoriasis PDC activationelicitation factor for psoriasis PDC activation may result from the release of skin-derivedmay result from the release of skin-derived products on infectious or mechanical stressproducts on infectious or mechanical stress (Nestle, et al 2005 JEM. 202, July 4:135–143).
  33. 33. In psoriatic skin,potential activation signalsIn psoriatic skin,potential activation signals may include pathogen- or self derivedmay include pathogen- or self derived single-stranded RNA.single-stranded RNA. IFN-IFN-δδ is the molecular mediator of PDCis the molecular mediator of PDC function in eliciting psoriasis.function in eliciting psoriasis. PDC-derived IFN-PDC-derived IFN- δδ may drive themay drive the “quiescent” autoimmune T cells in“quiescent” autoimmune T cells in prepsoriatic skin into activated pathogenicprepsoriatic skin into activated pathogenic effectors through the induction of dendreticeffectors through the induction of dendretic cell activation/maturation(cell activation/maturation(Nestle, et al 2005 JEM. 202, July 4:135–143). ..
  34. 34. The presence of high levels of lesional IFN-The presence of high levels of lesional IFN- δδ mightmight favor cross-presentation of sequestered tissue-favor cross-presentation of sequestered tissue- specific autoantigens by myeloid DCs.specific autoantigens by myeloid DCs. PDC derived IFN-PDC derived IFN- δδ may also enhance the survivalmay also enhance the survival and expansionof T cells through the induction of IL-and expansionof T cells through the induction of IL- 15 or may act directly on T cells by promoting their15 or may act directly on T cells by promoting their expression of T-bet and IL12-R 2 , thus potentiatingexpression of T-bet and IL12-R 2 , thus potentiating the Th1 cell bias of pathogenic T cells in psoriasis..the Th1 cell bias of pathogenic T cells in psoriasis.. (Nestle, et al 2005 JEM. 202, July 4:135–143).
  35. 35. IFN-IFN- δδ is a master cytokine in psoriasis development.is a master cytokine in psoriasis development. Production of IFN-Production of IFN- δδ is a tightly regulated, transient eventis a tightly regulated, transient event occurring early during the development of psoriasis.occurring early during the development of psoriasis. Production of IFN-Production of IFN- δδ in psoriatic skin seems to be confined toin psoriatic skin seems to be confined to dermal PDCs.dermal PDCs. Increasing evidence indicates that IFN-Increasing evidence indicates that IFN- δδ plays a pivotalplays a pivotal role in the pathogenesis of other autoimmune disorders such asrole in the pathogenesis of other autoimmune disorders such as SLE, insulin-dependent diabetes mellitus (IDDM), rheumatoidSLE, insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis and psoriasis.arthritis and psoriasis. As for psoriasis, IFN-As for psoriasis, IFN- δδ treatment for unrelated conditions cantreatment for unrelated conditions can induce or exacerbate these autoimmune diseases.induce or exacerbate these autoimmune diseases. PDCs and PDCderived IFN-PDCs and PDCderived IFN- δδ are being important upstreamare being important upstream initiators of psoriasis developmentinitiators of psoriasis development (Nestle, et al 2005 JEM. 202, July 4:135–143). ..
  36. 36. Dermal Dendritic Cells inDermal Dendritic Cells in PsoriasisPsoriasis Many insults can lead to the activation of dermal dendritic cells, a key initiating step in the development of psoriasis in predisposed individuals. Activated dendritic cells induce the proliferation of autoreactive T cells within the dermis, inducing production of IFN-γ and TNF-α, which in turn induces the production chemotactic cytokines by epidermal cells. These chemotactic agents induce influx of monocytes from the blood, which undergo differentiation into macrophages and myeloid dendritic cells.
  37. 37. PRR: pathogen-recognition receptor
  38. 38. STAT3 & Develoment of Dendritic Cells (DC) STAT3 activation is a checkpoint of Flt3L(fim-like tyrosine kinase-3 ligand)- regulated dendritic cell (DC) development Deletion of STAT3 causes a profound deficency in the DC compartment and abrogates the effect of Flt3L on DC development (Laouar etal Immunity, 19, 903–912, 2003).
  39. 39. Macrophages in PsoriasisMacrophages in Psoriasis The current classification of macrophages into classicallyThe current classification of macrophages into classically activated (M1) and alternatively activated (M2) cells isactivated (M1) and alternatively activated (M2) cells is parallel to the Th1/Th2 paradigm.parallel to the Th1/Th2 paradigm. Classically activated (M1) macrophages are activated byClassically activated (M1) macrophages are activated by IFN-γ,IFN-γ, alone or in concert with microbial products (e.g. LPS) oralone or in concert with microbial products (e.g. LPS) or cytokines (e.g.TNF) and have high capacity to presentcytokines (e.g.TNF) and have high capacity to present antigen.antigen. Alternatively activated (M2) macrophages are inducedAlternatively activated (M2) macrophages are induced by IL-4 and IL-13 and promote Type 2 responses.by IL-4 and IL-13 and promote Type 2 responses. CD163CD163, along with other macrophage markers such as, along with other macrophage markers such as Factor XIIIA (FXIIIA), CD206/macrophage mannoseFactor XIIIA (FXIIIA), CD206/macrophage mannose receptor (MMR), Macrophage Receptor with Collagenousreceptor (MMR), Macrophage Receptor with Collagenous structure (MARCO) and Stabilin-1 are classified asstructure (MARCO) and Stabilin-1 are classified as markers of alternatively activated macrophages.markers of alternatively activated macrophages.
  40. 40. Macrophages in PsoriasisMacrophages in Psoriasis Dermal macrophages are increased inDermal macrophages are increased in psoriasis compared with normal skin and arepsoriasis compared with normal skin and are identified by CD163identified by CD163 .. Macrophages treated with IFN-γ show thatMacrophages treated with IFN-γ show that many of the genes upregulated inmany of the genes upregulated in macrophages are found in psoriasis,macrophages are found in psoriasis, including STAT1, CXCL9, Mx1, and HLA-DR.including STAT1, CXCL9, Mx1, and HLA-DR. CD163+ macrophages produce inflammatoryCD163+ macrophages produce inflammatory molecules IL-23p19 and IL-12/23p40 as wellmolecules IL-23p19 and IL-12/23p40 as well as tumor necrosis factor (TNF) and inducibleas tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS).nitric oxide synthase (iNOS).
  41. 41. Macrophages in PsoriasisMacrophages in Psoriasis CD163CD163 is a superior marker of macrophages, andis a superior marker of macrophages, and identifies a subpopulation of “classically activated”identifies a subpopulation of “classically activated” macrophages in psoriasis.macrophages in psoriasis. Macrophages are likely to contribute to theMacrophages are likely to contribute to the pathogenic inflammation in psoriasis, a prototypicalpathogenic inflammation in psoriasis, a prototypical T helper 1T helper 1 ((Th1Th1) and) and Th17Th17 disease, by releasing keydisease, by releasing key inflammatory productsinflammatory products Dermal macrophages, once activated by T cell or dendritic cell cytokines, they produce large amounts of TNF-α, leading to the skin changes observed in psoriasis. ((Journal of InvestigativeJournal of Investigative DermatologyDermatology 130, 2412-2422 , 2010130, 2412-2422 , 2010).).
  42. 42. Stat 3 &MacrophagesStat 3 &Macrophages Interleukin (IL) 10 is an immunosuppressive cytokineInterleukin (IL) 10 is an immunosuppressive cytokine produced by T cells, B cells, dendritic cells&produced by T cells, B cells, dendritic cells& monocytes/macrophages.monocytes/macrophages. IL-10 acts by binding to the IL-10R1/IL-10R2 receptorIL-10 acts by binding to the IL-10R1/IL-10R2 receptor complex that recruits Jak1 and Tyk2, and these thencomplex that recruits Jak1 and Tyk2, and these then phosphorylate and activate the transcription factorphosphorylate and activate the transcription factor Stat3.Stat3. IL-10 itself may be controlled by Stat3 binding to aIL-10 itself may be controlled by Stat3 binding to a cognate motif in the IL-10 promoter . These studiescognate motif in the IL-10 promoter . These studies in human cells were supported by a report showingin human cells were supported by a report showing the absence of IL-10 production in peritonealthe absence of IL-10 production in peritoneal macrophages from animals that had a macrophage-macrophages from animals that had a macrophage- specific knockout of thespecific knockout of the Stat3Stat3 gene .gene . IL-10 will induce transactivation of the IL-10IL-10 will induce transactivation of the IL-10 promoter via Stat3 in primary human monocyte-promoter via Stat3 in primary human monocyte- derived macrophagesderived macrophages
  43. 43. Stat 3 &MacrophagesStat 3 &Macrophages IL-10 is an important immunosuppressive cytokine that can down-regulate expression of other cytokines and has been shown to down-regulate itself. Treatment of human monocyte-derived macrophages with IL-10 induces IL-10 mRNA in a dose- and time-dependent manner Mutation of Stat 3 motif ablated IL-10 activation Overexpression of a dominant-negative Stat3 protein will prevent IL-10 induction, of IL-10 mRNA. These data show that IL-10 induces IL-10 in monocyte-derived macrophages in an autocrine manner via activation of the transcription factor Stat3. (Staples et al 2007,The Journal of Immunology, 178: 4779–4785.)
  44. 44. Stat 3 &MacrophagesStat 3 &Macrophages In mice, epidermis specific deletion of inhibitor of NF-In mice, epidermis specific deletion of inhibitor of NF-kkB (IB (IkkB)B) kinase 2 (IKK2) results in a skin phenotype that mimics humankinase 2 (IKK2) results in a skin phenotype that mimics human psoriasis in several aspects.psoriasis in several aspects. Like psoriasis, this skin disease shows pronouncedLike psoriasis, this skin disease shows pronounced improvement when mice are treated with a TNF-neutralizingimprovement when mice are treated with a TNF-neutralizing agent.agent. This phenotype does not depend on the presence ofThis phenotype does not depend on the presence of abab TT lymphocytes. Elimination of skin macrophages bylymphocytes. Elimination of skin macrophages by subcutaneous injection of clodronate liposomes wassubcutaneous injection of clodronate liposomes was accompanied by inhibition of granulocyte migration into theaccompanied by inhibition of granulocyte migration into the skin and resulted in a dramatic attenuation of psoriasis-likeskin and resulted in a dramatic attenuation of psoriasis-like skin changes. The hyperproliferative, inflammatory skinskin changes. The hyperproliferative, inflammatory skin disease in K14-Cre-IKK2fl/fl mice was a direct consequence ofdisease in K14-Cre-IKK2fl/fl mice was a direct consequence of the presence of macrophages in the skin, as targeted deletionthe presence of macrophages in the skin, as targeted deletion of CD18, which prevented accumulation of granulocytes butof CD18, which prevented accumulation of granulocytes but not macrophages, did not lead to major changes in thenot macrophages, did not lead to major changes in the phenotypephenotype ((Stratis etal.,Stratis etal., J. Clin. Invest.J. Clin. Invest. 116116:2094–2104 2006).,:2094–2104 2006).,..
  45. 45. Bidirectional flow of ‘information’ and cells in aBidirectional flow of ‘information’ and cells in a mature psoriasis lesionmature psoriasis lesion There is close interdependence of theThere is close interdependence of the epidermis and dermal inflammatory infiltrate,epidermis and dermal inflammatory infiltrate, as well as a balance between the innate andas well as a balance between the innate and acquired immune systems.acquired immune systems. Chemokines produced by keratinocytes inChemokines produced by keratinocytes in the epidermis act on both the innate andthe epidermis act on both the innate and acquired immune systems, stimulating DCs,acquired immune systems, stimulating DCs, neutrophils and other innate mediators asneutrophils and other innate mediators as well as T cells.well as T cells. Keratinocytes also release cytokines andKeratinocytes also release cytokines and growth factors, leading to altered genegrowth factors, leading to altered gene expression and regenerative hyperplasia.expression and regenerative hyperplasia.
  46. 46. Bidirectional flow of ‘information’ and cells in aBidirectional flow of ‘information’ and cells in a mature psoriasis lesionmature psoriasis lesion Immune-system-derived cytokines, in turn,Immune-system-derived cytokines, in turn, act on keratinocytes to either induceact on keratinocytes to either induce inflammatory genes or increase proliferation.inflammatory genes or increase proliferation. Meanwhile, in the lymphoid-like tissue of theMeanwhile, in the lymphoid-like tissue of the psoriatic dermis, molecules of the innate andpsoriatic dermis, molecules of the innate and acquired immune systems also interact.acquired immune systems also interact. The genetic underpinnings of psoriasis areThe genetic underpinnings of psoriasis are known to be complex, with ten or moreknown to be complex, with ten or more susceptibility loci, and these probablysusceptibility loci, and these probably interact with various environmental factorsinteract with various environmental factors that act on the skin and/or immune systemthat act on the skin and/or immune system..
  47. 47. Immunocompetent CellsImmunocompetent Cells Interactions in PsoriasisInteractions in Psoriasis
  48. 48. Keratinocytes cross talks amongKeratinocytes cross talks among immune cellsimmune cells in psoriasisin psoriasis
  49. 49. Cytokines in PsoriasisCytokines in Psoriasis
  50. 50. Psoriasis: Evidence ofPsoriasis: Evidence of T-Cell MediationT-Cell Mediation Early cells in psoriatic lesionsEarly cells in psoriatic lesions Cyclosporine, anti-CD4 monoclonalCyclosporine, anti-CD4 monoclonal antibodies are used as treatmentantibodies are used as treatment Blocking T cell:APC 2nd signalBlocking T cell:APC 2nd signal prevents psoriatic lesionprevents psoriatic lesion Psoriasis altered in HIV infectionPsoriasis altered in HIV infection Streptococcal superantigens canStreptococcal superantigens can induce psoriasisinduce psoriasis
  51. 51. T-Cell in PsoriasisT-Cell in Psoriasis The pathogenesis of psoriasis is a multistepThe pathogenesis of psoriasis is a multistep process, and an array ofprocess, and an array of cytokinescytokines has anhas an impressive role in these processes .impressive role in these processes . IL-2IL-2 andand IFN-γIFN-γ are two important cytokines,are two important cytokines, which secreted uponwhich secreted upon Th1Th1 activation.activation. These cytokines activate different signalThese cytokines activate different signal transducers and augment transcription of atransducers and augment transcription of a large group of immune related genes andlarge group of immune related genes and may contribute to the overall pathogenicmay contribute to the overall pathogenic process (process (Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91))
  52. 52. T-Cell in PsoriasisT-Cell in Psoriasis TheThe Th1Th1 character of psoriasis is supported by thecharacter of psoriasis is supported by the development of skin lesions in quiescent patients treateddevelopment of skin lesions in quiescent patients treated withwith IL-2IL-2 for cancer therapy.for cancer therapy. Conversely, a therapeutic effect, accompanied by a shiftConversely, a therapeutic effect, accompanied by a shift toward Th2 cytokine expression patterns, is seen intoward Th2 cytokine expression patterns, is seen in psoriasis patients following administration of thepsoriasis patients following administration of the Th2Th2 cytokine,cytokine, IL-10IL-10.. T cellsT cells cloned from psoriatic skin can variously producecloned from psoriatic skin can variously produce IFNIFN-,-, TGFTGF-,-, IL-2IL-2,, IL-3IL-3,, IL-6IL-6,, IL-8IL-8, and, and GM-CSFGM-CSF, although, although none of these are singly responsible fornone of these are singly responsible for T cellT cell stimulationstimulation of keratinocyte growth, which appears to involveof keratinocyte growth, which appears to involve IFNIFN- in- in concert with other cytokines .concert with other cytokines . IL-7IL-7 ,, produced by both T cells & keratinocytes, is alsoproduced by both T cells & keratinocytes, is also present at elevated levels in lesional psoriatic comparedpresent at elevated levels in lesional psoriatic compared with nonlesional and normal skinwith nonlesional and normal skin (( Mollison et alMollison et al Journal of Investigative DermatologyJournal of Investigative Dermatology ,1999, 112: 729–,1999, 112: 729– 738;) .738;) .
  53. 53. Serum cytokine levels of psoriatic patients andSerum cytokine levels of psoriatic patients and controlscontrols ((Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91))
  54. 54. Serum levels of s IL - 2R in patients with psoriasis vulgarisSerum levels of s IL - 2R in patients with psoriasis vulgaris compared to healthy controlscompared to healthy controls ((Halla M. Ragab et alHalla M. Ragab et al J. ofJ. of American Science 2010;6(10):423-429American Science 2010;6(10):423-429))
  55. 55. Serum levels of IL - 6 in patients with psoriasisSerum levels of IL - 6 in patients with psoriasis vulgaris compared to healthy controlsvulgaris compared to healthy controls ((Halla M.Halla M. Ragab et alRagab et al J. of American Science 2010;6(10):423-J. of American Science 2010;6(10):423- 429429))
  56. 56. Serum IL17 & IL22 in psoriasisSerum IL17 & IL22 in psoriasis Inas Almakhzangy & A. Gaballa Egyptian Dermatology Online Journal 5 (1): 4, 2009
  57. 57. T Helper 1 versus 2 in psoriasisT Helper 1 versus 2 in psoriasis Psoriasis is an inflammatory skin disorder characterized by increasedPsoriasis is an inflammatory skin disorder characterized by increased activation of CD4+ T lymphocytes, and systemic and localactivation of CD4+ T lymphocytes, and systemic and local overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-overexpression of pro-inflammatory cytokines such as interleukin 2 (IL- 2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha,2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha, indicating that immunopathogenesis of the disease is T helper 1 (Th1)indicating that immunopathogenesis of the disease is T helper 1 (Th1) mediated.mediated. T helper cell precursors (Thp) can be skewed towards mutuallyT helper cell precursors (Thp) can be skewed towards mutually exclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes onexclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the cytokine environment.the basis of the cytokine environment. Several studies suggest a pivotal role of bacterial superantigens in theSeveral studies suggest a pivotal role of bacterial superantigens in the initiation and/or exacerbation of this illness. In contrast to controls,initiation and/or exacerbation of this illness. In contrast to controls, psoriasis patients in the early course of disease were characterized bypsoriasis patients in the early course of disease were characterized by significantly increased expression of the pro-inflammatory cytokinesignificantly increased expression of the pro-inflammatory cytokine IFN-, whilst a shift towards IL-10 secretion (Th2 response) wasIFN-, whilst a shift towards IL-10 secretion (Th2 response) was observed in those presenting with increased duration of disease.observed in those presenting with increased duration of disease. PDC derived IFN-PDC derived IFN- δδ may also enhance the survival and expansion of Tmay also enhance the survival and expansion of T cells through the induction of IL-15 or may act directly on T cells bycells through the induction of IL-15 or may act directly on T cells by promoting their expression of T-bet and IL12-R 2 , thus potentiatingpromoting their expression of T-bet and IL12-R 2 , thus potentiating the Th1 cell bias of pathogenic T cells in psoriasis..the Th1 cell bias of pathogenic T cells in psoriasis.. These observations suggest a possible shift from a Th1 to a Th2These observations suggest a possible shift from a Th1 to a Th2 cytokine response with superantigen-associated progression for thecytokine response with superantigen-associated progression for the duration of psoriasis, perhaps as an adaptive process by the immuneduration of psoriasis, perhaps as an adaptive process by the immune system in an attempt to downregulate abnormal inflammatory Th1system in an attempt to downregulate abnormal inflammatory Th1 immune responsesimmune responses ((Jain etal 2009 J Med Microbiol 58 :180-184).Jain etal 2009 J Med Microbiol 58 :180-184).
  58. 58. PSORIASIS IS aPSORIASIS IS aTH17TH17 DISEASE :A HypothesisDISEASE :A Hypothesis An initiating event such as trauma or skin surface microbesAn initiating event such as trauma or skin surface microbes triggerstriggers IL-23IL-23 production by keratinocytes and residentproduction by keratinocytes and resident dendritic cells, which in turn stimulates proliferation of CCR4+dendritic cells, which in turn stimulates proliferation of CCR4+ and CCR6+and CCR6+Th17Th17 cells found within skin.cells found within skin. These activatedThese activated Th17Th17 cells secrete Th17 cytokines includingcells secrete Th17 cytokines including IL-IL- 2222 andand IL-17AIL-17A, which cause keratinocyte growth and activation,, which cause keratinocyte growth and activation, respectively.respectively. Th17Th17 cytokines also induce CCL20 production bycytokines also induce CCL20 production by keratinocytes, which fosters additional chemotaxis of CCR6+keratinocytes, which fosters additional chemotaxis of CCR6+ ++Th17Th17 cells and CCR6 dendritic cells from blood into skin.cells and CCR6 dendritic cells from blood into skin. Cytokines released by these newly recruited cells maintainCytokines released by these newly recruited cells maintain psoriaticpsoriatic inflammation (inflammation (Fitch, etal., Current RheumatologyFitch, etal., Current Rheumatology Reports 2007, 9:461–467Reports 2007, 9:461–467))
  59. 59. PSORIASIS IS aPSORIASIS IS aTH17TH17 DISEASE :A HypothesisDISEASE :A Hypothesis CD4+ and CD8+ T-cell clones derived fromCD4+ and CD8+ T-cell clones derived from lesional psoriatic skin in humans expressedlesional psoriatic skin in humans expressed IL-17IL-17, irrespective of their IFN-γ or IL-4, irrespective of their IFN-γ or IL-4 production.production. IL-17IL-17 expression is detectable in biopsiesexpression is detectable in biopsies from lesional psoriatic skin, but not infrom lesional psoriatic skin, but not in nonlesional control biopsiesnonlesional control biopsies Th17Th17 cells are present in the inflammatorycells are present in the inflammatory infiltrate in psoriatic plaques to induceinfiltrate in psoriatic plaques to induce enhancement of neutrophil chemotaxisenhancement of neutrophil chemotaxis
  60. 60. PSORIASIS IS aPSORIASIS IS aTH17TH17 DISEASE :A HypothesisDISEASE :A Hypothesis The expression of IL-23 is highly enhanced inThe expression of IL-23 is highly enhanced in lesional psoriatic skin .lesional psoriatic skin . This IL 23, aThis IL 23, a Th17Th17-inducing factor, is-inducing factor, is produced by keratinocytes, Langerhans cellsproduced by keratinocytes, Langerhans cells and macrophages.and macrophages. The enhanced expression of both IL-23 andThe enhanced expression of both IL-23 and IL-17 within psoriatic lesions indicates thatIL-17 within psoriatic lesions indicates that the IL-23/IL-17 cytokine axis is fullythe IL-23/IL-17 cytokine axis is fully operational in the inflamed skin.operational in the inflamed skin.
  61. 61. PSORIASIS IS aPSORIASIS IS aTH17TH17 DISEASE :A HypothesisDISEASE :A Hypothesis IL-22, which mediates acanthosis, isIL-22, which mediates acanthosis, is preferentially expressed bypreferentially expressed by Th17Th17 cells and,cells and, likelike IL-17IL-17, can be induced by IL-23., can be induced by IL-23. The production ofThe production of IL-17IL-17 and IL-22, however,and IL-22, however, appears to be differentially regulated.appears to be differentially regulated. Whereas IL-6 alone can induce IL-22, but notWhereas IL-6 alone can induce IL-22, but not IL-17IL-17, the additional presence of TGFß dose, the additional presence of TGFß dose dependently inhibits the expression of IL-dependently inhibits the expression of IL- 22, while it promotes IL-17 production22, while it promotes IL-17 production
  62. 62. STAT3 REGULATION of CYTOKINE-STAT3 REGULATION of CYTOKINE- MEDIATED GENERATION of TH 17MEDIATED GENERATION of TH 17 IL-6 functions to up-regulate IL-23R and that IL-23 synergizedIL-6 functions to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi (with IL-6 in promoting THi (TH17TH17)generation.)generation. STAT3, activated by both IL-6 and IL-23, plays a critical role inSTAT3, activated by both IL-6 and IL-23, plays a critical role in THi development.THi development. A hyperactive form of STAT3 promoted THi development,A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired inwhereas this differentiation process was greatly impaired in STAT3-deficient T cells.STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acidMoreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor IL-17 -T (RORt), a THi-specificreceptor-related orphan receptor IL-17 -T (RORt), a THi-specific transcriptional regulator.transcriptional regulator. STAT3 deficiency impaired ROR t expression and led to elevatedSTAT3 deficiency impaired ROR t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkheadexpression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3).box P3 (Foxp3). There is a pathway whereby cytokines regulate THiThere is a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor thatdifferentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression (functions to regulate lineage-specific gene expression (Yang etYang et al.,2007 J.Biol Chem.,282,13:9358al.,2007 J.Biol Chem.,282,13:9358& Egwuagu :Cytokine 47 (2009) 149–156& Egwuagu :Cytokine 47 (2009) 149–156))..
  63. 63. Keratinocytes cross talks withKeratinocytes cross talks with immune cellsimmune cells in psoriasisin psoriasis
  64. 64. Through the production of pro- inflammatory type 1 cytokines (TNF-α, IFN-γ), lymphocyte activation leads to a cascade of recruitment and/or activation of many other cell populations, including alterations of keratinocytic proliferation and differentiation
  65. 65. T HelperT Helper 1717 ActivationActivation Mechanisms in PsoriasisMechanisms in Psoriasis (Fitch, etal., Current Rheumatology Reports 2007, 9:461–(Fitch, etal., Current Rheumatology Reports 2007, 9:461– 467467))
  66. 66. TH17 cells: effector cytokines and their function. Th17 cells characterized by production of IL-17A, IL-17F, IL-22, and IL- 21. Both IL-22 and IL-21 are not the exclusive cytokines produced byTh17 cells. IL-17A and IL-17F mediate tissue damages during organ specific autoimmunity via variety of mechanism including the activation of matrix metalloproteinases and recruitment o f neutrophils. IL-22 induces skin inflammation. IL-21 mediates amplification of T helper 17 pathway.
  67. 67. Proinflammatory Effects ofProinflammatory Effects of IL17IL17
  68. 68. The interleukin (IL)-23/Th17 axis in theThe interleukin (IL)-23/Th17 axis in the immunopathogenesis of psoriasisimmunopathogenesis of psoriasis T helper 17 (Th17) cells interact with skin-resident cells, contributing to the psoriaticT helper 17 (Th17) cells interact with skin-resident cells, contributing to the psoriatic disease phenotype, characterized by scaly plaques and thickened epidermis (acanthosis),disease phenotype, characterized by scaly plaques and thickened epidermis (acanthosis), with elongated rete ridges and hyperproliferative keratinocytes (KCs) retaining the nucleuswith elongated rete ridges and hyperproliferative keratinocytes (KCs) retaining the nucleus in the stratum corneum (parakeratosis), as well as dermal inflammatory cell infiltrate.in the stratum corneum (parakeratosis), as well as dermal inflammatory cell infiltrate. IL-23 secreted by dermal dendritic cells (DCs) is able to induce Th17 cell activation withIL-23 secreted by dermal dendritic cells (DCs) is able to induce Th17 cell activation with production of pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFN-γ.production of pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFN-γ. These cytokines act on KCs, inducing epidermal hyperplasia and KC activation. ActivatedThese cytokines act on KCs, inducing epidermal hyperplasia and KC activation. Activated KCs produce pro-inflammatory mediators, includingKCs produce pro-inflammatory mediators, including chemokines (chemokines (These include aThese include a broad spectrum of related mediators (up to 50 molecules havebroad spectrum of related mediators (up to 50 molecules have been identi®ed),6 known primarily for inducing chemotaxis ofbeen identi®ed),6 known primarily for inducing chemotaxis of various leukocyte subsets. On the basis of the presence orvarious leukocyte subsets. On the basis of the presence or absence of a single amino acid between two cysteine residues,absence of a single amino acid between two cysteine residues, these cytokines have been divided into two major classes,these cytokines have been divided into two major classes, namely C-X-C and C-Cnamely C-X-C and C-C).)., members of the S100 family, pro-inflammatory, members of the S100 family, pro-inflammatory cytokines and antimicrobial peptides. In particular, CCL20 is able to recruit more CCR6+cytokines and antimicrobial peptides. In particular, CCL20 is able to recruit more CCR6+ Th17 cells.Th17 cells. Moreover, KCs might produce IL-23, which could mediate crosstalk with Th17 cells inMoreover, KCs might produce IL-23, which could mediate crosstalk with Th17 cells in synergy with IL-23 produced by dermal DCs, thus further sustaining and amplifying skinsynergy with IL-23 produced by dermal DCs, thus further sustaining and amplifying skin inflammation.inflammation.
  69. 69. Adapted from Iwakura & Ishigame, J Clin Invest 116:1218-1222 (2006) Roles of IL-23 on T Helper 17 cellsRoles of IL-23 on T Helper 17 cells in Chronic Inflammation in Psoriasisin Chronic Inflammation in Psoriasis Dendritic cell Macrophage IL-23 IL-12 Th1 Th17 IFNγ IL-1, IL-6 TNF Inflammatory response Endothelial cells Stromal cells Epithelial cells Fibroblasts Macrophage IL-17, IL-6 IL-1 IL-6 IL-8 TNF IL-12R IL-23R IL-23R
  70. 70. Roles of IL-23 on T Helper 17 cellsRoles of IL-23 on T Helper 17 cells in Chronic Inflammation in Psoriasisin Chronic Inflammation in Psoriasis There is an important role for IL-23-inducedThere is an important role for IL-23-induced Th17Th17 cells and thecells and the Th17Th17-derived cytokines-derived cytokines IL-17IL-17 and IL-22and IL-22 in the immunopathogenetic mechanisms underlyingin the immunopathogenetic mechanisms underlying psoriasis.psoriasis. A clinical improvement in most psoriasis patientsA clinical improvement in most psoriasis patients was observed after therapy with blockingwas observed after therapy with blocking monoclonal antibodies against p40, the sharedmonoclonal antibodies against p40, the shared subunit of the heterodimeric cytokines IL-12 and IL-subunit of the heterodimeric cytokines IL-12 and IL- 23.23. The finding that this treatment causes aThe finding that this treatment causes a downregulation of p40 and IL-23 p19, but not of IL-12downregulation of p40 and IL-23 p19, but not of IL-12 p35 in psoriatic skin lesions suggests thatp35 in psoriatic skin lesions suggests that interference with IL-23 rather than IL-12 activity isinterference with IL-23 rather than IL-12 activity is responsible for this clinical improvementresponsible for this clinical improvement..
  71. 71. Interleukin-23 (IL-23Interleukin-23 (IL-23) helps to maintain the lesion by leading to the) helps to maintain the lesion by leading to the development ofdevelopment of Th17Th17 cells.cells. These in turn produce necrosis factor-alpha (TNF-a), IThese in turn produce necrosis factor-alpha (TNF-a), IL-17L-17 andand IL-22.IL-22. IL-22IL-22 is believed to drive many of the epidermal changes inis believed to drive many of the epidermal changes in psoriasispsoriasis.. Many autoimmune diseases, includingMany autoimmune diseases, including psoriasispsoriasis, are characterized by high, are characterized by high levels oflevels of Th17Th17.. Journal of Investigative Dermatology 2009;129:1339–1350Journal of Investigative Dermatology 2009;129:1339–1350..
  72. 72. Genetic PolymorphismGenetic Polymorphism Certain genetic changes in IL-12/23p40 andCertain genetic changes in IL-12/23p40 and IL-23R will lead to enhanced IL-23 productionIL-23R will lead to enhanced IL-23 production and IL-23 receptor-mediated signaling andand IL-23 receptor-mediated signaling and thus be correlative with psoriasisthus be correlative with psoriasis susceptibility in humans.susceptibility in humans. Certain IL-12/23p40 and IL-23RCertain IL-12/23p40 and IL-23R polymorphisms correlate with certainpolymorphisms correlate with certain disease presentations (e.g., guttate vs.disease presentations (e.g., guttate vs. pustular psoriasis) or with severity ofpustular psoriasis) or with severity of diseasedisease .. ((BlauveltBlauvelt J Invest Dermatol. 2008 ; 128(5):J Invest Dermatol. 2008 ; 128(5): 1064–10671064–1067).).
  73. 73. Schematic of the related heterodimers IL-23 and IL-12 and their relatedSchematic of the related heterodimers IL-23 and IL-12 and their related heterodimeric cytokine receptors, indicating (heterodimeric cytokine receptors, indicating (in red circlesin red circles) the) the subunits where polymorphisms in genes encoding these proteinssubunits where polymorphisms in genes encoding these proteins have been linked to development of psoriasishave been linked to development of psoriasis ((BlauveltBlauvelt J InvestJ Invest Dermatol. 2008 128(5): 1064–1067Dermatol. 2008 128(5): 1064–1067).).
  74. 74. Stat3 links activated keratinocytes andStat3 links activated keratinocytes and immunocytes required for developmentimmunocytes required for development of psoriasisof psoriasis Epidermal keratinocytes in psoriatic lesions are characterizedEpidermal keratinocytes in psoriatic lesions are characterized by activated Stat3.by activated Stat3. Transgenic mice with keratinocytes expressing a constitutivelyTransgenic mice with keratinocytes expressing a constitutively active Stat3 (active Stat3 (K5.Stat3C miceK5.Stat3C mice) develop a skin phenotype either) develop a skin phenotype either spontaneously, or in response to wounding, that closelyspontaneously, or in response to wounding, that closely resembles psoriasis.resembles psoriasis. Keratinocytes fromKeratinocytes from K5.Stat3C miceK5.Stat3C mice show upregulation ofshow upregulation of several molecules linked to the pathogenesis of psoriasis.several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions inIn addition, the development of psoriatic lesions in K5.Stat3CK5.Stat3C mice requires cooperation between Stat3 activation inmice requires cooperation between Stat3 activation in keratinocytes and activated T cells.keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotideFinally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions ininhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice.K5.Stat3C mice. Thus, targeting Stat3Thus, targeting Stat3 may be potentially therapeutic in themay be potentially therapeutic in the treatment of psoriasis.treatment of psoriasis.
  75. 75. Experimental Models ofExperimental Models of PsoriasisPsoriasis An interesting transgenic mouse model for psoriasis is transgenicAn interesting transgenic mouse model for psoriasis is transgenic mouse with constitutively active Stat3 overexpression.mouse with constitutively active Stat3 overexpression. Stat3, participates in cell proliferation, apoptosis, cell differentiationStat3, participates in cell proliferation, apoptosis, cell differentiation and other important biological functionsand other important biological functions In addition, its expression is elevated in psoriasis and in lesionalIn addition, its expression is elevated in psoriasis and in lesional keratinocytes, particularly in the nuclei of keratinocytes .keratinocytes, particularly in the nuclei of keratinocytes . Stat3 is activated by many different cytokines, including membersStat3 is activated by many different cytokines, including members of IL-20 subfamily cytokines, namely IL-19, IL-20, IL-22 and IL-24,of IL-20 subfamily cytokines, namely IL-19, IL-20, IL-22 and IL-24, which are all upregulated in psoriatic skin .which are all upregulated in psoriatic skin . Of these, IL-22 is produced by Th17 lymphocytes, in contrast toOf these, IL-22 is produced by Th17 lymphocytes, in contrast to the other related cytokines, and its production is induced by IL-23.the other related cytokines, and its production is induced by IL-23. Overexpression of IL-23 is profound in lesional psoriatic skin andOverexpression of IL-23 is profound in lesional psoriatic skin and Stat3 activation via IL-22 seems to be important in the IL-23-inducedStat3 activation via IL-22 seems to be important in the IL-23-induced epidermal acanthosis relevant in the pathogenesis of psoriasisepidermal acanthosis relevant in the pathogenesis of psoriasis ((Zhang et al 2007 J Invest Dermatol, 27:2544-2551 andZhang et al 2007 J Invest Dermatol, 27:2544-2551 and DANILENKO,2008 Vet Pathol 45:563–575)
  76. 76. Experimental Models ofExperimental Models of PsoriasisPsoriasis The scientists transplanted skin from their STAT3 miceThe scientists transplanted skin from their STAT3 mice to a mouse that produces no T cells, a key component ofto a mouse that produces no T cells, a key component of the immune system that is believed to be necessary forthe immune system that is believed to be necessary for development of psoriasis.development of psoriasis. The transplanted skin did not initially develop psoriasisThe transplanted skin did not initially develop psoriasis lesions.lesions. However, when the scientists injected activated T cellsHowever, when the scientists injected activated T cells into the skin grafts on T cell-free mice, the mice theninto the skin grafts on T cell-free mice, the mice then developed psoriasis following mild injury.developed psoriasis following mild injury. "This experiment showed it is necessary to have both"This experiment showed it is necessary to have both activated STAT3 in keratinocytes and infiltrating,activated STAT3 in keratinocytes and infiltrating, activated T cells to develop psoriasis. "activated T cells to develop psoriasis. "Neither isNeither is sufficient alone."sufficient alone." ((DiGiovanni’s et alDiGiovanni’s et al, the Journal Nature, the Journal Nature Medicine ,Jan.2005Medicine ,Jan.2005))
  77. 77. Experimental Models ofExperimental Models of PsoriasisPsoriasis Constitutive activation of Stat3Constitutive activation of Stat3 micemice ((K5.Stat3C miceK5.Stat3C mice)) increased theincreased the sensitivity of the epidermis tosensitivity of the epidermis to external stimuli, leading to aexternal stimuli, leading to a psoriatic phenotype, similar topsoriatic phenotype, similar to the clinical Koebnerthe clinical Koebner phenomenon(phenomenon(SanoSano etal., Journal ofetal., Journal of Dermatological Science (2008) 50, 1—14Dermatological Science (2008) 50, 1—14))..
  78. 78. Up-regulated molecules in keratinocytes ofUp-regulated molecules in keratinocytes of K5.Stat3CK5.Stat3C micemice (Sano(Sano etal., Journal of Dermatological Science (2008) 50, 1—etal., Journal of Dermatological Science (2008) 50, 1— 1414))
  79. 79. Blocking the function ofBlocking the function of STAT3STAT3 using antisense oligo-using antisense oligo- nucleotides inhibited the onset of, and reversed,nucleotides inhibited the onset of, and reversed, established psoriatic lesionsestablished psoriatic lesions.. Further analysis revealed a dual requirement of bothFurther analysis revealed a dual requirement of both activated STAT3 in keratinocytes as well as in T cells,activated STAT3 in keratinocytes as well as in T cells, indicating that the pathogenesis of psoriasis is rooted in aindicating that the pathogenesis of psoriasis is rooted in a co-operative process involving STAT3-regulated genes inco-operative process involving STAT3-regulated genes in both skin cells and the immune system .both skin cells and the immune system . Phosphatyrosyl peptides block STAT3-mediated DNAPhosphatyrosyl peptides block STAT3-mediated DNA binding activity, gene regulation and cell transformation.binding activity, gene regulation and cell transformation. ((VaradwajVaradwaj et al 2010et al 2010 EgyptianEgyptian Dermatology Online Journal 6 (1Dermatology Online Journal 6 (1)) ))
  80. 80. Development of psoriasis following woundDevelopment of psoriasis following wound healinghealing.. ((A)Psoriasis upon burn scar in a 74-year-old woman. (B) EpidermalA)Psoriasis upon burn scar in a 74-year-old woman. (B) Epidermal keratinocytes of psoriatic lesions show activated Stat3. Nuclei of the lesionalkeratinocytes of psoriatic lesions show activated Stat3. Nuclei of the lesional keratinocytes are positive for Stat3, suggesting activated status of Stat3keratinocytes are positive for Stat3, suggesting activated status of Stat3)) SanoSano etal., Journal of Dermatological Science (2008) 50, 1—14etal., Journal of Dermatological Science (2008) 50, 1—14))
  81. 81. Psoriatic lesions of K5.Stat3C micePsoriatic lesions of K5.Stat3C mice ((A)Psoriasis lesions and its histology (H and E staining,A)Psoriasis lesions and its histology (H and E staining, (B).(B). (Sano(Sano etal., Journal of Dermatological Scienceetal., Journal of Dermatological Science (2008) 50, 1—14(2008) 50, 1—14))
  82. 82. A Tender Piece of InformationA Tender Piece of Information
  83. 83. Do Other Therapies Work Within ThisDo Other Therapies Work Within This Framework?Framework? Anti–T-cell agents could affectAnti–T-cell agents could affect Th17Th17 cells as they would other T cells, butcells as they would other T cells, but this needs to be clarifiedthis needs to be clarified Anti-TNFAnti-TNF agents could decreaseagents could decrease activity ofactivity of Th1Th17 cells or work directly7 cells or work directly on keratinocyte responseson keratinocyte responses
  84. 84. Studies on Stat 3 in PsoriasisStudies on Stat 3 in Psoriasis
  85. 85. Stat 3 in PsoriasisStat 3 in Psoriasis
  86. 86. Oxidative stress in the pathogenesis of psoriasis
  87. 87. Nitric oxide(NO) in the skin NO is produced from L-arginine in an enzyme-catalyzed reaction The family of NO synthases (NOS) consists of constitutive enzymes such as the neural and endothelial NOS (nNOS and eNOS, respectively) and the inducible nitric oxide synthase (iNOS). Induction of iNOS expression by inflammatory cytokines and/or bacterial products results in the production of large amounts of NO
  88. 88. Psoriasis &inducible nitric oxidePsoriasis &inducible nitric oxide synthase (iNOS). Psoriasis Human iNOS mRNA and IL-8 mRNA colocalize in thePsoriasis Human iNOS mRNA and IL-8 mRNA colocalize in the epidermal keratinocytes in psoriatic skin lesions.epidermal keratinocytes in psoriatic skin lesions. Human Epidermal keratinocyte express iNOS in skin lesions ofHuman Epidermal keratinocyte express iNOS in skin lesions of psoriasis vulgaris.psoriasis vulgaris. Human Overexpression of iNOS mRNA in psoriatic lesions.Human Overexpression of iNOS mRNA in psoriatic lesions. Human NO release accounts for the reduced incidence ofHuman NO release accounts for the reduced incidence of cutaneous infections in psoriasis.cutaneous infections in psoriasis. Human Tenfold increase of NO production in psoriasis, asHuman Tenfold increase of NO production in psoriasis, as measured on the skin surface.measured on the skin surface. Localization of iNOS expression in psoriasis: papillary dermisLocalization of iNOS expression in psoriasis: papillary dermis and focally in keratinocytes.and focally in keratinocytes. iNOS expression correlates with proliferation andiNOS expression correlates with proliferation and inflammatory infiltratesinflammatory infiltrates ((Vira´etal., Experimental Dermatology 2002: 11: 189–202)
  89. 89. Oxidative stress in the pathogenesis of psoriasis The positive feedback loop involved in psoriatic lesion that’s trengthens the effect of ROS and amplifies the production of proinflammatory cytokines. ROS trigger activation of MAPK/AP-1, NF-κB, and JAK–STAT signaling pathways, which subsequently induce iNOS, resulting in the activation of NF-κB and AP-1, which evoke the expression of the target genes.
  90. 90. ROS-mediated activation of the JAK–STAT signaling pathway ROS activate Jak2, Tyk2, and the MAPK pathway, resulting in the activation of STAT. Activated STAT dimers translocate into the nucleus and bind to specific enhancer elements, leading to downstream gene expression (Zhou et al ,Free Radical Biology & Medicine 47:891, 2009).
  91. 91. The exacerbation of psoriasis by injury, infection, IFN-γ, and bacteria lipopolysaccharide could involve nitric oxide (NO) production. Many antipsoriatic agents, including methotrexate and cyclosporin, inhibit its production.
  92. 92. iNOS, one of thethree isoforms of NOS, is expressed in a wide variety of cell types including keratinocytes. It has been reported that iNOS is overexpressed in psoriatic lesions compared to uninvolved skin. iNOS expression is mediated by the activation of transcriptional factors such as p38 MAPK , NF-κB , and JAK–STAT.
  93. 93. Manipulation of PsorasisManipulation of Psorasis
  94. 94. Psoriasis: New Immunologic Approaches toPsoriasis: New Immunologic Approaches to TreatmentTreatment TNF inhibitionTNF inhibition – Antibodies to TNFAntibodies to TNF – Soluble TNF receptorsSoluble TNF receptors CostimulatoryCostimulatory blockadeblockade Adhesion moleculeAdhesion molecule inhibitioninhibition – LFA-1LFA-1 – CD2CD2 IL-2 activationIL-2 activation blockadeblockade
  95. 95. Therapeutic Targets inTherapeutic Targets in Psoriasis As a T Helper 17Psoriasis As a T Helper 17 Cell-Mediated DiseaseCell-Mediated Disease
  96. 96. Anti TNF approved forAnti TNF approved for psoriasis treatmentpsoriasis treatment JEADV 2010, 24 (Suppl. 5), 2–24JEADV 2010, 24 (Suppl. 5), 2–24
  97. 97. IL-12/IL-23 Inhibitors in PsoriasisIL-12/IL-23 Inhibitors in Psoriasis Kauffman et al., J Invest Dermatol 123: 1037, 2004Kauffman et al., J Invest Dermatol 123: 1037, 2004 Krueger et al.,Krueger et al., N Engl J Med 356: 580, 2007N Engl J Med 356: 580, 2007 Torti et al., J Am Acad Dermatol,Torti et al., J Am Acad Dermatol, 10.1016/j.jaad.2007.07.01610.1016/j.jaad.2007.07.016
  98. 98. Reviewed in Torti et al., J Am Acad Dermatol, 2007 doi: 10.1016/j.jaad.2007.07.016 IL-12/IL-23 as Therapeutic TargetsIL-12/IL-23 as Therapeutic Targets in Psoriasisin Psoriasis Role of IL-12/IL-23 in Mouse ModelsRole of IL-12/IL-23 in Mouse Models Experimental psoriasis is abolished by anti-p40 Ab therapyExperimental psoriasis is abolished by anti-p40 Ab therapy Transgenic overexpression of p40 results in skin inflammationTransgenic overexpression of p40 results in skin inflammation IL-23 injection results in skin inflammationIL-23 injection results in skin inflammation Expression of IL-12/IL-23 in Human PsoriasisExpression of IL-12/IL-23 in Human Psoriasis p40 mRNA and protein are increased in psoriatic lesionsp40 mRNA and protein are increased in psoriatic lesions p19 mRNA and protein are increased in psoriatic lesionsp19 mRNA and protein are increased in psoriatic lesions IL-12 and IL-23 decrease after conventional psoriatic therapyIL-12 and IL-23 decrease after conventional psoriatic therapy A polymorphism in p40 gene is associated with susceptibility to psoriasisA polymorphism in p40 gene is associated with susceptibility to psoriasis Clinical Studies with anti-p40 mAbClinical Studies with anti-p40 mAb
  99. 99. Effect of a single 5 mg/kg doseEffect of a single 5 mg/kg dose of anti-p40 mAb in psoriasisof anti-p40 mAb in psoriasis Kauffman et al., J Invest Dermatol 123: 1037, 2004
  100. 100. Current Rheumatology Reports 2007, 9:461–467
  101. 101. Topical Macrolactam AscomycinTopical Macrolactam Ascomycin Analog(Analog( ABT-281ABT-281) in Psoriasis) in Psoriasis Topical application of 3%Topical application of 3% ABT-281ABT-281 inin acetone/olive oil showed its superioracetone/olive oil showed its superior efficacy, its rapid systemicefficacy, its rapid systemic clearance following uptake into the bloodclearance following uptake into the blood stream .stream . Its ability to inhibit cytokine biosynthesis ofIts ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests thatboth Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value init will have a broad therapeutic value in inflammatory skin diseases, includinginflammatory skin diseases, including psoriasis (psoriasis ( Mollison et alMollison et al Journal ofJournal of Investigative DermatologyInvestigative Dermatology ,1999,,1999,112112, :729–, :729– 738;738;).).
  102. 102. A NEW CONCEPTA NEW CONCEPT Given the side effects and limitations ofGiven the side effects and limitations of current antipsoriatic therapies, includingcurrent antipsoriatic therapies, including blockers TNF-_ for long term diseaseblockers TNF-_ for long term disease control ,new strategies targeting PDCs andcontrol ,new strategies targeting PDCs and PDC-derived IFN-_ should be consideredPDC-derived IFN-_ should be considered both for prevention and early therapeuticboth for prevention and early therapeutic intervention in psoriasis and, potentially,intervention in psoriasis and, potentially, other related autoimmune diseasesother related autoimmune diseases (Nestle, et al 2005 JEM. 202, July 4:135–143).
  103. 103. Future Psoriasis TherapyFuture Psoriasis Therapy ((Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–189)
  104. 104. Future Psoriasis TherapyFuture Psoriasis Therapy ((Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172– 189)
  105. 105. IL-17A blocker & early promiseIL-17A blocker & early promise for psoriasisfor psoriasis Selective inhibition of the proinflammatory cytokineSelective inhibition of the proinflammatory cytokine interleukin-17A using a novel fully humaninterleukin-17A using a novel fully human monoclonal antibody (AIN457) showed considerablemonoclonal antibody (AIN457) showed considerable early promise for treatment of psoriasis .early promise for treatment of psoriasis . Participants were randomized to a singleParticipants were randomized to a single intravenous infusion of AIN457 at 3 mg/kg orintravenous infusion of AIN457 at 3 mg/kg or placebo and then followed for 12 weeks.placebo and then followed for 12 weeks. The mean decrease in PASI score 4 weeks after theThe mean decrease in PASI score 4 weeks after the infusion was 58% in the AIN457-treated patients andinfusion was 58% in the AIN457-treated patients and 4% with placebo4% with placebo ((BB JancinJancin Skin & Allergy NewsSkin & Allergy News,, 20092009 ))
  106. 106. TARGETS inTARGETS in PSORIASIS THERAPYPSORIASIS THERAPY
  107. 107. Message HomeMessage Home
  108. 108. Message HomeMessage Home STAT3STAT3 protein has emerged as an important determinant of whetherprotein has emerged as an important determinant of whether the naïve T cell differentiates into regulatory (the naïve T cell differentiates into regulatory (Treg)Treg) or an inflammatoryor an inflammatory ((Th17)Th17) T cell lineage.T cell lineage. STAT3STAT3 also has potent anti-inflammatory effects and regulates criticalalso has potent anti-inflammatory effects and regulates critical cellular processes such as, cell growth, apoptosis and transcription ofcellular processes such as, cell growth, apoptosis and transcription of inflammatory genes.inflammatory genes. It is necessary to have both activated STAT3 in keratinocytes andIt is necessary to have both activated STAT3 in keratinocytes and infiltrating, activated T cells to develop psoriasis. "infiltrating, activated T cells to develop psoriasis. "Neither is sufficientNeither is sufficient alonealone Dysregulation ofDysregulation of STAT3STAT3 pathway has therefore been implicated in thepathway has therefore been implicated in the development of chronic inflammatory diseases, as well as, a numberdevelopment of chronic inflammatory diseases, as well as, a number of malignant and neurodegenerative diseases.of malignant and neurodegenerative diseases. New insights from animal models of psoriasis as an exemplar ofNew insights from animal models of psoriasis as an exemplar of critical roles thatcritical roles that STAT3STAT3 pathways play in inflammatory diseasespathways play in inflammatory diseases including psoriasis and on how inhibitingincluding psoriasis and on how inhibiting STAT3STAT3 can be exploited tocan be exploited to mitigate pathogenic autoimmunity(mitigate pathogenic autoimmunity(EgwuaguEgwuagu Cytokine 47 (2009) 149–156Cytokine 47 (2009) 149–156))
  109. 109. Message HomeMessage Home Stat3 is Key intracellular signaling moleculeStat3 is Key intracellular signaling molecule important inimportant in Th17Th17 development and mediatesdevelopment and mediates IL-22IL-22–– induced keratinocyte hyperproliferation.induced keratinocyte hyperproliferation. Stat 3 is important for differentiation of dermalStat 3 is important for differentiation of dermal plasmacytoid dendritic cells.plasmacytoid dendritic cells. Blocking of stat3 pathway is good-to-excellentBlocking of stat3 pathway is good-to-excellent (similar to(similar to TNF-aTNF-a inhibitors): major signalinginhibitors): major signaling pathway inhibition may have expected goodpathway inhibition may have expected good clinical results in psoriasis .clinical results in psoriasis .
  110. 110. THANK YOUTHANK YOU

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