Psoriasis pathophysiology
|
Psoriasis Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Psoriasis pathophysiology On the Web |
|
American Roentgen Ray Society Images of Psoriasis pathophysiology |
|
Risk calculators and risk factors for Psoriasis pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Psoriasis is an immune-mediated disease with genetic predisposition, but no specific immunogen has been identified. The pathophysiology consists of interactions between cytokines, dendritic cells and T lymphocytes(particularly Th1 and Th17).[1]
Pathophysiology
There are two main hypotheses about the process that occurs in the development of the disease. The first considers psoriasis as primarily a disorder of excessive growth and reproduction of skin cells. The problem is simply seen as a fault of the epidermis and its keratinocytes. The second hypothesis sees the disease as being an immune-mediated disorder in which the excessive reproduction of skin cells is secondary to factors produced by the immune system. T cells (which normally help protect the body against infection) become active, migrate to the dermis and trigger the release of cytokines (tumor necrosis factor-alpha TNFα, in particular) which cause inflammation and the rapid production of skin cells. It is not known what initiates the activation of the T cells.
Immune Model
- The immune-mediated model of psoriasis has been supported by the observation that immunosuppressant medications can resolve psoriasis plaques.[2]
- Psoriasis can be triggered by many factors, including:[1]
- Injury
- Trauma (termed the Koebner effect)
- Infection
- Medications
- Topical biological response modifier imiquimod (a TLR7 agonist)
- TNFα and iNOS producing inflammatory dendritic cells, infiltrate psoriatic skin, and these dendritic cells have the ability to activate T-cells to differentiate into Th1 and Th17 cell lines.[3][4][5][6]
- Macrophages and innate immune cells, and in addition, increased number of endothelial cells (angiogenesis) have also been implicated in the pathogenesis of psoriasis.
- Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce numerous psoriatic cytokines, which include, IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to augment psoriatic inflammation.
- Injury to the skin causes cell death and the production of the AMP LL37 by keratinocytes. DNA/LL37 complexes bind to intracellular Toll-like receptor 9(TLR9) in dendritic cells (DCs), which causes activation and production of type I interferons IFN-α and -β.
- Myeloid DCs can be activated by the LL37/RNA complex as well as by type 1 interferons, leading to T cell proliferation, activation and the production of cytokines found in psoriasis.
- The fact that psoriasis is an immune mediated disease has been solidified by multiple studies, in which various treatments have been use which target and inhibit the proliferation and activation of T cells.[7][8][9]
- Activation and differentiation of T cell subsets are maintained by IL-12 and IL-23, which appear to be produced mainly from myeloid DC subsets in the skin. Psoriasis lesions contain T cells that produce IFN-γ, IL-17, and IL-22, produced by Th1, Th17, and Th22, respectively. There are also CD8+ T cell populations that make the same types of cytokines.
- In response to these cytokines, keratinocytes in the skin upregulate the production of mRNAs, which lead to the formation of many pro-inflammatory products.
- Chemokines produced by keratinocytes lead to migration of many leukocyte subsets, for example, dendritic cells (DCs) and neutrophils.
- Recent data also suggests an important role of the innate immune system in the development of psoriasis.
- Genes in the NF-κB pathway have been known to be associated with psoriasis.[10][11]
- IκB is an inhibitor of the NF-κB pathway. After initiation of NF-κB signaling by cytokines such as TNF-alpha, IκB is phosphorylated by IκB kinase (IKK) and subsequently targeted for proteosomal degradation. The degradation of IκB releases NF-κB for translocation to the nucleus and consequently leading to gene expression for pro-inflammatory products.[12]
However, the role of the immune system is not fully understood, and it has recently been reported that an animal model of psoriasis can be triggered in mice lacking T cells.
[13] Animal models, however, reveal only a few aspects resembling human psoriasis.
Genetics
- The first gene that was discovered to be linked to the development of psoriasis was HLA-Cw6, which is located at PSORS1 at chromosomal position 6p21.3.[14]
- HLA-Cw6 codes for a major histocompatibility complex I (MHCI) allele.
- Presentation of intra-cellular proteins by MHCI leads to activation of cytotoxic T cells (CD8+ T cells) and this T-cell priming plays a key role in the pathogenesis of psoriasis.
- The ERAP1 loci has also been known to be linked tp psoriasis and is found in individuals carrying the HLA-Cw6 mutation.[15]
- MICA (MHC class I polypeptide-related sequence A) is also associated with psoriasis.[16]
- The genes DDX58 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 58), which encodes the protein RIG-I, and IFIH1, which encodes the protein MDA5 have also been implicated in the pathogenesis of psoriasis.
- Activation of RIG-I or MDA5 results in gene expression changes mainly mediated NF-κB pathway.[17]
- Two cytokines known to be significant mediators of psoriasis, TNFα and/or IFNγ, can increase expression of RIG-I and MDA5 expression in keratinocytes.[18]
- Genes such as CARD14 and ZC3H12C, are found to not only potentially alter immune cell or keratinocyte behavior, but also the biology of the vasculature. These mutations might therefore play a part in the cardiovascular comorbidities linked to psoriasis.[19][20]
- Around one-third of people with psoriasis report a family history of the disease. Studies of monozygotic twins suggest a 70% chance of a twin developing psoriasis if the other twin has psoriasis. The concordance is around 20% for dizygotic twins. These findings suggest both a genetic predisposition and an environmental response in developing psoriasis.
[21] ===Gross morphology===[1]
- On gross inspection, psoriatic lesions have characteristic red colored plaques with well-defined borders and silvery-white dry scale, located usually on the extensor surfaces like elbows, knees, and scalp and in the lumbosacral area.
- The amount of surface area of the body affected by psoriasis can be measured roughly as a percentage of body area, using the palm to represent 1% of the body. One third of patients present with atleast 10 percent body involvement and is referred to as moderate to severe psoriasis.
===Microscopic pathology===[1]
- The epidermis is greatly thickened (acanthosis) as the keratinocytes migrate through the epidermis over 4–5 days.
- There is a loss of the normal granular layer of the skin and thickening of the stratum corneum (hyperkeratosis).
- There is retention of nuclei in the upper layers and stratum corneum (parakeratosis).
- Neutrophilic infiltration in the epidermis and stratum corneum (Kogoj pustules and Munro's microabscesses)
- In the dermis, there are abundant mononuclear cells, mainly myeloid cells and T cells.
- The red colored appearence of psoriatic lesions is due to dilated blood vessels.
References
- ↑ 1.0 1.1 1.2 1.3 Lowes MA, Suárez-Fariñas M, Krueger JG (2014). "Immunology of psoriasis". Annu. Rev. Immunol. 32: 227–55. doi:10.1146/annurev-immunol-032713-120225. PMC 4229247. PMID 24655295.
- ↑ Colombo MD, Cassano N, Bellia G, Vena GA (2013). "Cyclosporine regimens in plaque psoriasis: an overview with special emphasis on dose, duration, and old and new treatment approaches". ScientificWorldJournal. 2013: 805705. doi:10.1155/2013/805705. PMC 3745987. PMID 23983647.
- ↑ Nestle FO, Turka LA, Nickoloff BJ (1994). "Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines". J. Clin. Invest. 94 (1): 202–9. doi:10.1172/JCI117308. PMC 296298. PMID 8040262.
- ↑ Harden JL, Krueger JG, Bowcock AM (2015). "The immunogenetics of Psoriasis: A comprehensive review". J. Autoimmun. 64: 66–73. doi:10.1016/j.jaut.2015.07.008. PMC 4628849. PMID 26215033.
- ↑ Di Cesare A, Di Meglio P, Nestle FO (2009). "The IL-23/Th17 axis in the immunopathogenesis of psoriasis". J. Invest. Dermatol. 129 (6): 1339–50. doi:10.1038/jid.2009.59. PMID 19322214.
- ↑ Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin SL, Nussbaum R, Novitskaya I, Carbonaro H, Cardinale I, Kikuchi T, Gilleaudeau P, Sullivan-Whalen M, Wittkowski KM, Papp K, Garovoy M, Dummer W, Steinman RM, Krueger JG (2005). "Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a)". Proc. Natl. Acad. Sci. U.S.A. 102 (52): 19057–62. doi:10.1073/pnas.0509736102. PMC 1323218. PMID 16380428.
- ↑ Abrams JR, Lebwohl MG, Guzzo CA, Jegasothy BV, Goldfarb MT, Goffe BS, Menter A, Lowe NJ, Krueger G, Brown MJ, Weiner RS, Birkhofer MJ, Warner GL, Berry KK, Linsley PS, Krueger JG, Ochs HD, Kelley SL, Kang S (1999). "CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris". J. Clin. Invest. 103 (9): 1243–52. doi:10.1172/JCI5857. PMC 408469. PMID 10225967.
- ↑ Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T, Gilleaudeau P, Sullivan-Whalen M, Cardinale I, Khatcherian A, Novitskaya I, Wittkowski KM, Krueger JG (2005). "Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris". Proc. Natl. Acad. Sci. U.S.A. 102 (6): 2075–80. doi:10.1073/pnas.0409569102. PMC 545584. PMID 15671179.
- ↑ Chamian F, Lin SL, Lee E, Kikuchi T, Gilleaudeau P, Sullivan-Whalen M, Cardinale I, Khatcherian A, Novitskaya I, Wittkowski KM, Krueger JG, Lowes MA (2007). "Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis". J Transl Med. 5: 27. doi:10.1186/1479-5876-5-27. PMC 1906741. PMID 17555598.
- ↑ Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF (2013). "NF-κB: an essential transcription factor in psoriasis". J. Dermatol. Sci. 69 (2): 89–94. doi:10.1016/j.jdermsci.2012.11.002. PMID 23219896.
- ↑ Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, Gottlieb AB (2005). "Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept". J. Invest. Dermatol. 124 (6): 1275–83. doi:10.1111/j.0022-202X.2005.23735.x. PMID 15955104.
- ↑ Perkins ND (2007). "Integrating cell-signalling pathways with NF-kappaB and IKK function". Nat. Rev. Mol. Cell Biol. 8 (1): 49–62. doi:10.1038/nrm2083. PMID 17183360.
- ↑ Zenz R, Eferl R, Kenner L; et al. (2005). "Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins". Nature. 437 (7057): 369–75. doi:10.1038/nature03963. PMID 16163348.
- ↑ Bowcock AM (2005). "The genetics of psoriasis and autoimmunity". Annu Rev Genomics Hum Genet. 6: 93–122. doi:10.1146/annurev.genom.6.080604.162324. PMID 16124855.
- ↑ Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, Barton A, Band G, Bellenguez C, Bergboer JG, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Cork MJ, Corvin A, Deloukas P, Dilthey A, Duncanson A, Edkins S, Estivill X, Fitzgerald O, Freeman C, Giardina E, Gray E, Hofer A, Hüffmeier U, Hunt SE, Irvine AD, Jankowski J, Kirby B, Langford C, Lascorz J, Leman J, Leslie S, Mallbris L, Markus HS, Mathew CG, McLean WH, McManus R, Mössner R, Moutsianas L, Naluai AT, Nestle FO, Novelli G, Onoufriadis A, Palmer CN, Perricone C, Pirinen M, Plomin R, Potter SC, Pujol RM, Rautanen A, Riveira-Munoz E, Ryan AW, Salmhofer W, Samuelsson L, Sawcer SJ, Schalkwijk J, Smith CH, Ståhle M, Su Z, Tazi-Ahnini R, Traupe H, Viswanathan AC, Warren RB, Weger W, Wolk K, Wood N, Worthington J, Young HS, Zeeuwen PL, Hayday A, Burden AD, Griffiths CE, Kere J, Reis A, McVean G, Evans DM, Brown MA, Barker JN, Peltonen L, Donnelly P, Trembath RC (2010). "A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1". Nat. Genet. 42 (11): 985–90. doi:10.1038/ng.694. PMC 3749730. PMID 20953190.
- ↑ Okada Y, Han B, Tsoi LC, Stuart PE, Ellinghaus E, Tejasvi T, Chandran V, Pellett F, Pollock R, Bowcock AM, Krueger GG, Weichenthal M, Voorhees JJ, Rahman P, Gregersen PK, Franke A, Nair RP, Abecasis GR, Gladman DD, Elder JT, de Bakker PI, Raychaudhuri S (2014). "Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes". Am. J. Hum. Genet. 95 (2): 162–72. doi:10.1016/j.ajhg.2014.07.002. PMC 4129407. PMID 25087609.
- ↑ Reikine S, Nguyen JB, Modis Y (2014). "Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5". Front Immunol. 5: 342. doi:10.3389/fimmu.2014.00342. PMC 4107945. PMID 25101084.
- ↑ Kitamura H, Matsuzaki Y, Kimura K, Nakano H, Imaizumi T, Satoh K, Hanada K (2007). "Cytokine modulation of retinoic acid-inducible gene-I (RIG-I) expression in human epidermal keratinocytes". J. Dermatol. Sci. 45 (2): 127–34. doi:10.1016/j.jdermsci.2006.11.003. PMID 17182220.
- ↑ Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, Ryan C, Duan S, Helms CA, Liu Y, Chen Y, McBride AA, Hwu WL, Wu JY, Chen YT, Menter A, Goldbach-Mansky R, Lowes MA, Bowcock AM (2012). "PSORS2 is due to mutations in CARD14". Am. J. Hum. Genet. 90 (5): 784–95. doi:10.1016/j.ajhg.2012.03.012. PMC 3376640. PMID 22521418.
- ↑ Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, Duffin KC, Stuart PE, Goldgar D, Hayashi G, Olfson EH, Feng BJ, Pullinger CR, Kane JP, Wise CA, Goldbach-Mansky R, Lowes MA, Peddle L, Chandran V, Liao W, Rahman P, Krueger GG, Gladman D, Elder JT, Menter A, Bowcock AM (2012). "Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis". Am. J. Hum. Genet. 90 (5): 796–808. doi:10.1016/j.ajhg.2012.03.013. PMC 3376540. PMID 22521419.
- ↑ Krueger G, Ellis CN (2005). "Psoriasis--recent advances in understanding its pathogenesis and treatment". J. Am. Acad. Dermatol. 53 (1 Suppl 1): S94–100. doi:10.1016/j.jaad.2005.04.035. PMID 15968269.