Psoriasis pathophysiology: Difference between revisions
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==Overview== | ==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).<ref name="pmid24655295">{{cite journal |vauthors=Lowes MA, Suárez-Fariñas M, Krueger JG |title=Immunology of psoriasis |journal=Annu. Rev. Immunol. |volume=32 |issue= |pages=227–55 |year=2014 |pmid=24655295 |pmc=4229247 |doi=10.1146/annurev-immunol-032713-120225 |url=}}</ref> | |||
==Pathophysiology== | ==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 (skin)|epidermis]] and its [[keratinocytes]]. The second hypothesis sees the disease as being an [[immune-mediated disease|immune-mediated disorder]] in which the excessive reproduction of skin cells is secondary to factors produced by the [[immune system]]. [[T cell]]s (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. | 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 (skin)|epidermis]] and its [[keratinocytes]]. The second hypothesis sees the disease as being an [[immune-mediated disease|immune-mediated disorder]] in which the excessive reproduction of skin cells is secondary to factors produced by the [[immune system]]. [[T cell]]s (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.<ref name="pmid23983647">{{cite journal |vauthors=Colombo MD, Cassano N, Bellia G, Vena GA |title=Cyclosporine regimens in plaque psoriasis: an overview with special emphasis on dose, duration, and old and new treatment approaches |journal=ScientificWorldJournal |volume=2013 |issue= |pages=805705 |year=2013 |pmid=23983647 |pmc=3745987 |doi=10.1155/2013/805705 |url=}}</ref> | |||
*Psoriasis can be triggered by many factors, including:<ref name="pmid24655295">{{cite journal |vauthors=Lowes MA, Suárez-Fariñas M, Krueger JG |title=Immunology of psoriasis |journal=Annu. Rev. Immunol. |volume=32 |issue= |pages=227–55 |year=2014 |pmid=24655295 |pmc=4229247 |doi=10.1146/annurev-immunol-032713-120225 |url=}}</ref> | |||
**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.<ref name="pmid26215033">{{cite journal |vauthors=Harden JL, Krueger JG, Bowcock AM |title=The immunogenetics of Psoriasis: A comprehensive review |journal=J. Autoimmun. |volume=64 |issue= |pages=66–73 |year=2015 |pmid=26215033 |pmc=4628849 |doi=10.1016/j.jaut.2015.07.008 |url=}}</ref><ref name="pmid19322214">{{cite journal |vauthors=Di Cesare A, Di Meglio P, Nestle FO |title=The IL-23/Th17 axis in the immunopathogenesis of psoriasis |journal=J. Invest. Dermatol. |volume=129 |issue=6 |pages=1339–50 |year=2009 |pmid=19322214 |doi=10.1038/jid.2009.59 |url=}}</ref><ref name="pmid16380428">{{cite journal |vauthors=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 |title=Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a) |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=52 |pages=19057–62 |year=2005 |pmid=16380428 |pmc=1323218 |doi=10.1073/pnas.0509736102 |url=}}</ref> | |||
*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.<ref name="pmid10225967">{{cite journal |vauthors=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 |title=CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris |journal=J. Clin. Invest. |volume=103 |issue=9 |pages=1243–52 |year=1999 |pmid=10225967 |pmc=408469 |doi=10.1172/JCI5857 |url=}}</ref><ref name="pmid15671179">{{cite journal |vauthors=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 |title=Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=6 |pages=2075–80 |year=2005 |pmid=15671179 |pmc=545584 |doi=10.1073/pnas.0409569102 |url=}}</ref><ref name="pmid17555598">{{cite journal |vauthors=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 |title=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 |journal=J Transl Med |volume=5 |issue= |pages=27 |year=2007 |pmid=17555598 |pmc=1906741 |doi=10.1186/1479-5876-5-27 |url=}}</ref> | |||
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. | |||
<ref name=Zenz>{{cite journal |author=Zenz R, Eferl R, Kenner L, ''et al'' |title=Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins |journal=Nature |volume=437 |issue=7057 |pages=369–75 |year=2005 |pmid=16163348 |doi=10.1038/nature03963}}</ref> [[Animal model]]s, however, reveal only a few aspects resembling human psoriasis. | <ref name=Zenz>{{cite journal |author=Zenz R, Eferl R, Kenner L, ''et al'' |title=Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins |journal=Nature |volume=437 |issue=7057 |pages=369–75 |year=2005 |pmid=16163348 |doi=10.1038/nature03963}}</ref> [[Animal model]]s, however, reveal only a few aspects resembling human psoriasis. | ||
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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]
- 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.[6][7][8]
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. [9] Animal models, however, reveal only a few aspects resembling human psoriasis.
Genetics
Around one-third of people with psoriasis report a family history of the disease, and researchers have identified genetic loci associated with the condition. 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. [10]
References
- ↑ 1.0 1.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.