Psoriasis pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview[edit | edit source]

Psoriasis is an immune-mediated disease with a genetic predisposition, though no specific immunogen has been implicated in the development of psoriasis. The pathophysiology of psoriasis consists of interactions between cytokines, dendritic cells, and T lymphocytes (particularly Th1 and Th17).^[1] Common triggers of psoriasis include injury to the skin, trauma, infection, and medications. T cells play a key role in the pathogenesis of psoriasis via the production of pro-inflammatory cytokines. Certain genes increase the likelihood of developing psoriasis; 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. Microscopically, skin affected by psoriasis displays parakeratosis, acanthosis, hyperkeratosis, Kogoj pustules, and Munro's microabscesses. The red appearance of psoriatic lesions is due to dilated blood vessels in the skin.

Pathophysiology[edit | edit source]

There are two main hypotheses about the development of psoriasis. The first hypothesis considers psoriasis as primarily a disorder of excessive growth and reproduction of skin cells, in which psoriasis is a manifestation of a fault of the epidermis and its keratinocytes. The second hypothesis views the disease as 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.

Pathogenesis[edit | edit source]

Cutaneous psoriasis[edit | edit source]

The immune-mediated nature of psoriasis has been demonstrated by multiple studies in which various treatments that target and inhibit the proliferation and activation of T cells have been used successfully.^[2][3][4]

Triggers[edit | edit source]

• Psoriasis can be triggered by many factors, including:^[1]
  • Genetic susceptibility
  • Injury
  • Trauma (termed the "Koebner effect")
  • Infection
  • Medications
  • Topical biological response modifier imiquimod (a TLR7 agonist)^[5]

Role of Dendritic Cells[edit | edit source]

• TNFα and nitric oxide synthase isoform (iNOS)-producing inflammatory dendritic cells infiltrate psoriatic skin. These dendritic cells have the ability to activate T-cells to differentiate into Th1 and Th17 cell lines.^[6][7][8][9]
• Macrophages and innate immune cells, as well as an 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 Cathelicidin LL-37 (anti-microbial protein 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.

Role of T Cells[edit | edit source]

• 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 cause the migration of many leukocyte subsets (e.g., dendritic cells (DCs) and neutrophils).
• The innate immune system is also thought to play an important role in the development of psoriasis.

NF-κB Pathway[edit | edit source]

• Genes in the NF-κB pathway are associated with psoriasis.^[10][11]
• IκB is an inhibitor of the NF-κB pathway. After the 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, consequently leading to gene expression for pro-inflammatory products.^[12]

Psoriatic arthritis[edit | edit source]

The pathogenesis of psoriatic arthritis (PsA) involves the following events:^[13]

• In joints there is a prominent lymphocytic infiltrate, limited to the dermal papillae in skin and to the underlying stroma.
• T lymphocytes, particularly CD4 cells, are the most common inflammatory cells in the skin and joints, with a CD4/CD8 ratio of 2:1.
• High levels of tumor necrosis factor alpha (TNF), IL-8, IL-6, IL-1, IL-10, and matrix metalloproteinases are present in the joint fluid of patients with early PsA.
• Collagenase mediated degradation of cartilage collagen begins in early phases of the disease and may be the result of the proteases produced as a result of above mentioned cytokines.

Osteoclast mediated joint destruction[edit | edit source]

• The elevated levels of TNF leads to a high number of osteoclast precursor cells circulating in the blood.
• Osteoclast precursors migrate to the joint where they encounter increased expression of receptor activator of nuclear factor kappa B ligand ( NF-κB), which favors the differentiation and activation of osteoclasts.
• Osteoclasts eventually lead to the joint destruction seen in psoriatic arthritis.

Genetics[edit | edit source]

• 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 intracellular proteins by MHCI leads to the activation of cytotoxic T cells (CD8+ T cells). This T-cell priming plays a key role in the pathogenesis of psoriasis.
• The ERAP1 loci has also been shown to be linked to the development of 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 gene 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.^[17]
• Activation of RIG-I or MDA5 results in gene expression changes mainly mediated by NF-κB pathway.^[18]
• Two cytokines known to be significant mediators of psoriasis, TNFα and/or IFNγ, can increase expression of RIG-I and MDA5 expression in keratinocytes.^[19]
• 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.^[20][21]
• Approximately 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 20% for dizygotic twins. These findings suggest both a genetic predisposition and an environmental component in the development of psoriasis.^[22]

Associated conditions[edit | edit source]

Psoriasis is associated with the following conditions:^{[23][24][25][26][27][28][29][30][31][32][33][34]}

• Depression
• Psoriatic arthritis
• Chronic inflammatory bowel disease
• Non-alcoholic fatty liver disease
• Celiac disease
• Sensorineural hearing loss
• Osteopenia and osteoarthritis
• Diabetes
• Hypertension
• Conjunctivitis
• Uveitis
• Metabolic syndrome
• SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis)
• Alcohol abuse
• Smoking
• Migraine

Gross pathology[edit | edit source]

• On gross inspection, psoriatic lesions have the following characteristics:
  • Red or salmon-colored plaques
  • Well-defined borders
  • Silvery-white dry scale
  • Usually located on the extensor surfaces like elbows, knees, and scalp, and in the lumbosacral area^[1]
• The 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 at least 10 percent body involvement, which is referred to as moderate-to-severe psoriasis.

Microscopic pathology[edit | edit source]

Cutaneous psoriasis[edit | edit source]

• The epidermis is greatly thickened (acanthosis) as the keratinocytes migrate through the epidermis over 4–5 days.^[1]
• There is a loss of the normal granular layer of the skin and a thickening of the stratum corneum (hyperkeratosis).
• There is retention of nuclei in the upper layers and stratum corneum (parakeratosis).^[35]
• There is neutrophilic infiltration in the epidermis and stratum corneum (Kogoj pustules and Munro's microabscesses).^[36]
• In the dermis, there are abundant mononuclear cells (mainly myeloid cells and T cells).
• The red-colored appearance of psoriatic lesions is due to dilated blood vessels.

Psoriatic arthritis[edit | edit source]

• Psoriatic arthritis (PsA) affected synovial tissue is characterized by a T-cell infiltrate with an increase in vascularity.^[37]
• There is a reduction in macrophages compared with the synovial tissue found in rheumatoid arthritis.

References[edit | edit source]

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