Cause and pathogenesis of Psoriasis

Psoriasis

One to three per cent of most populations have psoriasis, which is most prevalent in European and North American white people, uncommon in American black people and almost non-existent in American Indians. It is a chronic non-infectious inflammatory skin disorder, characterized by well-defined erythematous plaques bearing large adherent silvery scales. It can start at any age but is rare under 10 years, and appears most often between 15 and 40 years. Its course is unpredictable but is usually chronic with exacerbations and remissions.

Cause and pathogenesis

The precise cause of psoriasis is still unknown. However, there is often a genetic predisposition, and sometimes an obvious environmental trigger.

There are two key abnormalities in a psoriatic plaque: hyperproliferation of keratinocytes; and an inflammatory cell infiltrate in which neutrophils and TH-1 type T lymphocytes predominate. Each of these abnormalities can induce the other, leading to a vicious cycle of keratinocyte proliferation and inflammatory reaction; but it is still not clear which is the primary defect. Perhaps the genetic abnormality leads first to keratinocyte hyperproliferation that, in turn, produces a defective skin barrier  allowing the penetration by, or unmasking of, hidden antigens to which an immune response is mounted. Alternatively, the psoriatic plaque might reflect a genetically determined reaction to different types of trauma (e.g. physical wounds, environmental irritants and drugs) in which the healing response is exaggerated and uncontrolled.

To prove the primary role of an immune reaction, putative antigens (e.g. bacteria, viruses or autoantigens) that initiate the immune response will have to be identified. This theory postulates that the increase in keratinocyte proliferation is caused by inflammatory cell mediators or signalling. Theories about the patho-genesis of psoriasis tend to tag along behind fashions in cell biology, and this idea is currently in vogue.

Genetics

A child with one affected parent has a 16% chance of developing the disease, and this rises to 50% if both parents are affected. Genomic imprinting  may explain why psoriatic fathers are more likely to pass on the disease to their children than are psoriatic mothers. If non-psoriatic parents have a child with psoriasis, the risk for subsequent children is about 10%. In one study, the disorder was concordant in 70% of monozygotic twins but in only 20% of dizygotic ones. These figures are useful for counselling but psoriasis does not usually follow a simple Mendelian pattern of inheritance. The mode of inheritance has therefore to be categorized as genetically complex, implying a polygenic inheritance.

Psoriasis is also genetically heterogeneous. Early onset psoriasis shows an obvious hereditary element and linkage analysis  revealed the first psori-asis susceptibility locus (S1), on 6paclose to the major histocompatibility complex Class I (MHC-I) region, but probably not HLA-C itself. The risk of those with the HLA-CW6 genotype developing psoriasis is 20 times that of those without it; 10% of CW6+ individuals will develop psoriasis. Other MHC-I associated diseases include Behçet’s disease, ulcer-ative colitis and anterior uveitis. Interestingly, T-cell mediation is also seen in these diseases. The heredit-ary element and the HLA associations are much weaker in late-onset psoriasis.

In 1994, a second psoriasis susceptibility locus (S2) was discovered on 17q, incidentally next to a Crohn’s disease susceptibility gene. Since then three more susceptibility loci have been confirmed (on 4q, 1q and 3q) and a few more await verification. It is unlikely to be coincidental that two of these loci (6p.21 and 1q.21–23) include genes that encode enzymes involved in cornification.

This large number of genetic linkages suggests that ‘psoriasis’ may in fact be a phenotypic expression of several different genetic aberrations, all characterized by well-defined erythematous and scaly plaques, which are clinically indistinguishable. This idea fits the view that psoriasis is a multifactorial disease with a complex genetic trait, and that an individual’s predisposition to it is determined by a large number of genes, each of which has only a low penetrance. Clinical expression of the disease is brought about by subsequent environ-mental stimuli.

Epidermal cell kinetics

The increased epidermal proliferation of psoriasis is caused by an excessive number of germinative cells entering the cell cycle rather than by a decrease in cell cycle time. The growth fraction  approaches 100%, compared with 30% in normal skin. The epi-dermal turnover time  is greatly shortened, to less than 10 days as compared with 60 days in normal skin. This epidermal hyperproliferation accounts for many of the metabolic abnormalities associated with psoriasis. It is not confined to obvious plaques: similar but less marked changes occur in the apparently normal skin of psoriatics as well.

The exact mechanism underlying this increased epidermal proliferation is uncertain. Cyclic guanosine monophosphate (cGMP), arachidonic acid metabolites, polyamines, calmodulin and plasminogen activator are all increased in psoriatic plaques but theories based on their prime involvement have neither stood the test of time nor provided useful targets for therapeutic intervention. Perhaps the underlying abnormality is a genetic defect in the control of keratinocyte growth. γ-Interferon (IFN-γ) inhibits growth and promotesthe differentiation of normal keratinocytes by the phosphorylation and activation of the transcription factor STAT-1α but IFN-γ fails to activate STAT-1α in psoriatic keratinocytes. These proliferate out of control, rather like a car going too fast because the accelerator is stuck, which cannot be stopped by putting a foot on the brake. Similarly, subnormal activation of another transcription factor, NFκB, may also be important for the formation of psoriatic plaques, as the absence of NFκB activity in gene knock-out mice has been shown to lead to epidermal hyperproliferation.

Others think that psoriasis is caused by a genetic defect of retinoid signalling and that is why it improves with retinoid treatment. In this context, there are two families of retinoid receptors in the epidermis: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Receptor-specific retinoids are now available that bind to RARs, reduce keratinocyte proliferation, normalize differentiation and reduce infiltration by inflammatory cells.

Altered epidermal maturation

During normal keratinization the profile of keratin types in an epidermal cell changes as it moves from the basal layer (K5 and K14) towards the surface. K6 and K16 are produced in psoriasis but their presence is secondary and non-specific, merely a result of increased epidermal proliferation.

Inflammation

Psoriasis differs from the ichthyoses in its accumulation of inflammatory cells, and this could be an immunological response to as yet unknown antigens. Certain interleukins and growth factors are elevated, and adhesion molecules are expressed or up-regulated in the lesions. Immune events may well have a primary role in the pathogenesis of the disease of psoriasis and a hypothetical model might run as follows.

1  Keratinocytes are stimulated by various insults (e.g. trauma, infections, drugs, ultraviolet radiation) to release IL-1, IL-8 and IL-18. 

2 IL-1 up-regulates the expression of intercellularadhesion molecule-1 (ICAM-1) and E selectin on vas-cular endothelium in the dermal papillae. CLA positive memory T lymphocytes accumulate in these papillary vessels because their lymphocyte function-associated antigen (LFA-1) sticks to adhesion molecules that are expressed on the vascular endothelium.

3  IL-8 from keratinocytes attracts T lymphocytes and neutrophils to migrate from papillary vessels into the epidermis where the T cells are held by adhesion of their LFA-1 with ICAM-1 on keratinocytes.

4 T cells accumulating in the epidermis are activatedas a result of their interactions with Langerhans cells (possibly presenting unmasked retroviral or myco-bacterial antigens or antigens shared by streptococci and keratinocytes;) and keratinocytes.

Activated T cells release IL-2, IFN-γ and tumour necrosis factor-α (TNF-α).

5 IL-2 ensures proliferation of the local T cells.

6 IFN-γand TNF-αinduce keratinocytes to expressHLA-DR, to up-regulate their ICAM-1 expression and to produce further IL-6, IL-8 and TGF-α.

7 TGF-αacts as an autocrine mediator and attachesto epidermal growth factor (EGF) receptors inducing keratinocyte proliferation. IL-6 and transforming growth factor-α (TNF-α) also have keratinocyte mito-genic properties.

Bacterial exotoxins produced by Staphylococcusaureus and certain streptococci can act as superantigens and promote marked T-cell proliferation. This appears to be a key mechanism in the pathogenesis of guttate psoriasis.

Cyclosporin  inhibits T-helper cell function and improves psoriasis. This fits in with the idea that psoriasis is a T-cell-driven disease. However, psoriasis is made worse by HIV infection; this paradox is hard to explain as the T-helper lymphocyte is a major target for the HIV retrovirus.

Neutrophils have also attracted attention, and some believe that psoriasis is a neutrophil-driven disease. Circulating neutrophils are activated, particularly in acute flares. They accumulate in the skin after sticking to endothelial cells (ICAM-1–MAC-1 family inter-action). They then migrate through the layers of the epidermis up to the horny layer forming (Munro’s) microabscesses, under the influence of chemotactic

factors produced by activated keratinocytes, including IL-8, Gro-α and leukotriene-B4. Scales of psoriasis also contain chemotactic factors and these provoke visible collections of subcorneal neutrophils as seen in pustular psoriasis.

The dermis

The dermis is abnormal in psoriasis. If psoriatic skin is grafted on to athymic mice, both epidermis and dermis must be present for the graft to sustain its pso-riasis. The dermal capillary loops in psoriatic plaques are abnormally dilated and tortuous, and these changes come before epidermal hyperplasia in the development of a new plaque. Fibroblasts from psoriatics replicate more rapidly in vitro and produce more glycosamino-glycans than do those from non-psoriatics.