Genetics and Pathogenesis of Psoriasis

Genetics of Psoriasis

Despite the long history of psoriasis and psoriatic arthritis (PsA), until recently, little had been known of their underlying genetics and pathogenesis. Without this knowledge, rational clinical management and drug development for this disease was limited. Thus, prior to undertaking a review of the management of this disease, it is critical to survey what is understood about the mechanisms that govern psoriasis.

The propensity for psoriasis to be more prominent in families has been known for some time. Early studies of the inheritance of psoriasis suggested that the prevalence of psoriasis in individuals with a first-degree relative with psoriasis is about four times that of the general population. Twin studies suggested about a 60% rate of concordance between monozygotic twins compared with 15% in dizygotic twins.

While these data suggest a high level of genetic influence on psoriasis, the correlations are not 100%. Additionally, no single gene has emerged to suggest a simple Mendelian inheritance pattern. Most now assume that the etiology of these diseases, like many others, is multifactorial, and that both complex genetics and environmental factors play a role in their pathogenesis.

More recent studies of psoriasis inheritance have concentrated on a polygenetic approach to disease. With more advanced genetic techniques, multiple gene loci have become associated with the inheritance of psoriasis. The most recent studies have identified about 16 to 23 main candidate genes from the screening of large numbers of patients, with over 60 minor loci identified. More potentially associated genes are likely to be identified in the future. Table 1-1 contains a brief listing of some of the candidate genes for psoriasis. According to genetic theory, the identified loci can explain a significant portion of the inheritance of psoriasis.

The most intriguing genes identified tend to be those consistent with present theories of the immunologic basis of psoriasis. The gene locus with the highest predictive value is PSORS 1, which falls within the major histocompatibility complex I (MHC I) genetic locus. This area of the genome is particularly important in control of the activity of T lymphocytes. Likewise, more recently discovered genetic correlates include variations around the genes for receptors for interleukin (IL)-12 and 23 (IL-12 and IL-23). The activity of these cytokines is thought to be critical in our present understanding of the pathophysiology of psoriasis.

More recently, PSORS 2, the second most clearly related genetic locus has been identified as a protein involved not in the immune response but in keratinocyte growth and maturation. The protein identified by this locus, CARD14, is a signaling protein that is expressed in keratinocytes and may serve as a key factor in the role of the local cells of the skin responding to local inflammation and inducing further inflammatory responses. Other candidate genes point to variations in immune function along with potential alterations in keratinocyte function as the factors that impact the likelihood of an individual developing psoriasis.

Enlarge 

Pathogenesis of Psoriasis

For most of its history, psoriasis has been thought of as a disease localized to the skin and primarily being driven by abnormalities in keratinocytes. In fact, evaluation of the clinical presentation of psoriasis and biopsies show a strong correlation with visible changes in keratinocytes. The cardinal clinical signs of psoriasis are scale, plaque elevation and redness. This can be correlated with decreased keratinocyte maturation, increased keratinocyte proliferation, and vascular proliferation and dilatation, respectively. Nowhere in the clinical presentation of psoriasis is there a clinical sign that associates with the inflammatory cells that inhabit biopsies from the psoriatic plaques, including T lymphocytes, monocytes, and dendritic cells. Thus, for many years, these cell types were considered to be bystanders in the pathogenesis of psoriasis.

The concept of the importance of the immune cells being central in inducing the changes in psoriatic keratinocytes came with the advent of new medications that specifically targeted immune pathways and were being used initially in organ transplant rejection treatment. Patients treated for other conditions with medications like cyclosporine, that specifically targeted T cell function, were found to have profound improvements in their psoriasis. Early clinical trials of cyclosporine and other T cell specific therapies lent credence to the idea that treatment of the immune process in psoriasis could be sufficient for improving the clinical manifestations of the disease.

The most recent view of the primary role of the immune activity in the pathogenesis of psoriasis has built on these initial clinical findings. Experiments on mouse models featuring explants of human skin from psoriasis patients demonstrated that the transfer of activated T cells was sufficient for inducing early lesions of psoriasis. Moreover, further animal modeling suggested that most of the components necessary for immune activation of the skin were present in unaffected skin in psoriasis patients. Multiple cytokines were felt to be central to this process including interferon-gamma and tumor necrosis factor (TNF)-alpha. In fact, inhibition of type I T cells, the primary producers of interferon-gamma, and inactivation of TNF-alpha showed efficacy in the treatment of psoriasis. Nonetheless, one critical element of psoriasis pathogenesis was not understood — how the immune processes directly affected the keratinocyte behavior that is representative of the clinical presentation of psoriasis.

The most recent view of the pathogenesis of psoriasis has developed from discoveries that directly connect the immune and keratinocyte findings in psoriasis. An unexpected discovery demonstrated that keratinocytes in psoriasis uniquely express high levels of an activated signal transduction protein called phosphorylated-STAT-3 (PY-STAT3) when compared with other hyperproliferative diseases of the skin. From multiple other conditions, primarily epithelial cancers, it was known that PY-STAT3 was under the control of a number of cytokines that were central to a newly described immunological pathway, the IL-17 pathway. Multiple cytokines were involved in the various arms of this immunologic pathway, important in the skin’s ability to fight off local infections. Many of these cytokines, including IL-17, IL-20, IL-22, and IL-23, were quickly identified as being increased in psoriatic plaques when compared with uninvolved skin.

Additionally, as mentioned above, some of these cytokines were connected to genetic variations that correlated to an increased propensity to develop psoriasis. Importantly, some of these cytokines, specifically IL-17, IL-20 and IL-22, have specific effects on keratinocytes that suggested a direct role of these immune proteins in the alteration of keratinocyte behavior in psoriasis. Finally, mechanisms of certain treatments such as blockade of TNF-alpha and inhibitors of IL-12 and IL-23 have been shown to specifically down regulate the IL-17 pathway.

The most recent model for the pathogenesis of psoriasis comes directly from the findings mentioned above and is represented in Figure 1-2. The sequence of events starts when some type of environmental factor initiates activation of immune cells, primarily dendritic cells or macrophages, which reside in the skin in a genetically susceptible individual. This initiation step could be local skin injury or an infection that causes skin cells to produce early response type cytokines such as interferon-alpha, IL-1, or TNF-alpha. These cytokines, in turn, induce local dendritic cells to produce a critical cytokine, IL-23, which is the primary activator of the IL-17 pathway.

Specific T cells in the skin then produce cytokines such IL-17 and IL-22 that, along with IL-20 produced by dendritic cells, have a direct impact on keratinocytes. Much of the keratinocyte response is mediated by the signaling protein, STAT-3, which is activated in response to these cytokines. Finally, many immune proteins, including IL-17 and chemokines like CCL-20, are produced, causing an upregulation and maintenance of the immune process in the skin. While this model seems complicated, a clear understanding of this sequence of events can be of great help in understanding the therapeutic pathways that are central to treatment of the cutaneous psoriasis.

Enlarge