The immunogenetics of Psoriasis: A comprehensive review

Abstract

Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.

Keywords: Genetics; Immunology; Innate immunity; Negative regulators; Psoriasis; Th17-axis.

Figure 1. The IL-23 axis genes associationed with psoriasis

IL-12 and IL-23 share both a common subunit (p40), as well as a common chain in their heterodimeric receptor, IL-12RB1. Both cytokines signal though JAK-STAT signaling. However, IL-12 is composed of p35 and p40, whereas IL-23 is composed of p19 and p40. The IL-12 receptor is composed of IL-12RB1 and IL-12R2, whereas the IL-23 receptor is composed of IL-12RB1 and IL-23R. Lastly, IL-12 signaling culminates in activation of STAT4, whereas IL-23 signaling results in activation of STAT3. Components underlined and bolded represent the protein products of genes found to have associations with psoriasis; specific details are provided to the right of the diagram. Although psoriasis was initially considered to be a Th1 mediated disease (and thus would have large contributions of the IL-12 axis), it is now well understood that the disease is mainly mediated through the IL-23 driven Th17 response. In summary, many components of the IL-23 axis have genetic associations with psoriasis, including the IL-23 cytokine itself, the IL-23 receptor, and downstream signaling through the IL-23 receptor.

Figure 2. T-cell polarization genes associated with psoriasis

Massive T-cell infiltration is a hallmark of psoriasis and both CD8+ and CD4+ T-cells have increased prevalence in lesional skin. In response to cytokine signaling during the elicitation of inflammation, T-cells (particularly CD4+T-cells), have the plasticity to acquire unique phenotypes. Many cellular factors play important roles in this phenotype determination. Psoriasis is characterized by a predominantly Th1 and Th17 infiltrate, although the latter is considered to be the key pathogenic response. Many factors which control T-cell polarization and fate have genetic associations with psoriasis. These include both genes associated with Th1 and Th17 phenotypes (RUNX1 and STAT3) and T-reg and Th2 phenotypes (RUNX1, IL4, and IL13). As T-cell polarization is a delicate balance of signals that determine the T-cell’s fate, both gain-of-function (i.e. RUNX1 and STAT3) and loss-of-function mutations (i.e. RUNX1, IL4, and IL13) may both contribute to disease susceptibility.

Figure 3. Multiple genes in the NF-κB pathway are associated with psoriasis

The NF-κB pathway is a critical pathway in elicitation of immune responses. Although psoriasis is considered a disease of an overactive adaptive immune response, as evidenced by the massive infiltration of T-cells and the success of treatment based upon elimination of these pathogenic T-cells, innate pathways may still play a central role in disease. Genetic associations with psoriasis have been found in both components that activate and components that repress the NF-κB pathway. It is likely that gain-of-function mutations in NF-κB activating components (left) and loss-of-function mutations in NF-κB inhibitory components (right) decreased the threshold for immune activation and the subsequent onset of psoriasis. Specific details regarding mutations and the functional consequences are provided near the corresponding gene.