Update on the Pathophysiology of Psoriasis
Psoriasis is a genetically programmed pathologic interaction among skin cells, immunocytes, and numerous biologic signaling molecules that is triggered by environmental stimuli. The immune response is a cellular one; type 1 (TH1) and type 17 (TH17) T cells are activated by IL-12 and IL-23 secreted by antigen-presenting cells (APCs) in the skin. Through various cytokines, such as tumor necrosis factor (TNF) α, these cells cause a chronic inflammatory state and alter epidermal hyperproliferation, differentiation, apoptosis, and neoangiogenesis that produce the cutaneous findings seen in this disease. The newer biologic therapies target the immunologic signaling pathways and cytokines identified in the pathogenesis of psoriasis and provide notable clinical improvement. Further study in the pathogenesis of psoriasis can help identify targets for future therapies.
Practice Points
- Psoriasis is a systemic inflammatory disease.
- We now have an increased understanding of the specific cytokines involved in the disease.
- Therapies have been developed to target these cytokines.
Genetic Basis of Psoriasis
Psoriasis is a disease of overactive immunity in genetically susceptible individuals. Because patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses, multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide linkage scans have established that PSORS1 is the strongest susceptibility locus demonstrable through family linkage studies; PSORS1 is responsible for up to 50% of the genetic component of psoriasis.61 More recently, HLA-Cw6 has received the most attention as a candidate gene of the PSORS1 susceptibility locus on the MHC class I region on chromosome 6p21.3.62 This gene may function in antigen presentation via MHC class I, which aids in the activation of the overactive T cells characteristic of psoriatic inflammation.
Studies involving the IL-23/TH17 axis have shown genetics to play a role. Individuals may be protected from psoriasis with a nonsynonymous nucleotide substitution in the IL23R gene,47-49 and certain haplotypes of the IL23R gene are associated with the disease47,49 in addition to other autoimmune conditions.
Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21, 3q21, 4q32-35, 16q12, and 17q25. Two regions on chromosome 17q were recently localized via mapping, which demonstrated a 6 megabase pairs separation, thereby indicating independent linkage factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region.63SLC9A3R1 and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell growth. RAPTOR is involved in T-cell function and growth pathways. Using these genes as an example, we can predict that the alterations of regulatory genes, even those yet undetermined, can enhance T-cell proliferation and inflammation manifested in psoriasis.
,Conclusion
Psoriasis is a complex disease whereby multiple exogenous and endogenous stimuli incite already heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular interactions and cytokines originates from developments, some meticulously planned, others serendipitous, in the fields of immunology, cell and molecular biology, and genetics. Such progress has fostered the creation of targeted immune therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the underlying pathophysiology of psoriasis may provide additional targets for therapy.
