Melanocytes: Target Cells of an HLA-C*06:02–Restricted Autoimmune Response in PsoriasisHLA-C*06:02 is the main psoriasis risk allele. By the unbiased analysis of a Vα3S1/Vβ13S1 T-cell receptor from pathogenic psoriatic CD8+ T cells, we had recently proven that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation in psoriasis and identified ADAMTSL5 as a melanocyte autoantigen. We concluded that psoriasis is based on a melanocyte-specific immune response and that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.
Recent Highlights in Psoriasis ResearchThis article highlights recent advances in the immunology, epidemiology, and genetics/genomics of psoriasis. Advances sometimes generate more questions, and this article makes an attempt to point out where controversies might exist in the literature. Many of the articles mentioned were published in the Journal of Investigative Dermatology, but many articles from the broader scientific literature are also cited, to provide context and to add further validity for some of these key findings. Among the themes we explore are the identification of antigens in psoriasis, the co-morbidities of psoriasis, and novel integrative approaches to genome-wide association studies.
CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for PsoriasisMutations in caspase recruitment domain-containing protein 14 (CARD14) have been linked to susceptibility to psoriasis. CARD14 is an intracellular scaffold protein that regulates proinflammatory gene expression. Recent studies have offered novel insights into the mechanisms of CARD14-mediated signaling in keratinocytes and the molecular impact of psoriasis-associated CARD14 mutations. CARD14 forms a signaling complex with BCL10 and the paracaspase MALT1, and this process is enhanced upon pathogenic CARD14 mutation, culminating in the activation of MALT1 protease activity and psoriasis-associated gene expression.
microRNAs in PsoriasisPsoriasis is a chronic inflammatory skin condition resulting from a complex interplay among the immune system, keratinocytes, susceptibility genes, and environmental factors. However, the pathogenesis of psoriasis is not completely elucidated. microRNAs represent a promising class of small, noncoding RNA molecules that function to regulate gene expression. Although microRNA research in psoriasis and dermatology is still relatively new, evidence is rapidly accumulating for the role of microRNAs in the pathogenesis of psoriasis and other chronic inflammatory conditions.
One SNP at a Time: Moving beyond GWAS in PsoriasisAlthough genome-wide association studies have revealed important insights into the global genetic basis of psoriasis, the findings require further investigation. At present, the known genetic risk loci are largely uncharacterized in terms of the variant or gene responsible for the association, the biological pathway involved, and the main cell type driving the pathology. This review primarily focuses on current approaches toward gaining a complete understanding of how these known genetic loci contribute to an increased disease risk in psoriasis.