The association of HLA-C and ERAP1 polymorphisms in early and late onset psoriasis and psoriatic arthritis patients of Hungary.

INTRODUCTION: Single nucleotide polymorphisms (SNPs) of the HLA-C and ERAP1 genes were recently determined to contribute to psoriasis susceptibility. However, data regarding the association of these genes with specific subgroups of psoriasis are scarce. AIM: To examine the possible association of the HLA-C and ERAP-1 polymorphisms with early and late onset psoriasis and psoriatic arthritis. MATERIAL AND METHODS: Five ERAP1 SNPs and two HLA-C SNPs were genotyped in 105 psoriatic arthritis patients, 214 cutaneous psoriasis patients and 200 healthy individuals. Haplotypes were constructed for three ERAP1 SNPs (rs17482078, rs10050860, rs30187), and interaction between HLA-Cw*0602 and ERAP1 was also analysed. RESULTS: The HLA-Cw*0602 rs10484554 SNP was found to be a strong susceptibility factor for early onset cutaneous psoriasis and early onset psoriatic arthritis. ERAP1 SNPs (rs10050860, rs17482078, rs27525) appear to have a protective function for early onset psoriatic arthritis. The haplotype B was identified as a susceptibility factor for late onset psoriatic arthritis. In HLA-C positive individuals the rs27524 ERAP1 SNP was associated with a significantly increased risk of psoriatic arthritis development, whereas the rs27525 ERAP1 SNP had the opposite effect. CONCLUSIONS: These results suggest that the HLA-C and ERAP1 genes contribute to the pathogenesis of psoriasis and psoriatic arthritis in an age-dependent manner.

Higher levels of autoantibodies targeting mutated citrullinated vimentin in patients with psoriatic arthritis than in patients with psoriasis vulgaris.

Antibodies against citrullinated proteins/peptides (ACPAs), and especially antibodies targeting mutated citrullinated vimentin (anti-MCVs), are novel biomarkers of rheumatoid arthritis (RA). Whereas ACPAs are specific and sensitive markers for RA, there have hardly been any reports relating to ACPAs in psoriatic arthritis (PsA) or in psoriasis without joint symptoms (PsO). The aim of the present study was to investigate the prevalence of anti-MCVs in PsA and PsO. Serum anti-MCV titers were measured in 46 PsA and 42 PsO patients and in 40 healthy controls by means of a commercial enzyme-linked immunosorbent assay. The potential correlations of the serum autoantibody levels with several clinical and laboratory parameters were examined. The anti-MCV levels in the PsA patients were significantly higher than those in the PsO group. Among the clinical variables, the presence of tender knee joints and nail psoriasis was significantly associated with anti-MCV positivity in the PsA patients. Higher anti-MCV titers in the PsO patients were associated with a more severe disease course and with the early onset of psoriatic skin symptoms. Our results suggest that anti-MCVs can be used as novel markers in the diagnosis of PsA and in a subset of PsO patients.

AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production.

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.

Genetic risk and protective factors of TNFSF15 gene variants detected using single nucleotide polymorphisms in Hungarians with psoriasis and psoriatic arthritis.

The aim of this study was to examine the role of single nucleotide polymorphisms (SNPs) and haplotypes of the tumor necrosis factor ligand superfamily member 15 (TNFSF15) gene in Hungarians with psoriasis and psoriatic arthritis. A case-control study was performed, and five TNFSF15 SNPs (rs3810936, rs6478108, rs6478109, rs7848647, rs7869487) were genotyped in 319 patients with psoriasis, 105 of whom also have psoriatic arthritis, and in 200 healthy individuals. Three haplotypes (A, B, C) based on these five SNPs were also analyzed. Our findings suggest that the rs6478109 SNP may be a genetic risk factor in psoriasis (p=0.0046), while haplotype C may be protective (p=0.0250). These results suggest that certain variants of the TNFSF15 gene contribute to the pathogenesis of the immune-mediated, multifactorial skin disease psoriasis, and that this difference is more readily apparent when groups of patients with and without psoriatic arthritis are examined separately.