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.

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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.

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.

ÖSSZEFOGLALÁS Key words: psoriasis -STAT1-non-lesional skinA pikkelysömör egy multifaktoriális, krónikus bôrbe-tegség, amelynek kialakulásában és fenntartásában mind a veleszületett, mind az adaptív immunitás szerepet ját-szik (1). A pikkelysömörös bôrben az epidermális keratinociták túlzott proliferációja és abnormális differenciá-ciója figyelhetô meg, mely megvastagodott epidermiszt, csökkent vagy hiányzó granuláris réteget eredményez. Emellett fokozottan infiltrálódó T-limfociták, neutrofilek és leukociták, emelkedett növekedési faktor, citokin és kemokin kifejezôdés figyelhetô meg pikkelysömörös tü-netes bôrben a celluláris immunrendszer aberráns aktivá-ciójának köszönhetôen (2-4). A makroszkópikusan normális fenotípust mutató, tünetmentes pikkelysömörös bôr -saját és más kutatócsoportok eredményei szerintkülönbözô eltéréseket hordoz magában az egészségeshez képest (5, 6).A kutatások szerint a pikkelysömör patogenezisében kulcsfontosságú szerepet töltenek be a JAK (Janus kináz) -STAT (signal transducer and activator of transcription) jelátviteli útvonalak, amelyek transzkripciós faktorai abnormális expressziót és aktivációt mutatnak, ezzel hozzá-járulnak a pikkelysömör gyulladásos folyamatainak kialakulásához (7,8). A különbözô JAK-ok (JAK1, JAK2, JAK3, Tyk2) eltérô STAT fehérjékkel tudnak kapcsolatba lépni. A STAT család 7 egymással nagyfokú homológiát mutató tagból áll (STAT 1, 2, 3, 4, 5a, 5b és 6), specifikus aktivitást mutatnak, így a funkciójuk széles skálája figyelhetô meg a JAK-STAT jelátviteli útvonalakon keresztül (9, 10). Számos gént képesek aktiválni, míg másokat gá-tolni, ezáltal hatással vannak olyan alapvetô celluláris folyamatokra, mint a sejtproliferáció és -differenciáció, a sejttúlélés, az apoptózis, a migráció és az angiogenezis (9). Aktivációjuk és deaktivációjuk precízen irányított, né-hány óra alatt lezajló folyamat (11).A STAT1 aktiválódása az interferon (IFN) két külön-bözô típusa, az IFNα és az IFNγ által valósul meg, ame-18