Molekulaarsed muutused kahe kroonilise dermatoosi – vitiliigo ja psoriaasi – patogeneesis

Väitekirja elektrooniline versioon ei sisalda publikatsiooneVitiliigo on krooniline nahahaigus, mis väljendub valgete laikudena nahal. Vitiliigo mõjutab patsiendi elukvaliteeti, sest avaldub tihti lapse- ja noorukieas ning haiguskolded paigutuvad enamasti avatud kehapiirkondadesse. Puudulikud teadmised vitiliigo tekkemehhanismidest on takistanud tõhusate ravimeetodite väljatöötamist. Psoriaas on sage krooniline põletikuline haigus, mis väljendub punetavate ja ketendavate haiguskolletena nahal, millele võib kaasneda küünte ja liigeste kahjustus. Kuigi bioloogilise ravi kasutuselevõtt on psoriaasi ravitulemusi parandanud, ei toimi see kõigil haigetel võrdväärselt tõhusalt ning senini ei osata ravitulemust ega haiguse kulgu täielikult ette ennustada. Selleks, et hankida uut informatsiooni vitiliigo ja psoriaasi tekkemehhanismide kohta, kaasasime uuringusse 23 vitiliigot ja 43 psoriaasi põdevat patsienti ning 32 tervet vabatahtlikku. Määrasime uuritavate nahast ja verest immuunsüsteemi töös osalevate geenide ja valkude avaldumist. Lisaks uurisime vitiliigoga haigete nahas mikroRNAde avaldumist. MikroRNAd on väikesed, aga võimsad pärilikkusaine osakesed, mis mõjutavad geenide avaldumist ja seoses sellega kaudselt kõiki protsesse organismis. Kui varasemalt arvati, et nii vitiliigo kui ka psoriaas on peamiselt autoimmuunsed haigused, st. et häirunud on eeskätt omandatud immuunsus, siis meie uuringus ilmnes, et häirunud on ka mitmed etapid kaasasündinud immuunsuse töös. See on immuunsüsteemi osa, mis on pidevas valmisolekus, et kaitsta organismi väliskeskkonnast pärinevate ohtude eest. Teiseks leidsime, et vitiliigo korral on nii pigmendi- kui ka naharakkudes aktiveerunud protsess nimega autofaagia, mille käigus õgitakse ära rakkude vigased koostisosad. Kolmandaks tuvastasime, et vitiliigot põdevate patsientide nahas on muutunud paljude mikroRNAde, mis osalevad pigmenditootmises ja põletikuprotsessis, avaldumine. Kui viisime ühe nendest mikroRNAdest pigmendi- ja naharakkude sisse, muutus omakorda paljude põletikus ja pigmenditootmises osalevate geenide avaldumine. Antud uurimistöö tulemused näitavad, et tulevikus on tarvis lisauuringuid selgitamaks kaasasündinud immuunsüsteemi, autofaagia ja mikroRNAde rolli vitiliigo ja psoriaasi kulgu ennustavate markeritena, diagnostiliste markeritena ja ravi märklaudadena.Vitiligo is a chronic skin disease that manifests as white spots on the skin. As the onset of vitiligo is often during childhood or adolescence and white spots mostly locate on visible body parts, vitiligo affects the quality of life. Lack of knowledge about the pathogenesis of vitiligo has impeded the development of effective methods of treatment. Psoriasis is a common chronic inflammatory disease that is characterized by red and scaly patches on the skin and often also by nail changes and joint inflammation. Biological therapy has improved the results of the treatment but the treatment is not always effective and to date we are unable to predict the results and the course of the disease. In order to obtain new information about the mechanisms of these diseases, we involved 23 patients with vitiligo, 43 patients with psoriasis and 32 healthy control individuals in the study. The expression of genes and proteins that participate in the immune system was measured in the skin and blood of the participants. Additionally, the expression of microRNAs was assessed in the skin of vitiligo patients. MicroRNAs are small but powerful parts of genetic information. They have a power to suppress the expression of genes and therefore to influence all the processes in the organism. Vitiligo and psoriasis are generally considered to be autoimmune disorders. It means that adaptive immunity is activated and attacks the body itself. However, we found that innate immunity is disturbed as well. Innate immunity is the part of immune system that normally is in constant state of readiness to attack. Secondly, we revealed that the process called autophagy is activated in the skin cells and pigment cells of vitiligo skin. Autophagy is a mechanism of the cell that removes unnecessary and dysfunctional components. Thirdly, the expression of many microRNAs that regulate immunity and pigmentation was disturbed in the skin of vitiligo patients. When we inserted one of these microRNAs into the skin cells and pigment cells, the expression of many immunity- and pigmentation-related genes changed as a result. The results of this study show that further studies are needed to specify the role of innate immunity components, autophagy and microRNAs as prognostic markers, diagnostic markers and treatment targets of vitiligo and psoriasis.https://www.ester.ee/record=b537478

Mitmepalgeline lame lihhen

Papuloskvamoossed haigused on kroonilised põletikulised nahahaigused, millel on märkimisväärselt halb mõju patsientide heaolule. Seda haiguste rühma eristatakse nahakollete morfoloogilise leiu alusel. Iseloomulikeks tunnusteks on ketendavad paapulid ja naastud. Histopatoloogiliselt on papuloskvamoossetele haigustele iseloomulik põletik ja keratinotsüütide ebanormaalne jagunemine. Nimetatud haiguste rühma peamisteks esindajateks on psoriaas, lame lihhen ja punane karva-kliiketendustõbi. Sageli on nende haiguste eristamine algfaasis keeruline, kuid samas oluline, kuna haigused vajavad erisugust ravi. Seetõttu on tarvidus paremini mõista nimetatud haiguste patogeneesi, misviiks täpsema biomarkeritest lähtuva diagnoosimiseni ja spetsiifilisema ravini. Sellest tulenevalt on artikli fookuseks üks mitmekülgsema avaldumisviisiga papuloskvamoosne haigus lame lihhen

Disease severity, treatment patterns, and quality of life in patients with moderate-to-severe psoriasis routinely managed with systemic treatment: results of the CRYSTAL observational study in Central and Eastern European countries

Psoriasis is a common, life-long skin disease with a significant negative health and societal impact. Data on rates of disease control and treatment strategies are lacking in Central and Eastern European countries. We aimed to describe the real-world disease severity, control, and treatment strategies for psoriasis in patients from Central and Eastern European countries. CRYSTAL (EUPAS36459) was a cross-sectional, retrospective study in adults (18–75 years) from Bulgaria, Estonia, Hungary, Latvia, Lithuania, Romania, and Russia. We enrolled patients with moderate-to-severe psoriasis receiving continuous systemic treatment for ≥24 weeks. We used the Psoriasis Area and Severity Index (PASI) to describe disease severity and the Dermatology Life Quality Index (DLQI) to assess quality of life (QoL) and collected other outcomes [psoriasis work productivity and activity impairment (WPAI-PSO), patient satisfaction] at enrollment. Analyses were descriptive. A total of 690 patients were included in the analyses. Median disease duration was 11.8 years. Current treatment was monotherapy for most patients (95.8%) with either biological (BIO group; 88.4%) or conventional (NON-BIO group; 7.4%) agents. Mean (± standard deviation) absolute PASI scores were 3.5 ± 5.7, 3.1 ± 5.3, and 6.6 ± 7.4 in the overall population, the BIO group, and the NON-BIO group, respectively. Among patients treated with monotherapy, absolute PASI scores ≤1, ≤3, and ≤5 were observed for 44.1%, 72.0%, and 82.6% of BIO patients and 21.6%, 33.3%, and 49.0% of NON-BIO patients. Mean DLQI total score was 3.3 ± 5.1; higher scores were noted for higher absolute PASI. The most impacted WPAI-PSO domain was presenteeism; for all domains, impact increased with increased absolute PASI. A total of 91.8% of BIO patients and 74.5% of NON-BIO patients were satisfied with the current treatment. We observed a better disease control in BIO than NON-BIO patients. However, around half of BIO patients did not reach clear skin status and reported an impact on QoL. An improvement in treatment strategies is still needed in Central and Eastern European countries to optimize outcomes of moderate-to-severe psoriasis

Changes in Lipoprotein Particles in the Blood Serum of Patients with Lichen Planus

Lichen planus is a chronic inflammatory mucocutaneous disease that belongs to the group of papulosquamous skin diseases among diseases like psoriasis, a widely studied disease in dermatology. The aim of the study was to identify the changes between the blood sera of lichen planus patients and healthy controls to widen the knowledge about the metabolomic aspect of lichen planus and gain a better understanding about the pathophysiology of the disease. We used high-throughput nuclear magnetic resonance (NMR) spectroscopy to measure the levels of blood serum metabolites, lipoproteins and lipoprotein particles. Dyslipidemia has relatively recently been shown to be one of the comorbidities of lichen planus, but the changes in the components of lipoproteins have not been described yet. We found statistically significant changes in the concentrations of 16 markers regarding lipoproteins, which included the components of intermediate-density lipoproteins, low-density lipoproteins and large low-density lipoproteins. We propose that the detected changes may increase the risk for specific comorbidities (e.g., dyslipidemia) and resulting cardiovascular diseases, as the turnover and hepatic uptake of the altered/modified lipoprotein particles are disturbed

miR‐10a‐5p is increased in atopic dermatitis and has capacity to inhibit keratinocyte proliferation

BACKGROUND: miR-10a-5p has been shown to regulate cancer cell proliferation and invasiveness and endothelial cell inflammatory responses. The function of miR-10a-5p in the skin has not been previously studied. The aim of the current study was to examine miR-10a-5p expression, regulation, and function in keratinocytes (KCs) in association with atopic dermatitis (AD). METHODS: The expression of miR-10a-5p and its target genes was analyzed using RT-qPCR, mRNA array analysis, in situ hybridization, and immunofluorescence. The transfection of miRNA mimics, cell cycle distribution analysis, and luciferase assays was used to study miR-10a-5p functions in human primary KCs. RESULTS: miR-10a-5p was found to be upregulated in lesional skin from patients with AD and in proliferating KCs. Array and pathway analysis of IL-1β-stimulated KCs revealed that miR-10a-5p inhibited many genes that affect cell cycle progression and only a few inflammation-related genes. Accordingly, fewer cells in S-phase and reduced proliferation were detected as characteristics of miR-10a-5p-transfected KCs. The influence of miR-10a-5p on cell proliferation was also evident in KCs induced by AD-related cytokines, including IL-4, IL-17, and IL-1β, as measured by the capacity to strongly suppress the expression of the proliferation marker Ki-67. Among AD-related putative direct target genes, we verified hyaluronan synthase 3, a damage-associated positive regulator of KC migration and proliferation, as a direct target of miR-10a-5p. CONCLUSIONS: miR-10a-5p inhibits KC proliferation and directly targets hyaluronan synthase 3 and thereby may modulate AD-associated processes in the skin