Molekularni in celični mehanizmi vpleteni v kožno simptomatiko vaskulitisa IgA in sistemske skleroze kot temelj za diagnostiko in zdravljenje

Bajželj, Matija (author), Lakota, Katja (mentor), Hočevar, Alojzija (comentor), Varga, John (comentor)

IgA vaskulitis (IgAV) in sistemska skleroza (SSc) sta sistemski avtoimunski bolezni, ki znatno prizadeneta kožo, vendar se njuna patofiziologija močno razlikuje. Pri IgAV je akutno vnetje kože posledica aktivacije prirojenega imunskega sistema, vendar so nekatere njegove komponente, kot so NK celice, premalo raziskane. Prepoznavanje biooznačevalcev za visceralno prizadetost pri IgAV bi lahko izboljšalo zgodnjo diagnozo in zdravljenje. Nasprotno je za SSc značilna postopna fibroza kože in notranjih organov, kar pomembno vpliva na kakovost življenja bolnikov in njihovo preživetje. Kljub temu ni učinkovitih zdravljenj za zaustavitev fibroze pri SSc, kjer imajo fibroblasti osrednjo vlogo v patološkem procesu. Cilj študije je bil raziskati različne komponente prirojenega imunskega sistema pri IgAV, da bi identificirali nove biomarkerje za podporo pri diagnostiki IgAV in preučiti kordicepin, spojino iz glive Cordyceps militaris, kot potencialno antifibrotično učinkovino pri SSc. Rezultati raziskave so pokazali prisotnost interferonskega podpisa pri bolnikih z IgAV, omejenim na kožo, ter zmanjšano citotoksično in imunomodulatorno funkcijo NK celic pri bolnikih z IgAV s prizadetostjo ledvic. Poleg tega smo na osnovi RNAseq kože bolnikov z IgAV ugotovili spremenjene koncentracije več proteinov, povezanih z odzivom prirojene imunosti, vključno z različnimi adipokini in proteini akutne faze. Večina teh je bila povišana v serumu bolnikov z IgAV in je korelirala z resnostjo bolezni ter prizadetostjo organov. Povišana raven LBP je bila povezana z nefritisom, medtem ko sta bili znižani ravni adiponektina in CXCL10 povezani s prizadetostjo prebavil. Haptoglobin se je izkazal kot nov kazalec visceralne prizadetosti in ponovitve bolezni. Na celičnih kulturah dermalnih fibroblastov smo pokazali, da kordicepin učinkovito zavira s TGF-ß-inducirano diferenciacijo fibroblastov v miofibroblaste, ki je ključni dejavnik pri razvoju fibroze kože. Naša raziskava je izboljšala razumevanje imunskih mehanizmov pri IgAV, predlagala nove biooznačevalce za pomoč pri diagnostiki IgAV in potencialno novo učinkovino za zaviranje fibroze pri SSc.

• Language: Slovenian
• Keywords: IgA vaskulitis pri odraslih, NK-celice, biomarkerji, sistemska skleroza, kordicepin
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2025
• PID: 20.500.12556/RUL-166608
• Publication date in RUL: 18.01.2025

Secondary language

• Language: English
• Title: Molecular and cellular mechanisms implicated in skin manifestations of vasculitis IgA and systemic sclerosis as the basis for diagnostics and treatment

Abstract

IgA vasculitis (IgAV) and systemic sclerosis (SSc) are systemic autoimmune diseases with significant skin involvement but distinct underlying mechanisms. In IgAV, acute skin inflammation is driven by innate immune cells, whereas a progressive skin fibrosis is a hallmark of SSc. In IgAV, research on innate immune cells like natural killer (NK) cells is limited, especially in adults, and biomarkers predicting organ involvement are needed. In contrast, in SSc there are limited treatment options to halt fibrosis, which is driven by fibroblast activation. We explored different components of the innate immune system as biomarkers in adult IgAV and their potential involvement in disease pathogenesis. The research findings suggested a presence of interferon signature in skin-limited IgAV patients and a decrease in NK cell cytotoxic and immunomodulatory function in IgAV patients with nephritis. Furthermore, RNAseq of IgAV patients’ skin suggested deregulation of several proteins linked to the innate immune response, including different adipokines and acute-phase proteins. Most of these were found to be elevated in IgAV patients' serum, correlating with disease severity and organ involvement, thus making them possible biomarkers. Specifically, increased serum LBP was associated with nephritis, while decreased adiponectin and CXCL10 indicated gastrointestinal involvement. Haptoglobin was found to be a novel marker of visceral involvement and relapse in IgAV. In context of SSc fibrosis the thesis explores cordycepin, 3’deoxyadenosin, as a potential antifibrotic treatment for skin involvement. Using cultures of skin fibroblasts we showed that cordycepin effectively suppresses TGF-β-induced myofibroblast differentiation, which is a key driver of skin fibrosis. This finding opens the possibility of developing new antifibrotic therapies, which are currently very limited. This research advances the understanding of immune mechanisms in IgAV, identifies novel biomarkers, and proposes a new therapy for SSc, emphasizing the importance of targeted approaches in treating systemic autoimmune diseases.

• Keywords: IgA vasculitis in adults, NK cells, biomarkers, systemic sclerosis, cordycepin