Značenje alarmina HMGB1 i S100A12 te njihova receptora RAGE u juvenilnom idiopatskom artritisu [The significance of alarmins HMGB1 and S100A12 and their receptor RAGE in juvenile idiopathic arthritis]

Bobek, Dubravka (2014) Značenje alarmina HMGB1 i S100A12 te njihova receptora RAGE u juvenilnom idiopatskom artritisu [The significance of alarmins HMGB1 and S100A12 and their receptor RAGE in juvenile idiopathic arthritis]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Our understanding of the imunopathogenesis of juvenile idiopathic arthritis (JIA) is still incomplete. The aim of this study was to determine the significance of high mobility group box 1 (HMGB1), calcium-binding protein S100A12 and their soluble receptor for advanced glycation end products (sRAGE) in JIA. We included 102 children with JIA (28 childen with systemic-onset JIA, 39 children with oligoarticular-onset JIA, and 35 children with polyarticular-onset JIA) and 28 children as control group and harvested peripheral blood before any therapy was introduced. The serum levels of the alarmins were determined by ELISA, while gene expression in mononuclears was assessed by quantitative PCR. The level of the HMGB1 protein was significantly higher in the group of children with systemic JIA (sJIA), as compared to the olygoarticular (P < 0,000) or polyarticular (P < 0,002) subtype of JIA and control group (P < 0,032). The children with sJIA had a significant reduction of sRAGE protein in the serum (P < 0.036) and the gene expression (P < 0,007) of sRAGE. Additionally, serum HMGB1 in sJIA children was positively correlated with ESR (r = 0,51; P < 0,001), C-reactive protein (r=0,52; P < 0,000) levels and α2 globulin (r= 0,50; P < 0,001), while sRAGE serum level showed significantly close but inverse relationship with the same proteins of acute phase. These data indicate that HMGB1, a mediator of innate immunity, through interactions with sRAGE contributes to imunopathogenesis of sJIA. Furthermore, HMGB1 may serve as a biomarker for determining disease activity and a potential target of therapy in systemic JIA patients.

Abstract in Croatian

Razumijevanje imunopatogeneze juvenilnog idiopatskog artritisa (JIA) još uvijek je nepotpuno. Cilj ovog rada bio je utvrditi značenje proteina visoke pokretljivosti iz skupine 1 (HMGB1,engl. high mobility group box 1), proteina koji veže kalcij S100A12 (S100A12, engl. calcium-binding protein S100A12) i njihova topljiva receptora za krajnje produkte uznapredovale glikozilacije sRAGE (engl. soluble receptor for advanced glycation end products) u JIA. Uključeno je 102 djece sa JIA i 28 djece kontrolne skupine kojima je izvađena periferna krv prije započetog liječenja. Serumska razina alarmina analizirana je ELISA testom, dok je izražaj gena određen u mononuklearima periferne krvi kvantitativnim PCR-om. U sistemskom tipu JIA (sJIA) utvrđene su značajno više serumske razine HMGB1 u odnosu na oligoartikularni (P < 0,000) i poliartikularni (P < 0,002) tip JIA te kontrolnu skupinu (P < 0,032). Istovremeno, serumska razina (P < 0,036) kao i genski izražaji (P < 0,007) sRAGE bili su statistički značajno niži u sJIA u odnosu na kontrolu. K tome, serumski HMGB1 u sJIA djece bio je statistički značajno povezan s ubrzanom sedimentacijom eritrocita (r = 0,51; P < 0,001), povišenom razinom C-reaktivnog proteina (r=0,52; P < 0,000) i povišenom razinom α2-globulina (r= 0,50; P < 0,001), dok je sRAGE i pokazao značajnu, ali negativnu korelaciju sa istim proteinima akutne faze. Navedeno ukazuje na to da HMGB1, kao medijator prirođene imunosti, u interakciji sa sRAGE sudjeluje u imunopatogenezi sJIA te može služiti kao biomarker za određivanje aktivnosti i moguća meta u liječenju sJIA.

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