Toll-uslični receptori u patogenezi sistemskog eritemskog lupusa [Toll-like receptors in pathogenesis of systemic lupus erythematosus]

Cepika, Alma-Martina (2012) Toll-uslični receptori u patogenezi sistemskog eritemskog lupusa [Toll-like receptors in pathogenesis of systemic lupus erythematosus]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by hyperreactive B cells that produce autoantibodies against nucleic acids and related structures. In lupus-prone mice, Toll-like receptor 9 (TLR9) stimulation with DNA-containing immune complexes leads to autoreactive B cell survival and differentiation which could be abolished by chloroquine, a TLR9 signaling inhibitor otherwise used in SLE treatment. Also, patients are at increased risk of an infection. Activation of innate immunity via TLR4 is necessary for the resistance to Gram- bacteria, one of the leading causes of mortality in SLE. Here we investigated if chloroquine and low-dose corticosteroid treatment modulate the expression of TLR9 in B cells, TLR4 on monocytes, levels of circulating DNA and B-cell stimulatory cytokines in peripheral blood of SLE patients and controls. In vitro, we interrogated if chloroquine or steroids modulate B cell activation by synthetic TLR9 ligand CpGor monocyte activation by TLR4 ligand LPS. Results suggest that chloroquine inhibits TLR9-induced B cell activation in vitro and contributes to a decrease in serum DNA level ex vivo, without affecting the pro-inflammatory cytokine production vital for the adequate response to bacterial infection. Thus, investigation of activation and signalization mechanisms of the innate immune system receptors in patients contributes to understanding of SLE pathogenesis.

Abstract in Croatian

Sistemski eritemski lupus (SLE) je autoimunosna bolest karakterizirana hiperreaktivnim B-limfocitima od kojih neki stvaraju auto-antitijela na nukleinske kiseline i srodne antigene, te povećanim rizikom za infekcije. Animalni modeli SLE-a pokazali su da aktivacija Toll-u sličnog receptora 9 (TLR9) DNA-imunokompleksima stimulira i diferencira autoreaktivne B-limfocite. To se dokida blokadom TLR9 signalnog puta klorokinom, koji se uspješno koristi u liječenju SLE-a. Aktivacija urođene imunosti nakon prepoznavanja bakterijskih komponenata putem TLR4 pak je ključna za adekvatnu obranu od Gram- bakterija, važnog uzroka smrtnosti u SLE-u. Ovdje je istraženo da li liječenje klorokinom i niskim dozama kortikosteroida modulira izražaj TLR9 i TLR4 u B-limfocitima odnosno monocitima SLEbolesnika, te cirkulirajuću DNA i citokine koji aktiviraju B-limfocite (IL-10 i BAFF) ex vivo. In vitro je ispitan utjecaj lijekova na aktivaciju B-limfocita sintetskom DNA i produkciju IL-10 i BAFF-a, te na aktivaciju monocita i sekreciju TNF-α i IL-6 stimulacijom TLR4 signalnog puta lipopolisaharidom. Rezultati su pokazali da klorokin inhibira aktivaciju TLR9 u B-limfocitima in vitro, te pridonosi sniženju razine cirkulirajuće DNA, potencijalnog TLR9 liganda, ex vivo. Klorokin ujedno ne ometa prepoznavanje komponenata Gram- bakterija i sekreciju proupalnih citokina važnih za obranu od infekcije. Razumijevanje aktivacije i signalizacije receptora urođene imunosti važno je za razumijevanje patogeneze SLE-a i razvoj ciljanih terapija.

Item Type: Thesis (PhD)
Mentors:
Mentor
Gagro, Alenka
Departments: Izvan medicinskog fakulteta
Depositing User: Marijan Šember
University: Sveučilište u Zagrebu
Institution: Medicinski fakultet
Number of Pages: 120
Status: Unpublished
Creators:
CreatorsEmail
Cepika, Alma-MartinaUNSPECIFIED
Date: 18 December 2012
Date Deposited: 30 Jan 2013 13:24
Last Modified: 30 Jan 2013 13:34
Subjects: /
Related URLs:
    URI: http://medlib.mef.hr/id/eprint/1806

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