Toll-uslični receptori u patogenezi sistemskog eritemskog lupusa

doctoral thesis

• Title (english): Toll-like receptors in pathogenesis of systemic lupus erythematosus
• Author: Alma-Martina Cepika; MBZ: 255222
• Mentor: Alenka Gagro (mentor)
• Committee member: nije dostupno (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2012-12-18, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

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.

Abstract (english)

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.

• Keywords: medicina
• Keywords (english): medicine
• Language: croatian
• URN:NBN: urn:nbn:hr:105:923835
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstva (doktor/doktorica znanosti, područje biomedicine i zdravstva)
• Type of resource: Text
• Extent: 120 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-05-05 07:04:24