Značaj dokazivanja anti-Epštajn Bar virusnih antitela u pacijenata sa sistemskim eritemskim lupusom: : udruženost sa kliničkim i imunoserološkim ispoljavanjem bolesti
Significance of determination anti-EBV antibodies in patients with systemic lupus erythematosus: association with clinical and immunoserological disease characteristics
Докторанд
Mišković, RadaМентор
Rašković, SanvilaЧланови комисије
Banko, AnaTomić-Spirić, Vesna
Perić-Popadić, Aleksandra
Miljanović, Danijela
Метаподаци
Приказ свих података о дисертацијиСажетак
Uvod: Sistemski eritemski lupus (SEL) je multisistemsko autoimuno oboljenje heterogene
kliničke prezentacije, koje prevashodno zahvata osobe ženskog pola, najčešće u reproduktivnom
periodu. Nastaje u kompleksnoj interreakciji genetičke osnove i faktora sredine, među kojima
infektivni agensi, posebno Epštajn-Bar virus (EBV) imaju značajnu ulogu.
Ciljevi istraživanja: Ciljevi ovog istraživanja su ispitati serološke i molekularne markere i
status EBV infekcije u ispitanika sa SEL u odnosu na kontrolnu grupu, utvrditi njihovu udruženost
sa stepenom aktivnosti, kliničkim i imunoserološkim manifestacijama bolesti, promenu markera i
statusa EBV infekcije u ispitanika sa aktivnim SEL nakon šest meseci u odnosu na postizanje
remisije/stanja niske aktivnosti SEL, identifikovati prediktore prelaska iz aktivne u latentnu EBV
infekciju i analizirati genetičke faktore koji bi mogli uticati na odgovor organizma na EBV
infekciju i način ispoljavanja SEL.
Materijal i metodologija: Sprovedena je prospek...tivna kohortna studija koja je obuhvatila
103 ispitanika sa dijagnozom SEL koji su lečeni na Klinici za alergologiju i imunologiju
Univerzitetskog kliničkog centra Srbije. Ispitanici sa aktivnim SEL (klinički SLEDAI ≥4 i ukupni
SLEDAI≥6) su praćeni tokom šest meseci, nakon čega je učinjena nova procena aktivnosti bolesti i
analiza markera EBV infekcije. Primarni ishod u ovoj grupi ispitanika bio je postizanje remisije ili
niske aktivnosti lupusa (eng. Lupus Low Disease Activity, LLDAS) nakon šest meseci praćenja.
Kontrolnu grupu činilo je 99 ispitanika starijih od 18. godina, koji nisu imali dijagnozu sistemske
autoimunske ili aktivne maligne bolesti, niti pozitivnu porodičnu anamnezu za iste. Određivana
su antitela na EBV antigene EBNA 1 (IgG), VCA (IgM, IgG) i EA(D) (IgM, IgG) u uzorcima seruma
primenom komercijalnih ELISA testova prema uputstvima proizvođača. Aktivna EBV infekcija je
definisana prisustvom virusne DNK (pozitivna EBNA1 i/ili LMP1) i/ili prisustvom anti-VCA IgM
i/ili anti-EA(D) IgM antitela. Komercijalni TaqMan SNP esej je korišćen za određivanje genotipova
IL10RA (rs10892202, rs4252270, rs3135932, rs2228055, rs2229113, rs9610), IL10RB
(rs999788, rs2834167, rs1058867) i IL22RA (rs16829204, rs3795299). Aktivnost bolesti
procenjivana je primenom sledećih skala i skorova: SLEDAI 2K, LFA-REAL ClinRO i PGA.
SLICC/ACR Damage Index je korišćen za procenu akumuliranog oštećenja. Od pacijenata je
traženo da daju svoju procenu aktivnosti bolesti primenom LFA REAL PRO, a stepen zamora
ocenjivan je primenom FACIT-F skale.
Rezultati: Ispitivanjem je obuhvaćeno 103 ispitanika sa SEL, većinom žena (91,3%),
prosečne starosti 45,42±12,9 godina. Limfopenija (50%), alopecija (39%), artritis (32%) i
leukopenija (32%) bile su najčešće kliničke manifestacije. Aktivna forma bolesti bila je prisutna
kod 51 (49,5%) ispitanika. Kontrolnu grupu činilo je 99 ispitanika, većinom žena (88%), prosečne
starosti 55,43±13,62 godine. Aktivna EBV infekcija je značajno češće bila prisutna u ispitanika sa
SEL (41,7%) u odnosu na kontrolnu grupu (9,2%). Ispitanici sa SEL imali su višu prevalencu i
titar anti-VCA IgM, anti-EA(D) IgG i anti-EA(D) IgM antitela u odnosu na kontrolnu grupu
(p<0,001, p<0,001, p=0,008, redom)...
ntroduction: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune
disease with a heterogeneous clinical presentation, which primarily affects women in the
reproductive period. It develops in a complex interaction of genetic and environmental factors,
among which infectious agents, especially the Epstein-Barr virus (EBV), play a significant role.
Aims: The aims of this research were to examine serological and molecular markers and
the status of EBV infection in subjects with SLE compared to the control group, to investigate
their association with the disease activity, clinical and immunoserological SLE manifestations,
changes in the markers and status of EBV infection in subjects with active SLE after six months in
relation to the achievement of remission/state of low lupus activity, identify predictors of
transition from active to latent EBV infection and analyze genetic factors that could affect the
response to EBV infection and the SLE manifestations.
Materials and method...s: A prospective cohort study was conducted that included 103
subjects with SLE who were treated at the Clinic for Allergy and Immunology University Clinical
Center of Serbia. Subjects with active SLE (clinical SLEDAI ≥4 and total SLEDAI≥6) were followed
for six months, after which a new assessment of disease activity and analysis of markers of EBV
infection was performed. The primary outcome was the achievement of remission or low lupus
activity (Lupus Low Disease Activity, LLDAS) after six months of follow-up. The control group
consisted of 99 subjects ≥18 yeras, without the diagnosis of systemic autoimmune or active
malignant disease, nor a positive family history. Antibodies to EBV antigens EBNA 1 (IgG), VCA
(IgM, IgG), and EA(D) (IgM, IgG) were determined in serum samples using commercial ELISA
tests according to the manufacturer's instructions. Active EBV infection was defined by the
presence of viral DNA (positive EBNA1 and/or LMP1) and/or the presence of anti-VCA IgM
and/or anti-EA(D) IgM antibodies. A commercial TaqMan SNP assay was used to determine the
genotypes of IL10RA (rs10892202, rs4252270, rs3135932, rs2228055, rs2229113, rs9610),
IL10RB (rs999788, rs2834167, rs1058867) and IL22RA (rs168292). 04, rs3795299). Disease
activity was assessed using the following scales: SLEDAI 2K, LFA-REAL ClinRO and PGA. The
SLICC/ACR Damage Index was used to assess accumulated damage. Patients were asked to assess
SLE activity using LFA REAL PRO, and the degree of fatigue was assessed using the FACIT-F scale.
Results: The study included 103 SLE patients, mostly women (91.3%), average age
45.42±12.9 years. Lymphopenia (50%), alopecia (39%), arthritis (32%) and leukopenia (32%)
were the most common clinical manifestations. The active SLE was present in 51 (49.5%)
subjects. The control group consisted of 99 participants, mostly women (88%), average age
55.43±13.62 years. Active EBV infection was significantly more often in subjects with SLE
(41.7%) compared to the controls (9.2%). Subjects with SEL had a higher prevalence and titer of
anti-VCA IgM, anti-EA(D) IgG and anti-EA(D) IgM antibodies compared to the control group
(p<0.001, p<0.001, p=0.008, respectively). Although the prevalence of active EBV infection in
subjects with active SLE (47.1%) was higher compared to subjects in remission/LLDAS (36.5%),
this difference was not statistically significant (p=0.321)...