Levels of soluble Fas/APO-1 in patients with Behçet's disease.

The aim of this study was to quantify soluble Fas/APO-1 (sFas/APO-1) protein in the serum of patients with Behcet's disease (BD) in active and inactive stages, compared with patients with systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). Soluble Fas/APO-1 was quantified using a sandwich enzyme-linked immunosorbent assay. Increased serum sFas/APO-1 levels were observed in active BD, compared with inactive BD, RA patients and SLE patients. Increased serum sFas/APO-1 levels were correlated with the presence of neurologic manifestations or pulmonary involvement in active BD. In conclusion, increased levels of sFas/APO-1 occurred frequently and exclusively in active BD patients. Preliminary evidence suggested that elevated levels of sFas/APO-1 are associated with the clinical stage and clinical manifestations in BD

Медицина путешествий: ее роль и значение в структуре отечественного здравоохранения

ПУТЕШЕСТВИЯИНФЕКЦИОННЫЕ БОЛЕЗНИПАРАЗИТАРНЫЕ БОЛЕЗНИЗДРАВООХРАНЕНИЯ СЛУЖБЫПРОФИЛАКТИЧЕСКИЕ СЛУЖБ

Soluble FAS and transforming growth factor beta 2 in infections with viral and bacterial zoonoses

Određivali smo razine sFas (signalna receptor molekula koja biva otpuštena tijekom apoptoze u cirkulirajućem obliku) i TGF-β2 (multifunkcionalni citokin) u bolesnika s različitim zoonozama. Serumi su dobiveni od bolesnika hospitaliziranih u Klinici za infektivne bolesti »Dr. Fran Mihaljević«, Zagreb, Hrvatska, s dijagnozama: hemoragijska vrućica s bubrežnim sindromom – HVBS (n=20), leptospiroza (n=9), borelioza (n=7) ili krpeljni meningoencefalitis – KME (n=7). Za mjerenje razina sFas i TGF-β2 u serumima koristili smo ELISA kitove prema uputama proizvođača. Značajno povišena razina sFas je nađena u svih bolesnika. Ipak, bolesnici s KME ili boreliozom imali su značajno niže razine nego bolesnici s leptospirozom. Nasuprot tome, bolesnici s KME ili boreliozom su imali značajno više razine TGF-β2 nego zdrave kontrole. Naši preliminarni podaci ukazuju da bi povišene razine sFas i TGF-β2 mogle imati ulogu u imunopatogenezi ispitivanih virusnih i bakterijskih zoonoza.We determined levels of sFas (signal receptor molecule released during apoptosis in a soluble circulating form) and TGF-β2 (multifunctional cytokine) in patients with different zoonoses. Serum samples were obtained from patients hospitalized at the University Hospital for Infectious Diseases, Zagreb, Croatia with diagnoses of hemorrhagic fever with renal syndrome – HFRS, (n=20), leptospirosis (n=9), Lyme borreliosis (n=7), or tick-borne encephalitis – TBE (n=7). In all sera samples the levels of sFAS or TGF-β2 levels were measured using ELISAkits according to the manufacturer\u27s protocol. Significant increase in the levels of sFas was found in all patients. However, the patients with TBE or Lyme borreliosis had significantly lower levels than patients with leptospirosis. In contrary, patients with TBE or Lyme borreliosis had significantly higher levels of TGF-β2 than healthy controls. Our preliminary data indicate that an increase of sFas and TGF-β2 levels may have a role in the immunopathogenesis of tested viral and bacterial zoonoses

Inflammatory biomarkers in multiple sclerosis

Tulehdukselliset biomerkkiaineet multippeliskleroosissa Multippeliskleroosi (MS) on tulehduksellinen keskushermostoa rappeuttava sairaus, jonka esiintyvyys Suomessa on maailman korkeimpia. MS-tauti puhkeaa 20 40 vuoden iässä ja se onkin yleisin nuorten aikuisten vakava neurologinen sairaus, josta aiheutuu merkittäviä kuluja yhteiskunnalle. Suomessa MS-potilaita on noin 7000 ja uusia tapauksia todetaan vuosittain noin 200 250. Useimmiten MS-taudin ensioireet esiintyvät jo nuorella aikuisiällä, mutta niiden tunnistaminen on edelleenkin hankalaa. MS-taudin syytä ei toistaiseksi tunneta, mutta perintö- ja ympäristötekijöiden tiedetään vaikuttavan taudin puhkeamiseen. Nykykäsityksen mukaan CD4+ T-lymfosyyttien ja niiden vapauttamien tulehdusvälittäjäaineiden uskotaan olevan keskeisessä asemassa tulehdusmuutosten synnyssä, mutta myös muut immuunipuolustuksen solut välittävät hermokudosvaurioiden syntyä. Viimeaikaisissa tutkimuksissa on pystytty osoittamaan, että taudin syntymekanismeissa on monimuotoisuutta ja vaihtelua potilaiden välillä. Näiden syntymekanismien selvittäminen parantaisi yksilöllisen hoidon edellytyksiä. Väitöskirjatyön päätavoitteena oli tunnistaa taudin syntymekanismeja kuvaavia veren immunologisia profiileja MS-taudin eri alatyypeissä. Lisäksi tutkimuksen tavoitteena oli tunnistaa biomerkkiaineita, jotka kuvaavat taudin aktiivisuutta ja sen etenemistä ja jotka ennustaisivat MS-taudin kehittymisen riskiä. Tutkimus koostui varhaisen ja myöhäisen vaiheen MS-potilaista ja terveistä kontrolleista, jotka tutkittiin neurologisesti ja aivojen kuvantamisella sekä heidän verinäytteistä tutkittiin ehdokasbiomerkkiaineiden ilmentymisprofiileja. MS-taudissa poikkeavia immunoprofiileja ilmentyi sekä proteiini- että geenitasolla. Primaarisprogressivisessa MS-taudissa havaittiin kohonneita seerumin proteiinipitoisuuksia kolmella tulehduksellisella molekyylillä (TNF-a, Fas ja CCL2), jotka kuvastivat meneillään olevaa tulehduksellista aktiivisuutta tässä tautityypissä. Lisäksi havaitsimme varhaisen vaiheen MS-potilailla poikkeavia ilmentymisprofiileja solukuolemaan liittyvissä geeneissä, jotka viittasivat lisääntyneisiin solukuolemaan liittyviin mekanismeihin taudin aktiivisuuden hillitsemiseksi. Uusia kandidaattimerkkiaineita havaittiin, joista kohonneet TRAIL ja MIF tasot olivat yhteydessä aaltomaisen taudin aktiivisuuteen, kun taas kohonneet Fas ja MIF proteiinien tasot ja TRAIL mRNA:n ilmentyminen invaliditeetin kertymiseen. Lisäksi useita ennustavia kandidaattibiomerkkiaineita löydettiin, joiden yli-ilmentyminen näyttää olevan yhteydessä MS-taudin kehittymisen riskiin. Saatujen tuloksien varmentaminen edellyttää suurempaa potilasaineistoa sekä pidempää seuranta-aikaa.Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) that is characterized by a variable clinical course and heterogeneous and complex pathology. Pathophysiological processes in MS contribute to the disease course and clinical manifestations, and therefore biomarkers that are indicative of these events would provide significant potential for diagnostics, prediction of disease course and optimization of therapeutic responses. The goal of this thesis was to identify biomarkers in the blood that could reflect pathogenetic processes in MS and be used as biomarkers of disease activity and progression. In this regard, the aims were to: 1) define immune profiles in different clinical subtypes of MS and clinically isolated syndrome (CIS); 2) search for biomarkers for disease activity and disability; 3) search for prognostic biomarkers for CIS to MS, and 4) explore whether the postpartum disease activation of MS is related to changes in the apoptotic molecules in the blood. The study included patients with different subtypes of MS, CIS and healthy controls that underwent neurological, magnetic resonance imaging (MRI) and immunological examinations. Altered expression of immune profiles in MS subtypes were found on both the protein and gene levels. Immune profiles in sera of primary progressive MS (PPMS) were characterized by elevated levels of tumor necrosis factor (TNF)-a, soluble Fas (sFas) and C-C chemokine motif ligand 2 (CCL2). Decreased serum levels of macrophage migration inhibitory factor (MIF) were found in relapsing-remitting MS (RRMS). Aberrant expression of six apoptosis-related genes (BAD, BBC3, BCL2L14, TNFRSF25, IKBKE, NFKBID), including B-cell lymphoma 2 (Bcl-2) and nuclear factor kappa B (NF-kB) families and death receptor pathway, were found in RRMS patients. Interestingly, atypical expression profiles of apoptosis-related genes were also seen in CIS (BNIP3, TNFRSF25, IKBKE). Active disease course was associated with upregulation of serum MIF and TNF-related apoptosis inducing ligand (TRAIL), and disease progression was associated with increased TRAIL mRNA, MIF and sTRAIL. In CIS, elevated expression of three apoptosis-related genes (APAF, BIRC6, CFLAR) was found in those patients who fulfilled the diagnostic criteria for MS over the two-year follow up. In the study of the immunomodulatory effect of pregnancy on MS, sTRAIL and sFasL were upregulated in both MS patients and healthy women from late pregnancy to postpartum. The increase in sTRAIL was significantly smaller in the MS patients in comparison with the controls. In summary, this thesis focusing on the identification of biomarkers in MS showed that PPMS was characterized by elevated levels of TNF-a, sFas and CCL2 indicating inflammatory activity in this subtype. Abnormal expression of apoptosis-related genes in RRMS and CIS suggested an enhanced potential for apoptosis in immune cells directed at controlling MS disease activity. Disease activity was associated with increased levels of serum TRAIL and MIF and disease progression was associated with upregulated levels of sFas, MIF and TRAIL mRNA, suggesting these molecules to be candidate biomarkers for disease activity and progression. Interestingly, three new prognostic biomarkers for conversion to MS were found. Increased MS disease activity postpartum may be related to inadequate inhibition of T-cell reactivation after pregnancy. Currently we are validating these findings using larger patient series and longer follow-up periods

ХАРАКТЕРИСТИКА УРОВНЕЙ СЫВОРОТОЧНЫХ МАРКЕРОВ FAS-СИСТЕМЫ АПОПТОЗА СРЕДИ ВИЧ МОНО-ИНФИЦИРОВАННЫХ ЛИЦ, ПАЦИЕНТОВ С ВИЧ-ВГС КОИНФЕКЦИЕЙ, ХРОНИЧЕСКИМ ВИРУСНЫМ ГЕПАТИТОМ С

The purpose of the study is to investigate aspects of concentrations of serum markers of FAS-system of apoptosis in HIV-positive people including people with hepatitis C (HCV). Materials and methods: determination of concentration of soluble FAS receptor (sFas/APO-1/CD95) and Fas ligand (sFas-L) by enzyme-linked immunosorbent assay in HIV/HCV-co-infected patients (n=84), HIV-mono-infected persons (n=84), patients diagnosed with chronic viral hepatitis C (control group, n=64) and among notionally healthy population (control group, n=87). Results: higher levels of sFas in HIV-mono- and HIV/HCVco-infected patients in comparison with control groups (notionally healthy population and patients with chronic viral hepatitis C) were detected. Conclusion: definite aspects of levels of apoptosis serum markers testify higher risk of developing paraneoplastic syndromes in HIV-positive patients including HCV-co-infected patients. Цель исследования: изучение особенностей концентрации сывороточных маркеров FAS-системы апоптоза среди ВИЧпозитивных лиц, в том числе инфицированных вирусом гепатита С (ВГС). Материалы и методы: проведено определение концентрации растворимых FAS-рецептора (sFas/APO-1/CD95) и Fas-лиганда (sFas-L) методом  иммуноферментного анализа среди ВИЧ-ВГС коинфицированных пациентов (n=84), ВИЧ моноинфицированных лиц (n=84), пациентов с диагнозом хронический вирусный гепатит С (контрольная группа, n=64) и условно-здорового населения (контрольная группа, n=87). Результаты: выявлены более высокие уровни sFas у ВИЧ-моно и ВИЧ-ВГС инфицированных лиц по сравнению с контрольными группами (условно-здоровое население и пациенты с хроническим вирусным гепатитом С). Заключение: определенные особенности уровней маркеров апоптоза свидетельствуют о более высоком риске развития паранеопластических процессов у ВИЧ позитивных пациентов, в том числе коинфицированных ВГС.</span

Sistemik lupus eritematozuzta solubl fas reseptörleri

38 ÖZET: Sistemik Lupus Eritematozus (SLE), sebebi bilinmeyen, cilt, eklem, böbrek, plevra, perikard gibi bir çok doku ve organın inflamasyonuna bağlı, çok sayıda semptom ve bulgularla değişik seyir gösteren ve çeşitli immünolojik anormalliklerle karakterize otoimmün, kronik, iltihabi ve sistemik bir hastalıktır. Hastalığın kesin sebebi bilinmemektedir. SLE'nin başlamasında ve devam etmesinde genetik olarak yatkın bireylerde çevresel faktörlerin rolü olduğu düşünülmektedir. Son bir kaç yıl içinde SLE benzeri otoimmün hastalığı olan farelerde 3 otozomal resesif gende mutasyonun olduğunun gösterilmesi SLE'deki bozulmuş toleransın incelenmesi için yeni olasılıkları ortaya koymuştur (2,3,4). Bu 3 gendeki mutasyonun ortak özelliği programlı hücre ölümünde (apoptozis) defekte sebep olmalarıdır. MRL/Ipr, gld sıçan modelleri ve bcl-2 veya bcl-X\, transgenic sıçan modellerinden elde edilen bulgular apoptozisin bu hastalıkların özellikle SLE'nin patogenezindeki rolü üzerine çalışmaların yoğunlaşmasına sebep olmuştur. Fas (APO-1, CD95) 48 kD moleküler ağırlıklı, glikoprotein yapıda bir hücre yüzeyi molekülü olup ilk kez apoptotik hücre ölümüne neden olan molekül olarak 1989 yılında tanımlanmıştır (21). Fas/APO-1, NGF (Nerve growth factor)/ TNF ailesine mensuptur. MKL/lpr, gld sıçan modelleri ve bcl-2 veya bcl-xL transgenic sıçan modellerinden elde edilen bulgular apoptozisin bu hastalıkların özellikle SLE'nin patogenezindeki rolü üzerine çalışmaların yoğunlaşmasına sebep olmuştur. MRL/lpr Sistemik Lupus Eritemalozusta Solubl Fas Reseptörleri. Ruçhan USLU® 199739 sıçanlarının aksine SLE hastaların periferal mononükleer kan hücrelerinde Fas-R ekspresyonunun kontrollerle karşılaştırıldığında artmıştır. Artmış FasR ekspresyonu hem B hem de T lenfositlerinde bulunmaktadır. FasR ekspresyonu ile klinik ve serolojik markırlar arasında herhangi bir korelasyon gösterilememiştir. Bu da SLE'de Fas/APO- l'in eksikliğinin muhtemelen hastalığın başlıca nedeni olamayacağını göstermektedir. Fas-APO-l'in otoimmün hastalıklarda diğer bir muhtemel rolü Cheng (40) ve arkadaşları tarafından 1994 yılında sFas/APO-1-R' formunun tanımlanmasından sonra ortaya çıkmıştır. SLE hastalarında sFas/APO-1-R düzeyleri ve klinik ve serolojik markırlarla ilişkisi konusunda yapılan çalışmalarda çelişkili sonuçlar elde edilmiştir. Çalışmamızdaki amaç solubl Fas reseptörlerinin SLE hastalarında serum düzeylerinin saptanması, solubl Fas reseptör düzeylerinin hastalık aktivitesi, klinik renal bulgu varlığı, böbrek tutuluşu ve böbrek tutuluşunun tipi arasında ilişki olup olmadığının araştırılmasıdır. Non invaziv yöntem olarak, solubl Fas reseptör düzeylerinin ölçülmesinin SLE'de böbrek tutuluşunun bir göstergesi olup olamayacağı da araştırılmıştır. Çalışmamızdan elde edilen bilgiler serum sFas/APO-1-R düzeylerinin SLE hastalarında ölçülmesinin herhangi bir klinik değeri olmadığını göstermektedir. sFas/APO-1-R'lerinin hastalığın patogenezinde önemli bir rol oynaması muhtemel değildir. Ayrıca SLE hastalarında hastalık aktivitesinin ve böbrek tutuluşunun ve tipinin Sistemik Lupus Eritematoaısta Solubl Fas Reseptörleri. Ruçhm USLU® 199740 değerlendirilmesinde serum sFas/APO-1-R düzeylerinin ölçülmesi anlamlı sonuçlar vermemektedir ve klinik değeri saptanmamıştır. Sistemik Lupus Eritematozusta Solubl Fas Reseptörleri. Rüçhan USLU® 199