Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC50s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI-EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.
- MeSH
- analýza přežití MeSH
- epitopy imunologie MeSH
- imunoglobulin G aplikace a dávkování imunologie MeSH
- klíšťová encefalitida imunologie prevence a kontrola virologie MeSH
- kohortové studie MeSH
- kultivované buňky MeSH
- lidé MeSH
- monoklonální protilátky aplikace a dávkování genetika imunologie MeSH
- myši inbrední BALB C MeSH
- neutralizující protilátky aplikace a dávkování genetika imunologie MeSH
- proteiny virového obalu genetika imunologie MeSH
- protilátky virové aplikace a dávkování genetika imunologie MeSH
- sekvence aminokyselin MeSH
- sekvenční homologie aminokyselin MeSH
- viry klíšťové encefalitidy účinky léků imunologie fyziologie MeSH
- zkřížené reakce imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
JC virus (JCPyV) has gained novel clinical importance as cause of progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease recently associated to immunomodulatory drugs, such as natalizumab used in multiple sclerosis (MS) cases. Little is known about the mechanisms leading to PML, and this makes the need of PML risk stratification among natalizumab-treated patients very compelling. Clinical and laboratory-based risk-stratification markers have been proposed, one of these is represented by the JCPyV-seropositive status, which includes about 54% of MS patients. We recently proposed to investigate the possible protective role of neutralizing humoral immune response in preventing JCPyV reactivation. In this proof-of-concept study, by cloning the first human monoclonal antibody (GRE1) directed against a neutralizing epitope on JCPyV/VP1, we optimized a robust anti-JCPyV neutralization assay. This allowed us to evaluate the neutralizing activity in JCPyV-positive sera from MS patients, demonstrating the lack of correlation between the level of anti-JCPyV antibody and anti-JCPyV neutralizing activity. Relevant consequences may derive from future clinical studies induced by these findings; indeed the study of the serum anti-JCPyV neutralizing activity could allow not only a better risk stratification of the patients during natalizumab treatment, but also a better understanding of the pathophysiological mechanisms leading to PML, highlighting the contribution of peripheral versus central nervous system JCPyV reactivation. Noteworthy, the availability of GRE1 could allow the design of novel immunoprophylactic strategies during the immunomodulatory treatment.
- MeSH
- epitopy genetika imunologie MeSH
- humanizované monoklonální protilátky škodlivé účinky terapeutické užití MeSH
- klonování DNA MeSH
- lidé MeSH
- monoklonální protilátky genetika imunologie MeSH
- neutralizační testy metody MeSH
- neutralizující protilátky genetika imunologie MeSH
- Polyomavirus imunologie MeSH
- progresivní multifokální leukoencefalopatie imunologie prevence a kontrola MeSH
- protilátky virové genetika imunologie MeSH
- roztroušená skleróza terapie MeSH
- virové plášťové proteiny antagonisté a inhibitory imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The clinical course of tick-borne encephalitis (TBE), a disease caused by TBE virus, ranges from asymptomatic or mild influenza-like infection to severe debilitating encephalitis or encephalomyelitis. Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood. In particular, the basis of the disease severity is largely unknown. METHODS: TBE virus growth, neutralizing antibody response, key cytokine and chemokine mRNA production and changes in mRNA levels of cell surface markers of immunocompetent cells in brain were measured in mice with different susceptibilities to TBE virus infection. RESULTS: An animal model of TBE based on BALB/c-c-STS/A (CcS/Dem) recombinant congenic mouse strains showing different severities of the infection in relation to the host genetic background was developed. After subcutaneous inoculation of TBE virus, BALB/c mice showed medium susceptibility to the infection, STS mice were resistant, and CcS-11 mice were highly susceptible. The resistant STS mice showed lower and delayed viremia, lower virus production in the brain and low cytokine/chemokine mRNA production, but had a strong neutralizing antibody response. The most sensitive strain (CcS-11) failed in production of neutralizing antibodies, but exhibited strong cytokine/chemokine mRNA production in the brain. After intracerebral inoculation, all mouse strains were sensitive to the infection and had similar virus production in the brain, but STS mice survived significantly longer than CcS-11 mice. These two strains also differed in the expression of key cytokines/chemokines, particularly interferon gamma-induced protein 10 (IP-10/CXCL10) and monocyte chemotactic protein-1 (MCP-1/CCL2) in the brain. CONCLUSIONS: Our data indicate that the genetic control is an important factor influencing the clinical course of TBE. High neutralizing antibody response might be crucial for preventing host fatality, but high expression of various cytokines/chemokines during TBE can mediate immunopathology and be associated with more severe course of the infection and increased fatality.
- MeSH
- buněčná imunita imunologie MeSH
- centrální nervový systém patologie MeSH
- chemokiny biosyntéza MeSH
- cytokiny biosyntéza MeSH
- genotyp MeSH
- klíšťová encefalitida imunologie patologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- membránové proteiny biosyntéza MeSH
- messenger RNA biosyntéza genetika MeSH
- mozek - chemie fyziologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- náchylnost k nemoci MeSH
- neutralizující protilátky biosyntéza MeSH
- odolnost vůči nemocem MeSH
- plakové testy MeSH
- protilátky virové biosyntéza genetika MeSH
- virová nálož MeSH
- viry klíšťové encefalitidy * MeSH
- zánět patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Enzymatickou imunoesejí (HCV Serotyping 1-6 Assay Murex) byla vyšetřena séra od 175 pacientů s biopticky prokázanou chronickou hepatitidou C nebo cirhózou jatemí, na podkladě chronické infekce virem hepatitidy C. Všichni pacienti byli anti-HCV pozitivní ELISA metodou 3. generace. Výše uvedenou eseji byl prokázán určitý sérotyp u 143 pacientů (81,7 %). Z nich bylo 82 mužů, 61 žen, průměrného věku 44,95 ± 15,44 roku, v rozmeziezí 18 - 76 let. Nejčastěji byl detekován sérotyp 1 (121 pacientů, 84,6 %). Typy 2 a 3 byly zjištěny méně Často (10 resp. 44 pacienti, tj. 7,0 a 2,8 %). Celkem v 8 případech (5,6 %) jsme zaznamenali smíšenou infekci sérotypu 1 s jiným sérotypem - 3x s typem 2 (2,1 %), Ix s typem 3 (0,7 %), Ix s typem 4 (0,7 %) a 3x s typem 5 (2,1 %).
Sera of 175 patients with biopsy-confimn rmed chronic hepatitis C, or cirrhosis of the liver linked with chronic hepatitis C virus infection, were examined by enzyme immunoassay (HCV Serotyping 1-6 Assay Murex). All patients were anti-HCV positive by the 3rd generation ELISA technique. By this assay a definite serotype was demonstrated in 143 patients (81.7 %). Of these, 82 were males and 61 females at an average age of 44.95 ± 15.44 yrs in the range of 18 to 76 years. Serotype 1 was detected most frequently (121 patients, i.e. 84.6%). Types 2 and 3 were less frequent, i.e., in 10 (7 %) and 4 (2.8 %) patients, respectively. Eight cases (5.6 %) were mixed infections of serotype 1 with another serotype: 3x with type 2 (2.1 %), Ix with type 3 (0.7 %), 1x with type 4 (0.7 %), and 3x with type 5 (2.1 %).
- MeSH
- antigenní variace MeSH
- dospělí MeSH
- genotyp MeSH
- hepatitida C diagnóza imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- protilátky virové analýza genetika MeSH
- senioři MeSH
- sérotypizace metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
