IgA nephropathy (IgAN) is an autoimmune disease in which poorly galactosylated IgA1 is the antigen recognized by naturally occurring anti-glycan antibodies, leading to formation of nephritogenic circulating immune complexes. Incidence of IgAN displays geographical and racial disparity: common in Europe, North America, Australia, and east Asia, uncommon in African Americans, many Asian and South American countries, Australian Aborigines, and rare in central Africa. In analyses of sera and cells from White IgAN patients, healthy controls, and African Americans, IgAN patients exhibited substantial enrichment for IgA-expressing B cells infected with Epstein-Barr virus (EBV), leading to enhanced production of poorly galactosylated IgA1. Disparities in incidence of IgAN may reflect a previously disregarded difference in the maturation of the IgA system as related to the timing of EBV infection. Compared with populations with higher incidences of IgAN, African Americans, African Blacks, and Australian Aborigines are more frequently infected with EBV during the first 1-2 years of life at the time of naturally occurring IgA deficiency when IgA cells are less numerous than in late childhood or adolescence. Therefore, in very young children EBV enters "non-IgA" cells. Ensuing immune responses prevent infection of IgA B cells during later exposure to EBV at older ages. Our data implicate EBV-infected cells as the source of poorly galactosylated IgA1 in circulating immune complexes and glomerular deposits in patients with IgAN. Thus, temporal differences in EBV primo-infection as related to naturally delayed maturation of the IgA system may contribute to geographic and racial variations in incidence of IgAN.
- MeSH
- černoši MeSH
- dítě MeSH
- IgA nefropatie * epidemiologie etnologie MeSH
- imunoglobulin A MeSH
- imunokomplex MeSH
- infekce virem Epsteina-Barrové * epidemiologie etnologie MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- virus Epsteinův-Barrové MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Geografické názvy
- Austrálie MeSH
PURPOSE: Heterozygous mutations in CTLA4 lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on CTLA4 mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition. METHODS: To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 CTLA4 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and Toxoplasma gondii. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by CTLA4 mutation carriers. RESULTS: The seroprevalence between affected and unaffected CTLA4 mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that CTLA4 mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A. CONCLUSIONS: Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.
- MeSH
- antigen CTLA-4 genetika MeSH
- imunoglobulin G MeSH
- infekce virem Epsteina-Barrové * komplikace epidemiologie MeSH
- lidé MeSH
- protilátky virové MeSH
- séroepidemiologické studie MeSH
- virus Epsteinův-Barrové * fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide. However, IgAN rarely affects African Blacks and is uncommon in African Americans. Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circulating immune complexes with nephritogenic consequences. Because human B cells infected in vitro with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1, we examined peripheral blood B cells from adult IgAN patients, and relevant controls, for the presence of EBV and their phenotypic markers. We found that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract. Upon polyclonal stimulation, these cells produced more galactose-deficient IgA1 than did cells from healthy controls. Unexpectedly, in healthy African Americans, EBV was detected preferentially in surface IgM- and IgD-positive cells. Importantly, most African Blacks and African Americans acquire EBV within 2 years of birth. At that time, the IgA system is naturally deficient, manifested as low serum IgA levels and few IgA-producing cells. Consequently, EBV infects cells secreting immunoglobulins other than IgA. Our novel data implicate Epstein-Barr virus infected IgA+ cells as the source of galactose-deficient IgA1 and basis for expression of relevant homing receptors. Moreover, the temporal sequence of racial-specific differences in Epstein-Barr virus infection as related to the naturally delayed maturation of the IgA system explains the racial disparity in the prevalence of IgAN.
- MeSH
- B-lymfocyty imunologie MeSH
- galaktosa MeSH
- IgA nefropatie epidemiologie virologie MeSH
- imunoglobulin A metabolismus MeSH
- infekce virem Epsteina-Barrové epidemiologie MeSH
- kojenec MeSH
- lidé MeSH
- prevalence MeSH
- rasové skupiny * MeSH
- virus Epsteinův-Barrové fyziologie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Geografické názvy
- Česká republika MeSH
- Klíčová slova
- GILENYA (fingolimod),
- MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- fingolimod hydrochlorid aplikace a dávkování farmakologie MeSH
- genetická predispozice k nemoci genetika MeSH
- glatiramer acetát aplikace a dávkování MeSH
- infekce virem Epsteina-Barrové epidemiologie komplikace MeSH
- interferon beta aplikace a dávkování MeSH
- lidé MeSH
- mladiství MeSH
- nedostatek vitaminu D MeSH
- relabující-remitující roztroušená skleróza * diagnostické zobrazování farmakoterapie patofyziologie patologie MeSH
- rizikové faktory MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region. METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls. RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL. CONCLUSIONS: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL. IMPACT: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- hlavní histokompatibilní komplex genetika MeSH
- Hodgkinova nemoc epidemiologie genetika patologie virologie MeSH
- infekce virem Epsteina-Barrové epidemiologie genetika patologie virologie MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 6 * MeSH
- mladiství MeSH
- mladý dospělý MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Nizozemsko epidemiologie MeSH
- Skandinávie a severské státy epidemiologie MeSH
BACKGROUND: Young age and thiopurine therapy are risk factors for lymphoproliferative disease among patients with inflammatory bowel disease (IBD). AIMS: The aims of this study were to evaluate the prevalence of seropositivity for the Epstein-Barr virus (EBV) and human cytomegalovirus (CMV) among children and adolescents with IBD, to assess the viral load of EBV, CMV, and BK and JC polyomaviruses (BKV, JCV) in these patients, and to assess the influence of different therapeutic regimens on seroprevalence and viral load. METHODS: Children who had been followed in our center were tested for EBV, CMV, BKV, and JCV in a cross-sectional study. One hundred and six children were included who had Crohn's disease (68%), ulcerative colitis (29%), and unclassified IBD (3%). RESULTS: We found that 64% of patients were EBV seropositive. The proportion of EBV seropositive patients increased during childhood. Azathioprine therapy (p = 0.003) was associated with EBV seropositivity in a multiple logistic regression model, after adjusting for gender, age, and disease activity at determination. We found a significant association between the number of polymerase chain reaction copies and infliximab dose (p = 0.023). We did not find any significant association between CMV serology and CMV, BKV, or JCV viral load, or any other therapeutic regimen or clinical characteristics. CONCLUSIONS: Treatment with azathioprine appears to be a risk factor for early EBV seropositivity in children with IBD, and the infliximab dose was associated with a higher EBV viral load.
- MeSH
- azathioprin škodlivé účinky MeSH
- Crohnova nemoc diagnóza farmakoterapie epidemiologie imunologie MeSH
- cytomegalovirové infekce diagnóza epidemiologie imunologie virologie MeSH
- dítě MeSH
- hostitel s imunodeficiencí MeSH
- imunosupresiva škodlivé účinky MeSH
- infekce virem Epsteina-Barrové diagnóza epidemiologie imunologie virologie MeSH
- infliximab škodlivé účinky MeSH
- lidé MeSH
- logistické modely MeSH
- mladiství MeSH
- multivariační analýza MeSH
- odds ratio MeSH
- oportunní infekce diagnóza epidemiologie imunologie virologie MeSH
- polyomavirové infekce diagnóza epidemiologie imunologie virologie MeSH
- předškolní dítě MeSH
- prevalence MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- séroepidemiologické studie MeSH
- sérologické testy MeSH
- ulcerózní kolitida diagnóza farmakoterapie epidemiologie imunologie MeSH
- věkové faktory MeSH
- virová nálož MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Virus Epsteina a Barrové (EBV) je ubikvitní gama herpesvirus, který specificky infikuje člověka. U imunokompetentního člověka dlouhodobě přetrvává v B-lymfocytech jako asymptomatická latentní infekce. Při reaktivaci EBV infekce, kterou umožní imunosuprese, jako je např. transplantace kmenových buněk krvetvorby a solidních orgánů, může docházet k nekontrolované proliferaci latentně infikovaných B-lymfocytů a ty pak jsou podkladem širokého spektra klinických jednotek, souhrnně označovaných jako potransplantační lymfoproliferativní onemocnění (PTLD). Článek přináší přehled EBV asociovaných klinických syndromů, epidemiologické údaje o výskytu PTLD, rizikových faktorech vzniku PTLD a klinické manifestaci.
EBV infections/reactivations; EBV-associated clinical syndromes, epidemiology and risk factors of the occurrence of post-transplantation lymphoproliferative disorders Epstein-Barr virus (EBV) is a ubiquitous human-specific ?-herpes virus that establishes a life-long asymptomatic infection in immunocompetent hosts by colonizing memory B lymphocytes. In immunosuppressed patients after solid organ or hematopoietic stem cell transplantation, the defect in EBV-specific immune responses allows the outgrowth of EBV-carrying B lymphocytes that may give rise to a spectrum of different clinical-pathologic entities encompassed by the term post-transplantation lymphoproliferative disorders (PTLD). Mechanisms of PTLD, epidemiology, risk factors and clinical picture are discussed.
- MeSH
- imunosupresivní léčba škodlivé účinky MeSH
- infekce virem Epsteina-Barrové diagnóza epidemiologie komplikace přenos MeSH
- lidé MeSH
- lymfoproliferativní nemoci * diagnóza imunologie patofyziologie virologie MeSH
- rizikové faktory MeSH
- transplantace orgánů metody škodlivé účinky MeSH
- virus Epsteinův-Barrové imunologie klasifikace patogenita růst a vývoj MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Infekcia vyvolaná Epsteinovým-Barrovej vírusom (EBV) u pacientov s hematologickými ochoreniami, ako aj u pacientov po transplantácii krvotvorných buniek, môže mať niekoľko foriem – od asymptomatického priebehu, primárneho syndrómu až po EBV asociované lymfoproliferatívne ochorenie (EBV-LPD) alebo EBV asociované ochorenie (encefalitída/myelitída, pneumónia, hepatitída). EBV asociované LPD po alogénnej transplantácii krvotvorných buniek (EBV-PTLP) je heterogénna skupina EBV ochorení s neoplastickou lymfoproliferáciou, ktorá je tvorená prevažne z donorských B-lymfocytov. EBV PTLD je život ohrozujúca komplikácia s obmedzenými terapeutickými možnosťami s incidenciou 0,5–1,3 % a s vysokou mortalitou od 80–90 %. Kľúčom včasnej liečby PTLD je pravidelné sledovanie nálože EBV-DNA PCR analýzou v korelácii s rizikovými faktormi a klinickými príznakmi pacienta. Keďže neexistuje kauzálna antivírusová terapia, do úvahy prichádza imunoterapeutická intervencia – redukcia imunosupresie, CD20 monoklonálna protilátka (rituximab) v monoterapii alebo v kombinácii s chemoterapiou alebo adoptívna imunoterapia s podávaním EBV-špecifických T-buniek alebo infúzií donorských lymfocytov (DLI).
Treatment and prophylaxis of EBV infection/reactivation/ associated lymphoproliferation in haematological patients Epstein-Barr virus (EBV) infection can have several forms in patients with haematological diseases as well as in patients after stem cell transplantation – asymptomatic course, primary syndrome as well as EBV-associated lymphoproliferative disease (EBV-LPD) or EBV-associated disease (encephalitis/myelitis, pneumonia, hepatitis). EBV-associated LPD after allogeneic stem cell transplantation (EBV-PTLP) is a heterogeneous group of diseases with neoplastic lymphoproliferation that consists primarily of donor B-lymphocytes. EBV PTLD is a life-threatening complication with limited therapeutic options, high mortality rate of 80–90 % and incidence between 0,5 and 1,3 %. The key to initiation of early treatment is regular EBV-DNA PCR monitoring in correlation with clinical symptoms and presence of risk factors. Since no causal antiviral therapy exists, immunotherapeutic intervention should be considered – reduction of immunosuppression, administration of CD20 monoclonal antibody (rituximab) as monotherapy or in combination with chemotherapy, adoptive immunotherapy with administration of EBV-specific T-cells or donor lymphocyte infusion (DLI).
- MeSH
- antigeny CD20 terapeutické užití MeSH
- antivirové látky terapeutické užití MeSH
- chemoprofylaxe metody MeSH
- hematologické nádory imunologie komplikace terapie MeSH
- hostitel s imunodeficiencí imunologie účinky léků MeSH
- imunosupresivní léčba škodlivé účinky MeSH
- imunoterapie metody MeSH
- infekce virem Epsteina-Barrové * epidemiologie farmakoterapie imunologie prevence a kontrola MeSH
- lidé MeSH
- lymfoproliferativní nemoci * imunologie prevence a kontrola terapie MeSH
- myší monoklonální protilátky terapeutické užití MeSH
- transfuze lymfocytů metody MeSH
- virová nálož normy účinky léků MeSH
- Check Tag
- lidé MeSH
Epstein-Barr virus (EBV) is associated with approximately one-third of Hodgkin lymphoma (HL) cases. EBV-DNA is often present in the plasma and whole blood of EBV-associated HL patients. However, the significance of EBV-DNA monitoring is debated. In a cohort of 165 adult HL patients, EBV-DNA viral load was prospectively monitored both in the plasma and whole blood. Diagnostic tissue samples of all patients were histologically reviewed; in 72% nodular sclerosis was detected, 24% presented with mixed cellularity (MC), and 5% had other type of HL. Tissues from 150 patients were also analyzed for the presence of latent EBV infection using in situ hybridization for EBV-encoded RNA (EBER) and immunohistochemistry for latent membrane protein (LMP1). Using these methods, 29 (19%) patients were classified as EBV positive. Using real-time quantitative PCR, 22 (76%) of EBV-positive HL patients had detectable EBV-DNA in the plasma and 19 (66%) patients in whole blood prior to therapy. In the group of EBV-negative HL cases, three (2%) patients had detectable plasma EBV-DNA and 30 (25%) patients whole blood EBV-DNA before treatment. EBV-positive HL was significantly associated with EBV-DNA positivity both in the plasma and whole blood in pretreatment samples, increasing age and MC subtype. Serial analysis of plasma EBV-DNA showed that response to therapy was associated with decline in viral load. Moreover, significantly increased plasma EBV-DNA level recurred before disease relapse in one patient. Our results further suggest that the assessment of plasma EBV-DNA viral load might be of value for estimation of prognosis and follow-up of patients with EBV-positive HL. 2010 The Authors. APMIS 2010 APMIS.
- MeSH
- DNA virů * krev MeSH
- dospělí MeSH
- Hodgkinova nemoc krev patologie virologie MeSH
- hybridizace in situ fluorescenční MeSH
- imunohistochemie MeSH
- infekce virem Epsteina-Barrové epidemiologie komplikace krev virologie MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- logistické modely MeSH
- mladiství MeSH
- mladý dospělý MeSH
- prospektivní studie MeSH
- proteiny virové matrix krev MeSH
- RNA virová krev MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- virová nálož MeSH
- virus Epsteinův-Barrové genetika izolace a purifikace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
