Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021345 (infectious mononucleosis)
 3,358 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytotoxic T lymphocytes (CTL) with the CD4+ phenotype that recognize major histocompatibility complex (MHC) class II antigens are detectable very frequently in cultures of human alloreactive or virus-specific T cells. The significance of these CD4+ CTL for an immune reaction in vivo is not clear. Since Epstein-Barr virus (EBV) transformed B cells express HLA-class I and class II antigens equally well both CD8+ and CD4+ CTL should be stimulated during an acute EBV infection. We analysed the MHC specificity and the phenotype of EBV-specific CTL from patients with infectious mononucleosis (IM). When tested directly without any previous culture, T cells from patients in the acute phase of IM showed specific MHC-restricted cytotoxicity against the autologous B cell line. Addition of a HLA class I specific monoclonal antibody (MoAb) but not of a HLA class II specific MoAb resulted in a complete blocking of the lytic activity. Cell sorting revealed that the entire cytotoxic activity was present in the CD8+ fraction whereas no specific CTL were detectable in the CD4+ fraction. The absence of cytotoxicity in CD4+ cells was not due to a lack of activation of these cells since both CD8+ and CD4+ cells were activated in situ, showing spontaneous growth in interleukin-2 (IL-2) and expressing the activation marker TP103. Frequency estimation revealed that 1/300-1/600 CD8+ but only 1/2000-1/4000 CD4+ T cells gave rise to a specific CTL colony after 10 days. If CD4+ colonies were tested repeatedly for cytotoxicity we found that CD4+ CTL acquired their cytotoxicity during in vitro culture. In addition, we isolated EBV-specific CD4+ T cell clones able to lyse their stimulator cells in the presence but not in the absence of lectin, even after a long period of culture. Taken together our results show that cytotoxicity mediated by CD4+ T cells does not play a role in an anti-viral immune response.
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PMID:Absence of Epstein-Barr virus-specific, HLA class II-restricted CD4+ cytotoxic T lymphocytes in infectious mononucleosis. 169 Jun 17

Primary Epstein-Barr virus (EBV) infection, when manifest as infectious mononucleosis (IM), induces a broad-ranging and apparently non-HLA-restricted cytotoxic response whose nature has not been resolved. In the present experiments the ability to cryo-preserve IM mononuclear cell preparations, after depletion of CD16+ natural killer cells, has allowed detailed analysis of the response on appropriately constructed target cell panels. The results show that IM effector preparations are polyclonal with separate HLA class I antigen-dependent reactivities against the autologous EBV-transformed lymphoblastoid cell line (LCL) and particular HLA class I-mismatched LCLs. The autologous LCL-directed response shows the hallmarks of immunologically specific T cell cytotoxicity; only EBV+ B cell blasts are recognized and the interaction can be blocked by monoclonal antibodies to CD3 and CD8 on the effector cell surface and to HLA class I antigens on the target cell. Such findings demonstrate, for the first time, that the primary cytotoxic response to EBV infection includes a virus-specific HLA-restricted component like that found in the T cell memory of persistently infected individuals. Separate components of the response are preferentially active against some (but not all) HLA-mismatched LCLs, the pattern of reactivity being distinct for each individual IM patient and reproducible on repeated testing. Monoclonal antibody blocking experiments show that these HLA-mismatched interactions also involve CD3 and CD8 antigens on the effector cell and HLA class I antigens on the target cell. Where tested, such lysis affected both EBV+ and EBV- B cell blasts from the relevant HLA-mismatched donors. We postulate that a widespread primary infection of the B cell system by EBV leads to a generalized expansion not just of the virus-specific response but also of other T cell responses coincidentally active at the time. The unusual activity of IM effector preparations against HLA-mismatched LCLs arises from fortuitous cross-recognition of allogeneic cells by immunologically specific cytotoxic T cell clones coincidentally expanded in vivo alongside the EBV-specific response.
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PMID:Multiple HLA class I-dependent cytotoxicities constitute the "non-HLA-restricted" response in infectious mononucleosis. 244 Jun 88

The cytotoxic T-cell response induced by primary Epstein-Barr virus (EBV) infection and detectable in the blood of infectious mononucleosis (IM) patients shows several unusual features when tested in in vitro assays. Lysis of EBV-transformed target lines occurs with no apparent HLA restriction, and the putative EBV specificity of the response has been seriously questioned. In the present work we show that the primary T-cell response in IM is polyclonal and indeed does contain a virus-specific HLA class I antigen-restricted component, which can be selectively expanded in vitro in the presence of appropriate stimulator cells and IL-2. This allows functional analysis of the virus-specific component of the response in the absence of co-resident reactivities. Studies on blood samples taken from individuals in the acute phase of IM and again post-convalescence suggest that functionally similar populations of HLA class I-restricted cytotoxic T cells are involved in the control of both the primary and persistent phase of EBV infection.
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PMID:In vitro expansion of Epstein-Barr virus-specific HLA-restricted cytotoxic T cells direct from the blood of infectious mononucleosis patients. 282 28

The reactive cell population in Hodgkin's disease consists of predominantly CD4+ helper T cells and lacks CD8+ cytotoxic T cells and natural killer cells. This lack of a CD8+ response is surprising in view of the expression of the latent Epstein-Barr viral protein LMP by Reed-Sternberg cells in many cases of Hodgkin's disease, Deficient HLA class I expression would be one possible mechanism to avoid a CD8+ cytotoxic immune response. To test this possibility we studied the expression of HLA class I and II determinants on Reed-Sternberg cells in tissue sections and cell suspensions of Hodgkin's disease. Frozen tissue sections of 40 cases and cytocentrifuge preparations from cell suspensions of 10 lymph nodes involved by Hodgkin's disease were studied with monoclonal antibodies reactive with HLA determinants. As a control frozen tissue sections of two cases of infectious mononucleosis were studied. Careful examination of the tissue sections and subsequently of cytospins of cell suspensions showed that the Reed-Sternberg cells frequently lacked HLA class I but showed strong staining for HLA class II. Absence of HLA class I expression on Reed-Sternberg cells and their variants provides an explanation for the lack of a CD8+ cytotoxic immune response against antigens expressed on Reed-Sternberg cells.
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PMID:Absence of HLA class I expression by Reed-Sternberg cells. 751 95

Using HLA class I-viral epitope tetramers to monitor herpes virus-specific CD8(+) T cell responses in humans, we have shown that a significant fraction of responding cells revert from a CD45RO(+) to a CD45RA(+) state after priming. All tetramer-binding CD45RA(+) cells, regardless of epitope specificity, expressed a phenotype LFA-1(high)CCR7(low) that was stable for at least 10 years in infectious mononucleosis patients and indefinitely in asymptomatic carriers. CD8(+)CD45RA(+)LFA-1(high) cells were not present in cord blood but in adults account for up to 50% of CD8(+)CD45RA(+) cells. These CD45RA(+)LFA-1(high) cells have significantly shorter telomeres than CD45RA(+)LFA-1(low) cells, suggesting that the latter represent a naive population, while the former are memory cells. CD45RA(+) memory cells are a stable population of noncycling cells, but on stimulation they are potent producers of IFN-gamma, while naive CD8(+) cells produce only IL-2. The chemokine receptor profile and migratory potential of CD45RA(+) memory cells is very similar to CD45RO(+) cells but different to naive CD8 cells. In accord with this, CD45RA(+) memory cells were significantly underrepresented in lymph nodes, but account for virtually all CD8(+)CD45RA(+) T cells in peripheral tissues of the same individuals.
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PMID:Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics. 1141 51

Post transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients is assumed to be the result of impaired Epstein-Barr Virus (EBV)-specific cellular immunity. We analyzed the absolute CD4 and CD8 T cell counts as well as the EBV-specific CD4 and CD8 T cell responses in relation to EBV load in SOT recipients with PTLD. A prospective, single center study was initiated and 10 immunosuppressed patients with diagnosis of PTLD were analyzed and compared to 3 patients without PTLD (2 SOT recipients with EBV-reactivation, 1 patient with Infectious Mononucleosis) and 6 healthy EBV positive controls. EBV-specific CD8 T cells were enumerated using HLA class I tetramers and the IFN-gamma cytokine secretion assay. EBNA1-specific CD4 T cells were analyzed after protein stimulation and EBV load was quantified by real-time PCR. Absolute CD8 T cell counts were highly variable in all 19 cases analyzed. In contrast, the absolute EBV-specific CD8 T cell count was found to be low in 7/9 patients with PTLD (<5/microl whole blood). These frequencies were similar to absolute EBV-specific CD8 T cell numbers observed in healthy EBV positive donors, but much lower compared to patients with EBV reactivation but no PTLD. Absolute CD4 T cell counts were significantly lower in PTLD patients (mean: 336/microl+/-161 vs. controls 1008/microl+/-424, p=0.0001), with EBNA1-specific CD4 T cell responses being also low, but highly variable. Moreover, low absolute CD4 T cell counts (<230/microl) were associated with an elevated EBV load (>1000 copies/microg DNA). We conclude that SOT recipients with PTLD have an inadequate functional EBV-specific T cell response. Our data suggest that the frequency and function of circulating EBV-specific CD8 T cells are dependent on absolute CD4 T cell counts. Further studies are needed to verify if a low absolute CD4 T cell count presents a risk factor for the development of PTLD in SOT recipients.
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PMID:Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD. 1733 48

Factors involved in determining whether infectious mononucleosis occurs after primary EBV infection may include age, dose of virus received, and various genetic markers. A study by McAulay and colleagues reported in this issue of the JCI shows that the presence of certain HLA class I alleles correlates with the incidence and severity of infectious mononucleosis. These same HLA alleles are also risk factors for EBV-associated Hodgkin lymphoma (HL), supporting recent epidemiology that indicates that a history of infectious mononucleosis predisposes to HL. Recent studies suggest that an EBV vaccine might help to prevent infectious mononucleosis, and further development of this should now be considered.
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PMID:Role for HLA in susceptibility to infectious mononucleosis. 1790 31

Infectious mononucleosis (IM) is an immunopathological disease caused by EBV that occurs in young adults and is a risk factor for Hodgkin lymphoma (HL). An association between EBV-positive HL and genetic markers in the HLA class I locus has been identified, indicating that genetic differences in the HLA class I locus may alter disease phenotypes associated with EBV infection. To further determine whether HLA class I alleles may affect development of EBV-associated diseases, we analyzed 2 microsatellite markers and 2 SNPs located near the HLA class I locus in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM. Specific alleles of the 2 SNPs were also significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients possessing the associated microsatellite allele had fewer lymphocytes and increased neutrophils relative to IM patients lacking the allele. These patients also displayed higher EBV titers and milder IM symptoms. The results of this study indicate that HLA class I polymorphisms may predispose patients to development of IM upon primary EBV infection, suggesting that genetic variation in T cell responses can influence the nature of primary EBV infection and the level of viral persistence.
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PMID:HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. 1790 22

A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.
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PMID:HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. 2030 68

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM) and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR)=1.89 (1.45-2.48% confidence interval (CI)), as did raised EBNA1 IgG OR=1.74 (1.38-2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385-420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR=3.60 (2.75-4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45-0.76 95%CI) and AP 0.39 (0.18-0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection.
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PMID:Epstein-Barr virus and multiple sclerosis: interaction with HLA. 2177 12


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