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Journal of Neuroimmunology May 2024Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have... (Review)
Review
Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity.
Topics: Humans; Multiple Sclerosis; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Animals; Autoantigens
PubMed: 38615370
DOI: 10.1016/j.jneuroim.2024.578343 -
Infection, Genetics and Evolution :... Aug 2023Epstein-Barr virus (EBV) infection is extremely common worldwide, with approximately 90% of adults testing positive for EBV antibodies. Human are susceptible to EBV...
Epstein-Barr virus (EBV) infection is extremely common worldwide, with approximately 90% of adults testing positive for EBV antibodies. Human are susceptible to EBV infection, and primary EBV infection typically occurs early in life. EBV infection can cause infectious mononucleosis (IM) as well as some severe non-neoplastic diseases, such as chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which can have a heavy disease burden. After primary EBV infection, individuals develop robust EBV-specific T cell immune responses, with EBV-specific CD8 and part of CD4 T cells functioning as cytotoxic T cells, defending against virus. Different proteins expressed during EBV's lytic replication and latent proliferation can cause varying degrees of cellular immune responses. Strong T cell immunity plays a key role in controlling infection by decreasing viral load and eliminating infected cells. However, the virus persists as latent infection in EBV healthy carriers even with robust T cell immune response. When reactivated, it undergoes lytic replication and then transmits virions to a new host. Currently, the relationship between the pathogenesis of lymphoproliferative diseases and the adaptive immune system is still not fully clarified and needs to be explored in the future. Investigating the T cell immune responses evoked by EBV and utilizing this knowledge to design promising prophylactic vaccines are urgent issues for future research due to the importance of T cell immunity.
Topics: Adult; Humans; Child; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Immunity, Cellular; Disease Susceptibility; T-Lymphocytes, Cytotoxic
PubMed: 37201619
DOI: 10.1016/j.meegid.2023.105443 -
Frontiers in Oncology 2023EBV is a lymphotropic virus, member of the family that asymptomatically infects more than 90% of the human population, establishing a latent infection in memory B... (Review)
Review
EBV is a lymphotropic virus, member of the family that asymptomatically infects more than 90% of the human population, establishing a latent infection in memory B cells. EBV exhibits complex survival and persistence dynamics, replicating its genome through the proliferation of infected B cells or production of the lytic virions. Many studies have documented the infection of T/NK cells by EBV in healthy individuals during and after primary infection. This feature has been confirmed in humanized mouse models. Together these results have challenged the hypothesis that the infection of T/NK cells by EBV could be a triggering event for lymphomagenesis. Extranodal NK/T-cell lymphoma (ENKTCL) and Epstein-Barr virus (EBV)-positive nodal T- and NK-cell lymphoma (NKTCL) are two EBV-associated lymphomas of T/NK cells. These two lymphomas display different clinical, histological and molecular features. However, they share two intriguing characteristics: the association with EBV and a geographical prevalence in East Asia and Latin America. In this review we will discuss the genetic characteristics of EBV in order to understand the possible role of this virus in the oncogenesis of ENKTCL and NKTCL. In addition, the main immunohistological, molecular, cytogenetic and epigenetic differences between ENKTCL and NKTCL will be discussed, as well as EBV differences in latency patterns and other viral molecular characteristics.
PubMed: 37781191
DOI: 10.3389/fonc.2023.1240359 -
Revista Espanola de Enfermedades... Apr 2024Case of a 24-year-old woman presenting due to edema in lower extremities. The patient had had infectious mononucleosis three weeks prior and had medical history of...
Case of a 24-year-old woman presenting due to edema in lower extremities. The patient had had infectious mononucleosis three weeks prior and had medical history of suspicion of Crohn's disease (CD) (due to a non-specific ileocolitis in a colonoscopy/EnteroRM). No ongoing medication. Laboratory evaluation unveiled hypoproteinemia with severe hypoalbuminemia, no renal abnormalities. A PLE was assumed, with post-infectious or CD being the most likely culprits. Alternative causes were extensively excluded. A videocapsule revealed white-tipped or granular villi, some white nodular villi and diffuse edema of the mucosa, and multiple extensive erosions and superficial ulcers in the jejunum and proximal ileum, not suggestive of CD. A push enteroscopy revealed unspecific histopathology. After incomplete response to enteral nutrition, corticotherapy was initiated resulting in sustained improvement. A follow-up Ileocolonoscopy and double balloon enteroscopy revealed no abnormalities. Six months post-treatment, the patient remains asymptomatic, with unremarkable laboratory results and no need for medication.
PubMed: 38685896
DOI: 10.17235/reed.2024.10461/2024 -
Critical Reviews in Microbiology Apr 2024Epstein-Barr Virus (EBV), a dsDNA herpesvirus, is believed to play a significant role in exacerbating and potentially triggering autoimmune and autoinflammatory... (Review)
Review
Epstein-Barr Virus (EBV), a dsDNA herpesvirus, is believed to play a significant role in exacerbating and potentially triggering autoimmune and autoinflammatory maladies. Around 90% of the world is infected with the virus, which establishes latency within lymphocytes. EBV is also known to cause infectious mononucleosis, a self-limited flu-like illness, in adolescents. EBV is often reactivated and it employs several mechanisms of evading the host immune system. It has also been implicated in inducing host immune dysfunction potentially resulting in exacerbation or triggering of inflammatory processes. EBV has therefore been linked to a number of autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and Sjögren's syndrome. The review examines the molecular mechanisms through which the virus alters host immune system components thus possibly resulting in autoimmune processes. Understanding the mechanisms underpinning EBV-associated autoimmunity is pivotal; however, the precise causal pathways remain elusive. Research on therapeutic agents and vaccines for EBV has been stagnant for a long number of years until recent advances shed light on potential therapeutic targets. The implications of EBV in autoimmunity underscore the importance of developing targeted therapeutic strategies and, potentially, vaccines to mitigate the autoimmune burden associated with this ubiquitous virus.
PubMed: 38634723
DOI: 10.1080/1040841X.2024.2344114 -
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome in childhood: a narrative review.Frontiers in Medicine 2023Despite being rare, the Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a serious, possibly fatal condition that may affect both adults and... (Review)
Review
Despite being rare, the Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a serious, possibly fatal condition that may affect both adults and children who may be also burdened by delayed sequelae. It is an adverse drug reaction characterized by widespread skin involvement, fever, lymphadenopathy, visceral involvement, and laboratory abnormalities (eosinophilia, mononucleosis-like atypical lymphocytes). It is more frequently triggered by anticonvulsants, sulphonamides, or antibiotics, the latter being responsible for up to 30% of pediatric cases. The disease typically develops 2-8 weeks after exposure to the culprit medication, with fever and widespread skin eruption; mild viral prodromes are possible. Unfortunately, diagnosis is challenging due to the absence of a reliable test; however, a score by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) allows to classify suspect patients into no, possible, probable, or definite DRESS cases. Moreover, rapid-onset DRESS syndrome has been described in recent years. It affects children more often than adults and differs from the most common form because it appears ≤15 days vs. >15 days after starting the drug, it is usually triggered by antibiotics or iodinated contrast media rather than by anticonvulsants and has a higher presence of lymphadenopathy. Differential diagnosis between rapid-onset antibiotic-driven DRESS syndrome, viral exanthems, or other drug eruptions may be challenging, but it is mandatory to define it as early as possible to start adequate treatment and monitor possible complications. The present review reports the latest evidence about the diagnosis and treatment of pediatric DRESS syndrome.
PubMed: 37575981
DOI: 10.3389/fmed.2023.1108345 -
PloS One 2023Previous studies have found that the persistence of herpesvirus significantly increases the risk of idiopathic pulmonary fibrosis (IPF), but it is unclear whether this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies have found that the persistence of herpesvirus significantly increases the risk of idiopathic pulmonary fibrosis (IPF), but it is unclear whether this effect is causal. We conducted a two-sample Mendelian randomization (MR) study to evaluate the causal relationship between three herpesvirus infections and IPF.
METHODS
We used genome-wide association studies (GWAS) data from three independent datasets, including FinnGen cohort, Milieu Intérieur cohort, and 23andMe cohort, to screen for instrumental variables (IVs) of herpesvirus infection or herpesvirus-related immunoglobulin G (IgG) levels. Outcome dataset came from the largest meta-analysis of IPF susceptibility currently available.
RESULTS
In the FinnGen cohort, genetically predicted Epstein-Barr virus (EBV) (OR = 1.105, 95%CI: 0.897-1.149, p = 0.815), cytomegalovirus (CMV) (OR = 1.073, 95%CI: 0.926-1.244, p = 0.302) and herpes simplex (HSV) infection (OR = 0.906, 95%CI: 0.753-1.097, p = 0.298) were not associated with the risk of IPF. In the Milieu Intérieur cohort, we found no correlations between herpesvirus-related IgG EBV nuclear antigen-1 (EBNA1) (OR = 0.968, 95%CI: 0.782-1.198, p = 0.764), EBV viral capsid antigen (VCA) (OR = 1.061, 95CI%: 0.811-1.387, p = 0.665), CMV (OR = 1.108, 95CI%: 0.944-1.314, p = 0.240), HSV-1 (OR = 1.154, 95%CI: 0.684-1.945, p = 0.592) and HSV-2 (OR = 0.915, 95%CI: 0.793-1.056, p = 0.225) and IPF risk. Moreover, in the 23andMe cohort, no evidence of associations between mononucleosis (OR = 1.042, 95%CI: 0.709-1.532, p = 0.832) and cold scores (OR = 0.906, 95%CI: 0.603-1.362, p = 0.635) and IPF were found. Sensitivity analysis confirmed the robustness of our results.
CONCLUSIONS
This study provides preliminary evidence that EBV, CMV, and HSV herpesviruses, and herpesviruses-related IgG levels, are not causally linked to IPF. Further MR analysis will be necessary when stronger instrument variables and GWAS with larger sample sizes become available.
Topics: Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Genome-Wide Association Study; Mendelian Randomization Analysis; Herpesviridae Infections; Herpesviridae; Herpes Simplex; Herpesvirus 1, Human; Cytomegalovirus; Idiopathic Pulmonary Fibrosis; Cytomegalovirus Infections; Immunoglobulin G
PubMed: 38015883
DOI: 10.1371/journal.pone.0295082 -
Children (Basel, Switzerland) Sep 2023Peripheral lymphadenopathy affects most children at least once in a lifetime and represents a major reason for concern. Therefore, we aimed to identify the most common...
Peripheral lymphadenopathy affects most children at least once in a lifetime and represents a major reason for concern. Therefore, we aimed to identify the most common causes of peripheral lymphadenopathy in hospitalized children and to determine the clinical, laboratory and ultrasound characteristics that enable fast, easy and accurate etiological diagnosis. We performed a cross-sectional study including 139 children who were hospitalized because of peripheral lymphadenopathy. Ultrasound of lymph nodes was performed in 113 (81.3%) patients. Lymphadenopathy was generalized in nine (6.5%) patients. Malignant etiology was established in only three (2.2%) patients. Bacterial lymphadenitis, infectious mononucleosis (IM) and cat scratch disease (CSD) were diagnosed in 66 (47.5%), 31 (22.3%) and 29 (20.9%) patients, respectively. Bacterial lymphadenitis was significantly associated with neutrophilia ( < 0.01), and increased C-reactive protein levels ( < 0.01). IM was associated with pharyngitis ( < 0.01), leukocytosis without neutrophilia ( = 0.03) and increased blood liver enzyme levels ( < 0.01). CSD was associated with recent contact with a cat ( < 0.01), absence of a fever ( < 0.01) and normal white blood cell count ( < 0.01). Thorough history and clinical examination in combination with a few basic laboratory tests enable fast and accurate differentiation between the most common etiologies of lymphadenopathy in children to avoid unnecessary procedures and hospitalizations.
PubMed: 37892252
DOI: 10.3390/children10101589 -
European Journal of Case Reports in... 2024Cytomegalovirus (CMV) infection is often asymptomatic. However, in certain individuals, it can cause non-specific signs and symptoms that maybe hard to recognise. The...
UNLABELLED
Cytomegalovirus (CMV) infection is often asymptomatic. However, in certain individuals, it can cause non-specific signs and symptoms that maybe hard to recognise. The condition may therefore be overlooked or misdiagnosed, leading to prolonged illness and serious sequelae. In this case report, we present a rare instance of CMV infection in an HIV-negative patient who had a remote history of splenectomy and was experiencing prolonged fever and markedly elevated white blood cell (WBC) count.
LEARNING POINTS
The clinical presentation of CMV infection in a post-splenectomy patient can be intricate and deceptive, involving non-specific symptoms such as prolonged fever and a markedly elevated WBC count.The decision on treatment among individuals without apparent risk factors (such as AIDS, transplant, or cancers) led to in-depth deliberations and discussion.Post-splenectomy patients with CMV infection may exhibit prolonged illness, potentially leading to severe consequences if left untreated.
PubMed: 38352817
DOI: 10.12890/2024_004263 -
Brain : a Journal of Neurology Apr 2024Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the...
Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 (EBNA-1, truncated=aa[325-641], peptide=aa[385-420]) and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched controls. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 (OR=1.74, 95% CI=1.60-1.88) and EBNA-1, particularly the peptide (OR=3.13, 95% CI=2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to twelve times the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g., DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defense against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defense against EBV. Lastly, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.
PubMed: 38630618
DOI: 10.1093/brain/awae110