CD4+ Cytotoxic T Cells Involved in the Development of EBV-Associated Diseases

Ruiz-Pablos, Manuel

doi:10.3390/pathogens11080831

Cited by 8 publications

(23 citation statements)

References 300 publications

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“…Epstein–Barr virus (EBV) is known to be involved in the development of some autoimmune diseases and certain cancer and is suspected to underlie the development of chronic fatigue syndrome/myalgic encephalomyelitis and LC [ 2 , 8 , 23 , 26 , 33 , 129 , 133 , 134 , 136 – 138 , 171 – 182 ]. However, the pathways it exploits leading to the development of these diseases remain unclear, although it is thought to be mainly related to the genetic susceptibility of an individual [ 171 ].…”

Section: Common Model Of Ebv-acquired Immunodeficiencymentioning

confidence: 99%

“…For example, HLA-DR4 alleles are associated with increased clearance of hepatitis B virus infection [ 186 ], and HLA-DRB1*0401 or DRB1*1501 alleles are associated with increased clearance of hepatitis C virus infection [ 187 ]. Surviving a greater number of pathogens has allowed these ancestral haplotypes to be inherited from generation to generation, but with the disadvantage that those older pathogens with which they have coexisted have also acquired resistance against them via co-evolution of their evasion mechanisms [ 171 , 183 ]. One of these pathogens is EBV, which is the only member of the genus Lymphocryptovirus adapted to humans and was transferred to a hominid ancestor millions of years ago [ 188 ].…”

Section: Common Model Of Ebv-acquired Immunodeficiencymentioning

confidence: 99%

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Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it present in long COVID?

Ruiz-Pablos,

Paiva,

Zabaleta

2023

J Transl Med

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Both myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) and long COVID (LC) are characterized by similar immunological alterations, persistence of chronic viral infection, autoimmunity, chronic inflammatory state, viral reactivation, hypocortisolism, and microclot formation. They also present with similar symptoms such as asthenia, exercise intolerance, sleep disorders, cognitive dysfunction, and neurological and gastrointestinal complaints. In addition, both pathologies present Epstein–Barr virus (EBV) reactivation, indicating the possibility of this virus being the link between both pathologies. Therefore, we propose that latency and recurrent EBV reactivation could generate an acquired immunodeficiency syndrome in three steps: first, an acquired EBV immunodeficiency develops in individuals with “weak” EBV HLA-II haplotypes, which prevents the control of latency I cells. Second, ectopic lymphoid structures with EBV latency form in different tissues (including the CNS), promoting inflammatory responses and further impairment of cell-mediated immunity. Finally, immune exhaustion occurs due to chronic exposure to viral antigens, with consolidation of the disease. In the case of LC, prior to the first step, there is the possibility of previous SARS-CoV-2 infection in individuals with “weak” HLA-II haplotypes against this virus and/or EBV.

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Section: Common Model Of Ebv-acquired Immunodeficiencymentioning

confidence: 99%

Section: Common Model Of Ebv-acquired Immunodeficiencymentioning

confidence: 99%

Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it present in long COVID?

Ruiz-Pablos,

Paiva,

Zabaleta

2023

J Transl Med

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“…EBV is not only linked to the malignancies, but is associated with the development of autoimmune diseases, such as systemic lupus erythematosus ( 166 ), myasthenia gravis ( 167 ), multiple sclerosis ( 168 ), rheumatoid arthritis ( 169 ), celiac disease ( 170 ), and Sjögren’s syndrome (SS) ( 171 ). The development of SS has been linked to EBV infection, as salivary gland biopsies taken from SS patients demonstrate elevated levels of EBV DNA compared to healthy salivary glands.…”

Section: Cd4 + Ctl In Chronic Virus Infections And...mentioning

confidence: 99%

Cytotoxic CD4+ T cells in chronic viral infections and cancer

Malyshkina,

Brüggemann,

Paschen

et al. 2023

Front. Immunol.

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CD4+ T cells play an important role in immune responses against pathogens and cancer cells. Although their main task is to provide help to other effector immune cells, a growing number of infections and cancer entities have been described in which CD4+ T cells exhibit direct effector functions against infected or transformed cells. The most important cell type in this context are cytotoxic CD4+ T cells (CD4+ CTL). In infectious diseases anti-viral CD4+ CTL are mainly found in chronic viral infections. Here, they often compensate for incomplete or exhausted CD8+ CTL responses. The induction of CD4+ CTL is counter-regulated by Tregs, most likely because they can be dangerous inducers of immunopathology. In viral infections, CD4+ CTL often kill via the Fas/FasL pathway, but they can also facilitate the exocytosis pathway of killing. Thus, they are very important effectors to keep persistent virus in check and guarantee host survival. In contrast to viral infections CD4+ CTL attracted attention as direct anti-tumor effectors in solid cancers only recently. Anti-tumor CD4+ CTL are defined by the expression of cytolytic markers and have been detected within the lymphocyte infiltrates of different human cancers. They kill tumor cells in an antigen-specific MHC class II-restricted manner not only by cytolysis but also by release of IFNγ. Thus, CD4+ CTL are interesting tools for cure approaches in chronic viral infections and cancer, but their potential to induce immunopathology has to be carefully taken into consideration.

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“…EBV reactivation has been observed in an array of conditions where the immune system is compromised, including haematopoietic and solid organ transplantation (10,11), HIV infection (12,13), and stress (14). While it is still unknown how EBV is linked to the development of fatigue, it is thought that genetic susceptibility (15) and viral-induced chronic inflammation ( 16) may both have a role. Suppression of some aspects of systemic immune function is a common feature of stroke and is associated with infection vulnerability and worse outcomes (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Evidence of aberrant anti-Epstein-Barr virus antibody response, though no viral reactivation, in people with post-stroke fatigue

Mouat,

Zhu,

Aslan

et al. 2024

Preprint

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BACKGROUND Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke. AIMS We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue. METHODS In a chronic ischemic stroke cohort (>6 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F <40) and low fatigue (FACIT-F >41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fishers exact test for categorical data. RESULTS We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar between the groups, we observed an altered antibody response against EBV antigens in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (VCA; 2.244 +/- 0.926 vs 3.334 +/- 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to EBV (3.23 x 10^5 +/- 4.44 x 10^4 high fatigue versus 4.60 x 10^5 +/- 9.28 x 10^4 low fatigue; P= 0.288). CONCLUSIONS These findings indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke and warrants further investigation.

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CD4+ Cytotoxic T Cells Involved in the Development of EBV-Associated Diseases

Cited by 8 publications

References 300 publications

Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it present in long COVID?

Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it present in long COVID?

Cytotoxic CD4+ T cells in chronic viral infections and cancer

Evidence of aberrant anti-Epstein-Barr virus antibody response, though no viral reactivation, in people with post-stroke fatigue

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