Epstein-Barr virus

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A stained sample of Epstein-Barr virus.

The Epstein-Barr virus (EBV) or HHV4 is a herpesvirus. The most common cause of infectious mononucleosis or "glandular fever," it infects 90% of adults worldwide.[1] It has been implicated in numerous immune diseases including chronic fatigue syndrome, multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus. It is known to turn on "risk genes" for autoimmune disease in the cells it infects.[2][3]

Initial infection[edit | edit source]

Age of infection[edit | edit source]

Most people acquire EBV in early childhood. Typically, young children who acquire EBV are either not symptomatic or have mild symptoms that are hard to distinguish from a cold or other other mild, childhood illnesses.

In adolescents and young adults, EBV can cause infectious mononucleosis (IM), also known as glandular fever.[4] IM is characterized by fever, sore throat, swollen lymph nodes, body aches, and fatigue. It generally resolves with rest and only rarely causes serious complications.

Transmission[edit | edit source]

EBV is transmitted through saliva.

Latency[edit | edit source]

In healthy adults, the virus remains latent for life in memory B cells. It is estimated that 1 in every one hundred thousand to one million circulating B cells carry EBV.[5] In healthy hosts, EBV populations are kept in check by CD4+ and CD8+ T-cell responses.

The equilibrium can be disrupted in individuals with compromised immune systems such as patients with AIDS or transplant patients taking immune system suppressing drugs.[6] It has been observed that these patients are more susceptible to EBV-related cancers, such as certain lymphomas and carcinomas.[7] In immunocompromised patients, EBV can induce lymphoproliferation, lymphoma, and hemophagocytic lymphohistiocytosis (HLH).[8]

Natural killer T cells[edit | edit source]

It is thought that natural killer T cells (NKT) play a pivotal role in the control of EBV-infected B cells through their recognition of CD1d expressing cells.[9]

Neuronal infection[edit | edit source]

A 2015 study[10] demonstrated that human neuronal cells could be directly and actively infected with EBV and another herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV).

Neuronal cells were infected with EBV or KSHV viruses which had been combined with a fluorescent protein so that the infection could be observed. The infection was seen to produce new virus cells (productive) and spread efficiently. Significantly, it not only infected surrounding neuronal cells but also nearby peripheral blood mononuclear cells.

EBV is known to be linked to many neuronal diseases[11] but this is the first evidence of how this may occur. The researchers note that this research supports the presence of EBV in neuronal diseases, but does not indicate why this is so.

In human disease[edit | edit source]

Epstein-Barr virus has been associated with a wide number of immune diseases including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus,[12] Chronic fatigue syndrome, and myasthenia gravis. EBV was recently discovered to turn on "risk genes" for autoimmune disease in the cells it infects. EBNA2, a protein produced by EBV-infected cells, and its related transcription factors activate half the human genes known to be associated with the risk for lupus as well as genes associated with several other autoimmune diseases including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease. EBV activation can thus increase the risk of developing these diseases.[2][3]

Chronic fatigue syndrome[edit | edit source]

A prospective study of 250 primary care patients revealed a higher prevalence of chronic fatigue syndrome after infectious mononucleosis (glandular fever) when compared to an ordinary upper respiratory tract infection.[13] Anti-early antigen titers to EBV were elevated in CFS patients and associated with worse symptoms.[14]

Multiple sclerosis[edit | edit source]

Infection later in life, high serum titers against EBV, and mononucleosis have all been associated with an increased risk of multiple sclerosis. MS relapses are correlated with EBV reactivation.[15]

Several studies by Alberto Ascherio, MD, DrPH, and his team at the Harvard School of Public Health have suggested that Epstein-Barr virus is involved in multiple sclerosis, specifically in people with a certain immune-related gene and high levels of antibodies to EBV in their blood.[16]

Systemic lupus erythematosus[edit | edit source]

In a study of young patients with lupus, 99% had EBV as compared to 70% of healthy controls.[17] Another study found that patients with SLE had an ∼40-fold increase in EBV viral loads compared with controls, likely stemming from altered t cell responses against EBV.[18]

Myasthenia gravis[edit | edit source]

B cells from myasthenia gravis patient stimulated in vitro by Epstein-Barr virus produced acetylcholine autoantibodies.[19] Ongoing EBV infection of the thymus has been posited as a causative agent for the production of acetylcholine receptor autoantibodies in myasthenia gravis.[20][21]

Gastrointestinal disease[edit | edit source]

One study of EBV in patients with gastritis, Crohn's disease, and ulcerative colitis and normal controls found essentially undetectable levels of EBV in normal gastric mucosa. However, EBV was detected in 46% of gastritis lesions, 44% of normal colonic mucosa, 55% of Crohn’s disease, and 64% of ulcerative colitis samples.[22]

Lyme Disease[edit | edit source]

Several herpesviruses including Epstein-Barr virus[23] may cause false positives on Lyme Disease tests.

X-MEN Disease[edit | edit source]

A 2014 study found chronic Epstein-Barr infection was linked to a magnesium transporter(MAGT-1) mutation. Dysfunction in this transporter also resulted in decreased NK cell function, and neoplasia (sometimes-cancerous growths). [24] This disorder, termed 'X-MEN' (for X-linked, EBV, and neoplasia) was identified as a recessive, X-linked disorder that would therefore be many times more common in men.

Since chronic Epstein-Barr virus infection has been associated with chronic fatigue syndrome, this error in magnesium transport may be worth considering in male patients, especially with slow onset and history of childhood infection.[24][25] However, in this disorder, EBV would be seen as an indicator of the illness rather than the cause.

Vitamin D[edit | edit source]

Some recent research is finding links between EBV and Vitamin D

An Epstein-Barr virus protein EBNA-3 has an affinity for VDR and may actually block the activation of VDR-dependent genes by Vitamin D.[26]

Vitamin D receptor may be required for the normal development of natural killer T cells that react to cells expressing CD1d, as in cells infected by EBV.[27]

As low Vitamin D is also a risk factor for MS, some studies have attempt to find a link between low Vitamin D status, EBV and MS. One study of healthy individuals found no link between EBV load and Vitamin D status. However, over half the subjects were Vitamin D deficient and none had optimal levels[28] (i.e., above 100 nmol/l)

Treatment[edit | edit source]

Epstein-barr is thought to persistent harmlessly in immunocompetent individuals but in those with compromised immune systems has been associated with certain cancers and possibly autoimmune disease.

Antivirals[edit | edit source]

Several antivirals are active against EBV including valganciclovir, valacyclovir[29], acyclovir[30] and spironolactone[31].

Acyclovir, an antiviral drug which inhibits (but does not destroy) herpesviruses, was shown to also inhibit the virus production. This suggests that EBV replicates via lytic replication.

A theoretical immunotherapy treatment proposes that inducing CD1d expression on EBV-infected B cells could prompt effective immune suppression of EBV by NKT cells.[32]

Rituximab[edit | edit source]

Rituximab may be effective in completely eliminating Epstein-Barr virus infection from the peripheral blood.[33] A study of seventeen patients with low-grade B cell lymphoma found that after three cycles of Rituximab, the virus had been completely eliminated from the peripheral blood in all but one patient.

Herbs and nutraceuticals[edit | edit source]

Herbs shown to have antiviral properties against EBV including licorice.[34] Vitamin C and Vitamin D[35] might also decrease duration and severity of the symptoms of EBV infection.[36]

References[edit | edit source]

  1. ↑ Saha, Abhik; Robertson, Erle S (May 15, 2011), "Epstein-Barr Virus–Associated B-cell Lymphomas: Pathogenesis and Clinical Outcomes", Clinical Cancer Research, 17 (10): 3056–3063, doi:10.1158/1078-0432.CCR-10-2578, ISSN 1557-3265, PMID 21372216
  2. ↑ 2.0 2.1 Harley, John (April 16, 2018). "Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity". Nature genetics.
  3. ↑ 3.0 3.1 "Epstein-Barr virus protein can "switch on" risk genes for autoimmune diseases". National Institutes of Health. April 16, 2018. Cite has empty unknown parameter: |dead-url= (help)
  4. ↑ http://www.cdc.gov/epstein-barr/about-ebv.html
  5. ↑ http://www.ncbi.nlm.nih.gov/pubmed/10781747/
  6. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/
  7. ↑ http://www.ncbi.nlm.nih.gov/pubmed/17049016
  8. ↑ Tangye, Stuart (January 20, 2017). "Human immunity against EBV—lessons from the clinic". Journal of Experimental Medicine.
  9. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/
  10. ↑ Jha, HC; Mehta, D; et al. (December 1, 2016), "Gammaherpesvirus Infection of Human Neuronal Cells", mBio, 6 (6), doi:10.1128/mBio.01844-15, PMID 26628726
  11. ↑ Kleines, M; Schiefer, J; Stienen, A; Blaum, M; Ritter, K; Häusler, M (May 15, 2011), "Expanding the spectrum of neurological disease associated with Epstein-Barr virus activity", European Journal of Clinical Microbiology & Infectious Diseases, 30 (12): 1561–1569, doi:10.1007/s10096-011-1261-7, ISSN 1435-4373
  12. ↑ Lossius, Andreas (December 2012). "Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation". Virus.
  13. ↑ http://www.ncbi.nlm.nih.gov/pubmed/9926075
  14. ↑ http://www.ncbi.nlm.nih.gov/pubmed/8730646
  15. ↑ Holmøy, Trygve (2008). "Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis". Medical Hypotheses. 70.
  16. ↑ http://www.nationalmssociety.org/What-is-MS/What-Causes-MS/Viruses
  17. ↑ James, JA (December 15, 1997). "An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus". The Journal of Clinical Investigation.
  18. ↑ Kang, Insoo (January 15, 2004). "Defective Control of Latent Epstein-Barr Virus Infection in Systemic Lupus Erythematosus". The Journal of Immunology.
  19. ↑ http://www.ncbi.nlm.nih.gov/pubmed/2553772
  20. ↑ http://www.academia.edu/20258853/Epstein-barr_virus_Trigger_for_autoimmunity/
  21. ↑ http://journals.lww.com/neurologynow/_layouts/15/oaks.journals.mobile/post.aspx?blogId=2&postId=10
  22. ↑ Ryan, Julie (2013). "Epstein-Barr Virus Infection is Common in Inflamed Gastrointestinal Mucosa". Dig Dis Sci.
  23. ↑ Goossens, HA; Nohlmans, MK; van den Bogaard, AE, "Epstein-Barr virus and cytomegalovirus infections cause false-positive results in IgM two-test protocol for early Lyme borreliosis", Infection, 27:231 (1999), PMID 10378140
  24. ↑ 24.0 24.1 Li, F.-Y.; Chaigne-Delalande, B; Su, H; Matthews, H; Lenardo, M.J. (2014), "XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus.", Blood, doi:10.1182/blood-2013-11-538686
  25. ↑ Ravell, J; Chaigne-Delalande, B; Lenardo, M (2014), "XMEN disease: a combined immune deficiency with magnesium defect.", Current Opinion in Pediatrics, doi:10.1097/MOP.0000000000000156
  26. ↑ http://www.ncbi.nlm.nih.gov/pubmed/20593215
  27. ↑ http://www.pnas.org/content/105/13/5207.short
  28. ↑ http://www.ncbi.nlm.nih.gov/pubmed/24192216?dopt=Abstract
  29. ↑ Hoshino, Yo. "Long-Term Administration of Valacyclovir Reduces the Number of Epstein-Barr Virus (EBV)-Infected B Cells but Not the Number of EBV DNA Copies per B Cell in Healthy Volunteers". Journal of Virology.
  30. ↑ Rafaillidis, Pl (November 2013). "Antiviral treatment for severe EBV infections in apparently immunocompetent patients". Journal of Clinical Virology.
  31. ↑ Verma, Dinesh; Thompson, Jacob; Swaminathan, Sankar (March 29, 2016), "Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function", Proceedings of the National Academy of Sciences, 113 (13): 3609–3614, doi:10.1073/pnas.1523686113, ISSN 1091-6490, PMID 26976570
  32. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063158/
  33. ↑ http://www.ncbi.nlm.nih.gov/pubmed/24324119
  34. ↑ http://www.ncbi.nlm.nih.gov/pubmed/18423902
  35. ↑ Rolf, L (July 2017). "Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis". Multiple Sclerosis.
  36. ↑ Mikirova, N (May 2014). "Effect of high dose vitamin C on Epstein-Barr viral infection". Med Sci Monit.

B cell B lymphocyte, or a type of white blood cell, which is involved in the immune response by secreting antibodies to ward off infections. In mammals, they are mostly matured in the bone marrow.

T cell A type of white blood cell which is mostly produced or matured in the thymus gland (hence T-cell) and is involved in the adaptive immune response on a cellular level. Also known as a T lymphocyte. (Learn more: www.youtube.com)

serum The clear yellowish fluid that remains from blood plasma after clotting factors have been removed by clot formation. (Blood plasma is simply blood that has had its blood cells removed.)

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

autoantibody An antibody that works against the body's own antigens, a hallmark of autoimmune diseases. Autoantibodies are the opposite of an antibodies.

limbic cortex Part of the brain (within the cerebral cortex) involved in emotion, memory and behavior. Part of the limbic system.

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