The Epstein-Barr virus: What is it and what does it mean for people?

Epstein-Barr virus (EBV), also known as infectious mononucleosis virus, is a member of the herpesvirus family, which causes various lymphoproliferative syndromes affecting the central nervous system, in which the virus can be detected in the cerebrospinal fluid (CSF). It was discovered in 1964 by researchers Epstein and Barr, who identified the association of the virus with certain types of cancer, such as Burkitt's lymphoma and nasopharyngeal carcinoma.

This virus is one of the most common in the human species and it is estimated that a large majority of the world's population is infected at some point in their lives, and it is estimated that more than 90% of the world's population is seropositive for EBV.

In patients without lymphoproliferative disease, when the virus is detected in the CSF, it is difficult to interpret clinically due to the poor clinical picture that it may sometimes present.

There are several investigations that describe EBV as one of the causal agents of encephalitis and meningitis in both immunocompetent and immunosuppressed patients; in addition to evidence of cases of cerebellar ataxia, acute disseminated encephalomyelitis, myelitis and rhombencephalitis, so its involvement as a causal agent of many diseases of the nervous system is already known.

Characteristics of the Epstein-Barr Virus

EBV is an enveloped virus containing a double DNA chain. It has a diameter of approximately 120 to 200 nanometers. Its viral genome is made up of a capsid made up of a protein icosahedron, which contains the viral genome. The envelope is a lipid membrane that contains glycoproteins important for the entry of the virus into host cells.

And its genome is approximately 172 kilobases long, encoding more than 80 proteins. These proteins are essential for the replication of the virus and for the establishment of latent infection.

Life Cycle

The life cycle of EBV can be divided into several stages:

• EntranceThe virus enters the body mainly through saliva. It adheres to the epithelial cells of the oropharynx and to the B cells of the immune system.
• Initial infection: After entry, EBV activates B cells, where it begins to replicate. During this phase, the virus can cause inflammation and symptoms such as fever and sore throat.
• Replication: Once the virus multiplies, it is released into the bloodstream and can spread to other tissues, including the lymph nodes.
• Latency: After initial infection, EBV can establish a latent infection in memory B cells. During this phase, the virus remains dormant and can be reactivated later, usually under conditions of immunosuppression.
• Reactivation: Factors such as stress, immunosuppression, or concurrent infections can induce reactivation of the virus, resulting in the production of new viral particles and, in some cases, the development of diseases such as mononucleosis.

Pathogenesis and Clinical Manifestations

EBV is known to cause several clinical manifestations, the most well-known being infectious mononucleosis. However, the virus is also implicated in a variety of other conditions.

Infectious Mononucleosis

Infectious mononucleosis is the most common manifestation of EBV in young individuals and adults. Its signs and symptoms include:

• Fever: An increase in body temperature.
• Pharyngitis: Inflammation of the throat that can make swallowing painful.
• Lymphadenopathy: Swollen lymph nodes, especially in the neck and armpits.
• Intense fatigue: Feeling of extreme tiredness that can last for weeks.
• Skin rashes: In some cases, rashes that resemble those seen in other viral infections may occur.

Associated malignant diseases

EBV is linked to several types of cancer, including:

• Burkitt's lymphoma: A type of infectious cancer most common in Africa, related to EBV and malaria.
• Nasopharyngeal carcinoma:This type of head and neck cancer has a high incidence in certain regions and has been associated with EBV infection.
• Hodgkin's lymphoma:EBV has been shown to be present in many cases of Hodgkin lymphoma, a type of cancer of the lymphatic system.

Autoimmune Diseases

EBV has also been implicated in autoimmune diseases, such as:

• Multiple sclerosis: Studies have shown a possible association between EBV infection and an increased risk of developing multiple sclerosis.
• Rheumatoid ArthritisResearch is underway to understand the link between EBV and this autoimmune disease.

EBV primarily infects B lymphocytes, which are a type of white blood cell that is essential in the immune system. After the initial infection, the virus can induce a proliferation of these cells, which can lead to a significant immune response. During this phase, the virus can cause acute symptoms and, in some cases, complications.

Once EBV is established in the body, it can remain dormant in B cells for long periods. This means that a person can be infected with the virus without showing symptoms, although it can be transmitted to others through saliva.

Infectious Mononucleosis

Infectious mononucleosis is the most common clinical manifestation of EBV infection, usually in adolescents and young adults. Symptoms include fever, sore throat, extreme fatigue, and often lymphadenopathy (swollen lymph nodes in the neck and armpits). Diagnosis is often made by serologic tests that detect specific antibodies to EBV and, in some cases, by a complete blood count that shows an increase in atypical lymphocytes.

Although most people recover completely from infectious mononucleosis within several weeks, some may experience prolonged fatigue that can last for several months. Complications, although rare, may include splenomegaly (enlargement of the spleen) and other disorders, such as hepatitis.

Other Associated Diseases

In addition to infectious mononucleosis, EBV has been associated with a number of other conditions. These include:

1. Burkitt's lymphoma: A type of B-cell cancer that is most common in Africa and is linked to malaria. EBV infection is a major risk factor.
2. Nasopharyngeal carcinoma: A type of cancer affecting the nasopharynx, most prevalent in certain regions of the world, including Southeast Asia and North Africa.
3. Multiple sclerosis: Some studies have suggested a possible association between EBV infection and the development of multiple sclerosis. However, the exact relationship and underlying mechanisms are still being investigated.
4. Autoimmune Disease:There is evidence to suggest that EBV infection may be involved in the development of autoimmune diseases, although further research is needed to understand the mechanisms.

Diagnosis and Treatment

Diagnosis of EBV infection is usually based on clinical evaluation of symptoms and serologic testing that looks for specific antibodies. Key tests include:

• Heterophile antibody tests (such as the Paul-Bunnell test): These tests determine the presence of antibodies that may indicate mononucleosis.
• Specific IgM and IgG antibody tests: These tests help determine if the infection is recent or if it is a past infection.

There is no specific antiviral treatment for EBV infection. Care is usually symptomatic, focusing on symptom relief through rest, hydration, and medications to reduce fever and pain. In severe cases, more advanced treatments, using antivirals, may be considered.

We can prevent EBV, because it is transmitted mainly through saliva, prevention measures include hygiene practices, such as not sharing utensils, glasses or toothbrushes. It is also advisable to avoid close contact with people suspected of being infected during episodes of acute mononucleosis.

Epstein-Barr virus is a common viral infection that, although often associated with infectious mononucleosis, has a broader spectrum of clinical implications. Most infections are asymptomatic and resolve spontaneously, but the virus can be linked to serious conditions, such as certain types of cancer and autoimmune diseases.

Involvement in the immune system and does it promote autoimmune diseases?

Numerous studies support the theory of how it affects the immune system by triggering autoimmune disorders. These studies reported the presence of antibodies against myelin basic protein (MBP) in 58% of autistic children, and specialists observed that there could be a direct relationship between anti-MBP antibodies and the development of autistic behavior.

Another study showed the presence of antibodies against nucleus, mitochondria, DNA and smooth muscle, using indirect immunofluorescence (IFI) in the serum of pediatric patients with autism, mental retardation and with a control population of healthy children, and observed the presence of said antibodies in 37,5% of children with autism, which was directly related to the clinical severity of the disease, antibodies against the caudate nucleus, cerebral cortex, cerebellum were also found in 49%, 18% and 9% of autistic children, respectively.

These researchers propose that autoimmune reactivity in specific brain regions may cause neurological and psychological impairment in autistic children. 

Other studies have shown autoreactivity against brain tissue in patients with autism; this response could represent a protective effect of the immune system against brain injury that occurs during neurodevelopment. And so many more studies have shown an active inflammatory process, with marked activation of microglia, astroglia and proinflammatory cytokines, in the cerebral cortex, white matter and notably in the cerebellum of patients with autism. 

These investigations also show reactivity against three brain proteins in 37% from children with autism, particularly in the hypothalamus, when compared with 13% from the control group; the immunoglobulin involved in this reactivity was IgG.

Therefore, control with autoantibody tests is essential to detect in cases without symptoms, patients who do not have lymphoproliferative diseases or in patients with Neurodevelopment, in order to identify specific antibodies in the serum of mothers of children with autism that recognize brain antigens expressed prenatally, or in patients suggesting that these autoantibodies could cross the placenta and alter fetal brain development, in prenatal cases, as well as in cases of older children in whom associated or not viral encephalitis is suspected.

The co-existence of serum antibodies against measles, mumps, and herpes simplex virus type 6 (HSV-6), as well as antibodies against the brain proteins PBM and neuroaxial filament (NAFP) was determined in children with autism. These investigations support a hypothesis based on the fact that the autoimmune response against brain tissue may be induced by a viral infection, which is a potential causal factor in autism. 

In another study, elevated IgG, IgM and C3 titres were observed in children with autism, suggesting that the activation of an immune response by constant autologous or exogenous antigenic stimulation could be the origin of the antibody levels and the clinical severity of the disease. In addition, elevated antibody levels against gluten and casein proteins were found in 50% and 83% children with autism, respectively, while a low antibody response was observed against other viruses such as measles, mumps and rubella.

These are the classic clinical presentations that we can observe in children with neurodevelopmental disorders, thus reinforcing with these investigations how the immune system is affected in different ways by viruses, generating unregulated responses.

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Article written by Enevia Health Advisor and Collaborator: Dr. Julianny Albarran 

Medical surgeon, general medicine with more than 5 years of experience in the field.

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