Epstein-Barr Virus and Systemic Autoimmune Diseases

Abstract

Epstein-Barr Virus (EBV) is an extremely successful human herpes virus, which infects essentially all human beings at some time during their life span. EBV infection and the associated immune response results in production of antibodies (seroconversion), which occurs mainly during the first years of life, but may also happen during adolescence or later in life. Infection of adolescents can result in infectious mononucleosis, an acute serious condition characterized by massive lymphocytosis. Transmission of EBV mainly occurs through saliva but can rarely be spread through semen or blood, e.g. through organ transplantations and blood transfusions. EBV transmission through oral secretions results in infection of epithelial cells of the oropharynx. From the epithelial cells EBV can infect B cells, which are the major reservoir for the virus, but other cell types may also become infected. As a result, EBV can shuttle between different cell types, mainly B cells and epithelial cells. Moreover, since the virus can switch between a latent and a lytic life cycle, EBV has the ability to cause chronic relapsing/reactivating infections. Chronic or recurrent EBV infection of epithelial cells has been linked to systemic lupus erythematosus and Sjögren's syndrome, whereas chronic/recurrent infection of B cells has been associated with rheumatoid arthritis, multiple sclerosis and other diseases. Accordingly, since EBV can shuttle between epithelial cells and B cells, the systemic autoimmune diseases often occur as overlapping syndromes with symptoms and characteristic autoantibodies (e.g. antinuclear antibodies and rheumatoid factors) reflecting epithelial and/or B cell infection.

Keywords: Epstein-Barr virus; antibodies; connective tissue disease; human herpes virus; systemic autoimmune diseases.

Figure 1

Schematic presentation of Epstein-Barr virus. (A) Schematic illustration of the basic EBV structure. (B) Enlargement of membrane section showing viral envelope glycoproteins (entry complex) and putative host-derived membrane proteins.

Figure 2

Schematic illustration of EBV fusion with the cellular lipid bilayer of B cells. For gP42 to become active, the protein is cleaved N-terminally. gP42 interacts with gH/gL, and the complex interacts with gB. gP42 interacts with the β1 domain of MHC-II, which ultimately results in membrane fusion.

Figure 3

Common basic EBV infection scheme. Viral entry can occur by direct fusion of the viral plasma membrane-derived envelope with the target cell membrane or by endocytosis/phagocytosis of virus followed by fusion of virus envelope and endosome/phagosome membrane. Both processes release virions and viral tegument proteins into the cytoplasm. Released virions are transported to the nuclear membrane and the viral genome introduced into the nucleus together with associated proteins. This initiates transcription of viral genes in a sequence of immediate-early (iE) genes, coding for regulatory alfa-proteins, early genes, coding for catalytic beta-proteins, and late (L) genes, coding for structural gamma proteins. Translation of viral messenger RNAs takes place on ribosomes in the cytoplasm and on the endoplasmic reticulum, and the viral proteins are routed to different locations for subsequent virus assembly. Successful replication of viral genomes and transport of capsid proteins to the nucleus results in assembly of virions, which travel to the plasma membrane by a series of envelopment/fusion events involving intracellular membranes (stippled lines) ending with budding of mature virus with a plasma membrane envelope, containing viral glycoproteins and host-derived membrane proteins. Premature cell death releases a mixture of “naked” virions and diffentially enveloped viruses.

Figure 4

EBV Infection cycle in B cells of systemic autoimmune diseases.