Viral factors which act as triggers for autoimmune diseases identified

Aug 25, 2015

A research team from Osaka University pinpointed how autoimmune diseases are developed by the Epstein-Barr virus *1 (EBV) which is known as the cause of infectious mononucleosis and for being involved in malignant lymphomas and autoimmune diseases.

EBV is a human herpesvirus, with which 90% of adults are infected. Once infected, the virus remains inside the body for the infected individual’s entire life. Most are infected during childhood and show little to no symptoms, but if infected during puberty or adulthood, the virus can cause infectious mononucleosis. Additionally, it has been suggested from epidemiological findings that the EB virus is related to various autoimmune diseases such as lymphoma, systemic lupus erythematosus, and multiple sclerosis. It had been known through previous research that the latent membrane protein 2A (LMP2A) expressed in cells latently infected with EBV encourages the survival of B cells *2 by mimicking B-cell receptor (BCR) signaling. However, the period of LMP2A expression in the body is limited to a stage of differentiation called germinal center B cells *3 , and analysis appropriately expressing these proteins in this period had not been conducted to this point.

A research group led by Associate Professor Teruhito YASUI and Professor Hitoshi KIKUTANI of the Research Institute of Microbial Diseases/Immunology Frontier Research Center at Osaka University generated a mouse model in which LMP2A are specifically expressed in germinal center (GC) B cells and considered the effects of LMP2A. As a result, it was found that the mice presented symptoms of auto-immune diseases such as production of autoantibodies and antibody deposition in the glomeruli in the kidneys. Autoimmune diseases were thought to be associated with EBV infection. This research demonstrated for the first time that they were developed by the expression of LMP2A, i.e., it was suggested that LMP2A facilitated the development of autoimmune diseases in humans. In addition, it was found that, in B cells which express LMP2A, BCR’s antigen affinity reduced due to impaired B cell selection and that Zbtb20 , a factor which facilitates plasma cell differentiation, increased. In actuality, in B cells expressing LMP2A, the differentiation into antibody-producing cells was promoted. From these results, it is thought that, through the furtherance of the survival and differentiation of B cells, LMP2A allows B cells which would normally die because of low antibody affinity to survive, contributing to the survival and spread of cells infected by EBV. From this, the development of treatment and prevention of autoimmune diseases related to EBV targeting LMP2A is anticipated.

This research was published in the online edition of the Proceedings of the National Academy of Sciences on August 25, 2015.

Figure 1: This figure shows the possibility of EBV pathogenesis in the germinal center B cells. EBV preferentially infects germinal center B cells where the EBV-gene product, LMP2a is expressed to induce transcription factor Zbtb20.  EBV infection could cause autoimmune diseases by inducing impaired B cell selection and plasma cell differentiation.

※1 Epstein-Barr Virus

The Epstein-Barr virus is not only known for being a human herpesvirus and causal virus for mononucleosis, but it is also known for its connection with various kinds of lymphoma and autoimmune diseases.

※2 B cells

B cells are extremely susceptible to cell death. B cell receptors (BCR) on the surface of the cell receive proper signals. Signaling through the B-cell antigen receptor (BCR) is required throughout B-cell development. B cells which do not receive proper signals cease to develop.

B cells differentiate into plasma cells that produce antibodies.

※3 Germinal center B cells

After infiltration of a pathogenic agent or foreign substance enters the system, B cells become active and differentiate into plasma cells and begin to produce antibodies. In order to further enhance the affinity of antigens, some B cells actively proliferate cells and introduce a random mutation to antibody genes. Most of the massive number of B cells to which mutation was introduced reduce antibody affinity and go on to die, but a small number of B cells with a high affinity will survive and differentiate into high-affinity plasma cells. This process is called the “affinity maturation process” and occurs in the germinal center. The B cells that undergo affinity maturation in the germinal center are called germinal center B cells.

※4 Zbtb20(Zinc finger and BTB domain containing 20)

This is a protein which facilitates B cell differentiation into plasma cells and works to maintain the life of these cells.

To learn more about this research, please view the full research report entitled "Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A" at this page of the Proceedings of the National Academy of Sciences of the United States of America.

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