Immune Regulation

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Molecular pathogenesis by which Epstein-Barr virus (EBV) induces immunological disorders.

EBV is a human herpesvirus that causes infectious mononucleosis in healthy donors and proliferative disorders in immune-suppressive conditions induced by aging, immunesuppresant therapy and HIV infection. In some case it has been considered that EBV infection is associated with B cell malignancies such as Burkitt’s lymphomas and Hodgkin’s lymphomas and also with some autoimmune diseases of which Systemic lupus erythematosus (SLE) and Multiple sclerosis (MS) are developed. It infects B cells latently and is prevalent worldwide. By studying EBV biology, we are keen to determine how EBV leads to human carcinogenesis. Furthermore, the outcomes from this study may reveal attractive therapeutic strategies for EBV-associated immune disorders (Figure 3).

a) Elucidation of molecular mechanism by which EBV latent genes bring altered immune response in human host: Of EBV latent genes, Latent membrane protein 1 (LMP1) mimics CD40 signal as a constitutively activated form in B cells. Our group has indicated that LMP1 contributes to EBV infection by inhibiting the germinal center formation where the generation of high-affinity antibody-producing cells and memory B cells take place by using LMP1 transgenic mouse (Science 1999). We are now focusing on the role of host factors interacting with both LMP2a which mimic BCR signal and EBNA2 modifying Notch-mediated signaling on B cell differentiation and the growth transformation induced by EBV.

b) Molecular mechanism of EBV infection: It has been known that EBV infection give rise to B cell growth transformation and the immortalization. How does EBV invade B cells? There are multiple steps in EBV infection:virus entry, latency and lytic infection. We are now trying to establish analysis system by which the infection dynamics and the frequency of cell growth transformation can be traced in vitro and in vivo. In this valuable system we developed the visualization of EBV infection into human peripheral B cells with recombinant EBV particles carrying the gene for GFP (Figure 4).

Fig.3. EBV and host immune system

The mechanism by which EBV induces human B cell growth transformation is closely associated with the vulnerability of the host immune system.

Fig.4. Immortalization of human peripheral blood B lymphocytes by recombinant EBV carrying GFP gene.

Principal Investigator

Hitoshi Kikutani Professor

Research field:
  1. Molecular mechanisms involved in regulation of immune responses.
  2. Molecular mechanisms by which semaphorins are involved in embryonic development.
  3. Molecular mechanism by which Epstein-Barr virus (EBV) induces B-cell growth transformation and modifies B-cell differentiation.
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Shuhei Sakakibara Assistant Professor
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Tsai Chao-Yuan Specially Appointed Researcher
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