Research
Immune system, which protects our body from microviral invasion, is composed of various kinds of cells. Among these immune cells, we foucs on the molecular mechanism that regulates the activation and development of B cells which is the only cell that produce effector molecule 'antibody'. In other words, we are trying to find a novel molecule and/or regulatory mechanisms that is essentail for B cell acitvation and development.
Molecular mechanisms of generation, activation and maintenace of memory B cells
It has been known that the protection against influenza and other viruses and effective vaccination require generation and maintenance of memory B cells.
Based on many previous studies, it has been revealed that most of the memory B cells are generated in a so called germinal center formed in the lymphoid tissues. However, the precise molecular mechanism of memory B cell differentiation from germinal center B cells is remained to be solved. We focused on this issue and tried to clarify the differentiation mechanisms of germinal center B cells (Publication 1 and 4). As the result, it was shown that signaling molecules that regulate the B cell receptor (BCR) signals are playing essetial roles in germinal center B cell differentiation. This promoted us to search for a novel unknown BCR signaling molecules.
Most of the previous studies utilized B cells that express IgM type BCR, which is expressed in the naive newly formed B cells. Our aprroach was to search for a novel signaling molecule that is selectively expressed in the B cells with IgG type BCR, which is one of the hallmark of the memory B cells. We have succeeded in identifying various molecules that seems to play a essential roles in memory B cell activation. Now, we are analyzing the physiological role of these molecules in vitro. Analysis using knock-out mice is also on the way.Mechanisms of the development of self-reactive B cells in auto-immune diseases.
It is well known that self reactive antibodies, that attacks the components of our body, is formed under autoimmune-disease conditions including systemic lupus erythematosus (SLE).
Many of the previous studies assumed that aberrant activation of T cells that control the immune system triggers the onset of the diseases. On the otherhand, following the development of medical technologies, it has been revealed that depletion of B cells ameliorates the symptoms of the diseases in some cases. This suggests the importance of not only T cells but B cells, which produces auto-reactive antibodies, are also important in the onset of disease conditions. However, the mechanisms why these abonormal B cells escape from the negative selection and differentiate to antibody forming cells are awaiting to be solved.
So far, it is almost impossible to deplete the unwanted autoreactive B cells selectively. Because of this limitation, depletion of B cells removes not only self-reactive B cells, but also normal protective B cells from the body, which results in the immunodepressive condition.
We are now focusing on the molecular mechanisms of aberrant generation of auto-reactive B cells and also trying to establish a novel method to identify and deplete the unwanted auto-reactive B cells selectively.
Regulatory mechanisms of B cell activation in allergy diseases.
Allergy diseases such as japanese cedar pollen allergy became one of the social issues. However, causal treatment of the diseases has not been established yet.
Many of these allergic diseases are triggered by the aberrant production of IgE antobody. Unfortunately, molecular mechamisms underlying the over production of IgE antibody is still remained to be solved. However, previous studies that focued in the aberrant activation of T cells that regulate B cell differentaitaion has been succeeded to some extet.
Our idea is to approach the issue not only from the T cell view point, but from the B cell that produces IgE. However, the rareness of the IgE-expressing B cells, less than 1% of immune cells, makes it difficult to promote the study. In order to over come this problem, we are developing sensitive method to identify IgE-expressing B cells and also trying to develop a novel method to deplet the IgE-expresing cells selectively.