Roles Of Phospholipase Cγ2 And Protein Phosphatease 2 AC α In B Cell Autoimmunity And Development

The B lymphocyte is the principal cellular mediator of the specific humoral immune response to infection.B cells are generated from hematopoietic stem cells(HSCs)in the bone marrow.B cell development passes through pre-B cell,pro B cell,immature B cells and transitional B cells,eventually maturing into mature follicular B cell.This complex process stages involve the interaction of various cell types and cytokines.The immune system has evolved clonal selection mechanisms to prevent the maturation of B cells that would produce autoreactive antibodies.Thus,ligation of the antigen receptors leads to receptor editing,cellular anergy and/or death by apoptosis of immature B cells,to prevent emergence of autoreactive B cells into the periphery.B cell development and anergy are focused in this thesis.Anergy in self-reactive B cells is one major physiological mechanism for establishing immune tolerance.Phospholipase Cγ2(PLCy2)is a critical signaling molecule for the B cell receptor(BCR).Previous studies carried out in our group and other labs have shown that PLCy2 is essential for B cell lineage development.In the first part of this study(chapter 2),The role PLCy2 in self-antigen B cell anergy using PLCy2 deficient mice was studied.We found that PLCy2 plays an essential role in the regulation of B cell anergy.PLCy2-deficient mice lack anergic B cells in their B cell repertoire and display a marked increase in proportion of auto-reactive antibodies and lymphocyte infiltration in their organs.PLCy2 deficiency also prevents self antigen-induced B cell anergy in a transgenic model of B cell anergy,resulting in elevation of self-reactive antibodies.Furthermore,PLC,y2 deficiency markedly enhances BCR proximal signaling.Therefore,PLCγ2 plays a critical role in regulation of B tolerance possibly through both positive and negative regulation of BCR signaling.Protein phosphorylation and dephosphorylation are essential aspects of biological signaling networks.Protein phosphatase 2A(PP2A)is an important serine/threonine phosphatase that plays an important role in cellular physiology,including cell cycle,cell proliferation,development,DNA replication and regulation of multiple signal transduction pathways.In the second part of the thesis(chapter 3),we investigated the effect of PP2A Ca deficiency on B cell lineage developmemt using conditional knockout PP2A Ca mice.The result showed that PP2A Ca deficiency led to absence of early B cell,immature B cells and reduced mature B cells.Therefore,our result indicated that PP2A Ca is essential for B cell early development.