Establishment of human abzymes-generation system by using light chain shifting in human B cells

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One mechanism whereby the immune system recognizes and distinguishes foreign antigens is by generating a large and diverse repertoire of antibody molecules. This diversity protects organisms from a wide range of pathogens and toxic agents and has been exploited to produce high affinity-selective receptors for use as diagnostics, molecular probes, and therapeutic agents. On the other hands, autoantibodies attack self as an antigen, which characterizes most autoimmune diseases. Although a number of possibilities have been investigated, the mechanism responsible for the production of autoantibodies remains unsolved.Antibody genes are assembled during B cell development through a series of site-specific recombination events collectively termed V(D)J recombination. Although the V(D)J recombination at the light chain loci occur in immature B cells, we have found that the original light chain is replaced with another light chain which results from secondary V(D)J recombination (light chain shifting) in some human antibody-secreting B cells. Light chain shifting can be induced upon treatment with agents with phosphatase inhibitory activity such as caffeine and okadaic acid, the agent that stimulates protein kinase C, whereas factors that increase intracellular cAMP and calcium, and inhibit serine/threonine protein kinase did not induce light chain shifting. A light chain that is resulting from the light chain shifting has a protease activity.