Regulation of the Antibody Response by Transcription Factors, Scaffold Proteins and MicroRNAs

Download or read book Regulation of the Antibody Response by Transcription Factors, Scaffold Proteins and MicroRNAs written by Clayton Alexander White and published by . This book was released on 2013 with total page 183 pages. Available in PDF, EPUB and Kindle. Book excerpt: Immunoglobulin somatic hypermutation (SHM), class switch DNA recombination (CSR) and plasma cell differentiation are critical for the maturation of antibody responses to foreign and self-antigens. These processes are coordinated by a complex interplay of genetic programs, macromolecular assemblies of proteins and epigenetics. When dysregulated, these powerful processes can manifest in autoimmunity and cancer. By careful analysis of genetic knockouts, I have discovered a novel role for the Rev1 translesion DNA synthesis polymerase as a scaffold protein in the process of CSR, whereby it recruits another critical component, Ung, to switch regions through the Rev1 non-catalytic domain. Building upon previous work in the lab, I analyzed the contribution of the transcription factor HoxC4, which we had previously found regulates AID expression, to disease in lupus-prone MRL/Faslpr/lpr mice. I found that in both lupus patients and lupus-prone MRL/Faslpr/lpr mice, there is significant upregulation of AID and HoxC4. I demonstrated that HoxC4 deficiency reduced AID expression, impaired CSR, decreased serum anti-dsDNA autoantibodies and significantly reduced interchromosomal translocations, which are a source of cancer in these mice. The emerging knowledge of the importance of epigenetics in the development and function of the immune response, as well as in disease, caused me to screen epigenetic compounds for their involvement in antibody responses. I found that histone deacetylase inhibitors were potent inhibitors of the antibody and autoantibody responses in normal C57BL/6 mice and MRL/Faslpr/lpr mice. I discovered a mechanism by which HDIs directly upregulate microRNAs that target key genes of the antibody response in B cells to inhibit CSR, SHM and plasma cell differentiation. This treatment resulted in amelioration of disease and extension of lifespan in lupus-prone mice. Further, these inhibitors demonstrated similar effects on human B cells, suggesting that they may be useful in treating human disease. My studies shed light on the multiple levels of regulation that control the antibody response and demonstrate a viable class of therapeutic candidates for treating diseases that result from aberrant antibody responses.