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Paolo Casali, MD


University of Texas Health Science Center

Microbiology, Immunology and Molecular Genetics


B cell histone modifications and non-coding RNA as targets in lupus therapy

Epigenetic marks include histone modifications, DNA methylation and non-coding RNAs. These “interact” with genetic programs to regulate intrinsic B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody and autoantibody response. Epigenetic dysregulation can result in aberrant antibody responses to exogenous antigens or self-antigens, such as chromatin, histones and dsDNA in lupus. It compounds genetic susceptibility to mediate systemic lupus.


We hypothesize that the epigenetic modulators histone deacetylase (HDAC) inhibitors (HDIs) upregulate B cell microRNAs to suppress CSR/SHM and plasma cell differentiation and, therefore, blunt the lupus autoantibody response and prevent/“cure” the disease. Our hypotheses uniquely focus on B cells and are supported by our compelling preliminary data in human and mouse B cells in vitro. Our in vivo data have also shown that HDIs prevent autoimmunity and even cure disease in mice in an advanced stage of lupus.


We will assess the effect of HDIs in (Aim 1.1) inhibiting CSR/SHM and plasma cell differentiation in Lyn–/– and MRL/lpr lupus-prone mice, (Aim 1.2) suppressing the production of pathogenic IgG, IgA and IgE lupus autoantibodies, and (Aim 1.3) preventing disease development in those mice and “curing” and prolonging life of mice in an advanced stage of lupus. To understand the molecular mechanisms underpinning the HDI inhibition of CSR/SHM and plasma cell differentiation, we will (Aim 2.1) analyze HDI downregulation of genes important for these B cell-intrinsic functions, such as TLR7 (important for lupus), Irak2 (transducing TLR signals), Stat6 (CSR to IgG1 and IgE), Smad3 and Runx2 (CSR to IgA) and Blimp1 (encoded by Prdm1, plasma cell differentiation), and upregulation of microRNAs that can target the mRNAs of these genes, such as miR-150 (targeting Tlr7 and Irak2), miR-23b (Stat6, Smad3, Runx2 and Prdm1) and miR-30 (Stat6, Runx2 and Prdm1). We will further determine the critical role of B cell microRNAs in mediating HDI suppression of the autoantibody response using a two-prong in vivo approach by constructing (Aim 2.2) conditional KO Lyn–/– mice lacking Drosha, which critically mediates microRNA biogenesis, in AID-expressing B cells, and (Aim 2.3) conditional knockin Lyn–/– and MRL/lpr mice that express a “sponge” inhibitor that abrogates the activity of miR-150, miR-23b and miR-30 in AID-expressing B cells.


Our strengths in B cell biology, CSR/SHM mechanisms and autoimmunity, and our cutting-edge epigenetic tools make us uniquely poised to test our hypotheses. Our proposal is highly innovative and exquisitely translational. It will provide mechanistic insights and future directions in epigenetics and immunoregulation, including B cell histone modifications and non-coding RNA as mediators of autoantibody responses and as new targets in lupus therapy.

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