Paolo Casali, M.D.
University of Texas Ashbel Smith Professor and Distinguished Research Professor of Microbiology, Immunology & Molecular Genetics, Professor of Medicine, UT Long School of Medicine
Molecular genetics of B cell antibody generation, epigenetics of the antibody response, in vivo antibody response in humanized mice. Mechanisms of immunoglobulin locus activation and targeting, as well as regulation of genome-wide and specific gene expression by epigenetic marks and gut microbiota, in antibody/autoantibody responses and immune memory.
The Casali lab continues to focus on the B cell mechanisms underpinning the maturation of T-dependent (CD40) or T-independent (toll-like receptor) antibody and autoantibody responses, that is, Ig locus class-switch DNA recombination (CSR)/somatic hypermutation (SHM), memory B cell and plasma cell differentiation, and their regulation. Using biochemical and molecular genetic approaches, we elucidated the mechanisms by which AID inserts staggered-end double-strand breaks in S and V(D)J DNA to initiate CSR/SHM, and identified 5’-AGCT-3’ repeats and 14-3-3 adaptors as essential elements in targeting/stabilizing AID to IgH locus. We also defined roles for translesion DNA synthesis polymerases ζ (Rev3) and Ɵ in SHM, a non-enzymatic role for DNA polymerase Rev1 in CSR and a role for the homologous recombination DNA repair Rad52 in alternative non-homologous end-joining (A-NHEJ) of CSR. We have identified HoxC4 as a critical transcription factor in Aicda activation and estrogen-ERs in activation of the HoxC4 promoter and, therefore, AID expression, as modulated by Rab7 small GTPase. Estrogen-activated HoxC4 potentiates AID expression and AID off-targeting, thereby promoting chromosomal translocations, autoimmunity and lymphomagenesis. Recently, we have tackled the role of epigenetic modifications and factors, e.g., histone posttranslational modifications, non-coding RNAs, histone deacetylases (HDACs) and DNA methylases, in regulating Aicda (AID gene) expression, targeting the CSR/SHM machinery to the IgH locus, Prdm1 (Blimp1 gene) expression and plasma cell differentiation. These studies have unveiled important roles for Zn2+-dependent Class I, II, IV HDACs and NAD+-dependent Class III Sirt1 in regulating CSR/SHM and plasma cell differentiation. Also, they indicate that some of such HDACs synergize with epigenetic factors for new outcomes. As one example, we show critical and concerted roles of the NAD+-Sirt1 histone/non-histone protein deacetylase with Tet2 DNA demethylase/histone glycosylase, in B cell-intrinsic epigenetic modulation of AID and Blimp1 in autoantibody responses. Having perfected the construction of humanized huNSG/cKitW-41J mice (H-Mice®), we can now extend the analysis of such epigenetic modulation human antibody responses in vivo. We are now set to analyze in vivo the central role of the active DNA demethylator Tet2 in the epigenetic modulation of human antibody and autoantibody responses. To address the role of Tet2 in lupus autoantibody response, we have induced a full-fledged lupus in H-Mice® mice by pristane treatment. We are using our H-Mice® to model the generation of bNAbs to HIV by sequential gp121 peptide immunization in collaboration with Dr. Facundo Batista (MIT) and Dr. William R. Schief (Scripps).; we are also using our H-Mice® to study the biology pf the antibody response to SARS-COV-2 virus. I have mentored more than 40 graduate students and postdoctoral fellows who have gone on to careers in academia, industry, journal editorship and executive consulting. Byperforming first class research using cutting-edge technology and open communication, my laboratory will continue to train next generation scientists to become future leaders in molecular immunology and epigenetics. Finally, having recently relinquished my administrative departmental chair duties, I am now in the position to dedicate most of my time and attention to my scientific endeavors.
Related diseases: Lupus, Cancer, Allergy, Autoimmunity
Techniques: Deep Sequencing, ATAC-sequencing, humanized mice, cell sorting.
Complete List of Publications
- Gan H., T. Shen, D.P. Chupp, J.R. Taylor, H.N. Sanchez, X. Li, Z. Xu, H. Zan and P. Casali. 2020. B cell Sirt1 deacetylates histone and non-histone proteins for epigenetic modulation of AID expression and the antibody response. Science Adv. 6:eaay2793. (PMCID: PMC7112761).
- Moroney J.B., A. Vasudev, A. Pertsemlidis, H. Zan and P. Casali. 2020. Integrative analysis of coding, non-coding transcriptome and chromatin accessibility reveals a distinct gene expression and epigenetic landscape in human memory B cells. Nature Comm., in press.
- Hui Y., M. Fernandez, J. Wang, S. Wu, R. Wang, Z. Lou, J.B. Moroney, C.E. Rivera, J,R. Taylor, H. Gan, H. Zan, D. Kolvaskyy, D. Liu, P. Casali* and Z. Xu* 2020. B cell endosomal RAB7 promotes TRAF6 K63 polyubiquitination and NF-kB activation for antibody class-switching. J. Immunol. 204(5):1146-1157. [*Co-corresponding authors] (PMCID: PMC7033007).
- Sanchez H.N., J.B. Moroney, H. Gan, T. Shen, J.H. Im, T. Li, J.R. Taylor, H. Zan and P. Casali. 2020. B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber derived short-chain fatty acids. Nature Comm. 11:60. (PMCID: PMC6940392).
- Casali P.*, T. Shen, Y. Xu, Z. Qiu, J.H. Im, D.P. Chupp and H. Zan*. 2020. Estrogen reverses epigenetic HDAC inhibitor-mediated reduction of Aicda and class-switch DNA recombination in antibody and autoantibody responses by repressing miR-26a. Front. Immunol. [*Co-corresponding authors] (PMCID: PMC7105609).
- Sanchez, H. N., T. Shen, D. Garcia, Z. Lai, P. Casali, and H. Zan. 2017. Genome-wide analysis of HDAC inhibitor-mediated modulation of microRNAs and mRNAs in B cells induced to undergo class-switch DNA recombination and plasma cell differentiation. J. Vis. Exp. e55135 (PMCID: PMC5731236).
- Zan, H., C. Tat, Z. Qiu, J.A. Guerrero, J. R. Taylor, T. Shen and P. Casali. 2017. Rad52 competes with Ku70/Ku86 for binding to S-region DSB ends to modulate antibody class-switch DNA recombination. Nature Commun. 8:14244. PMID: 28176781; PMCID: PMC5309807. DOI: 10.1038/ncomms14244.
- Casali, P. 2017. DNA recombination and somatic hypermutation in the immune system. In: Lewin’s GENES XII, J.E. Krebs, E.S. Goldstein, S.T. Kilpatrick, Eds. (12th Edition), Jones & Bartlett Publishers. Boston, Toronto, London, Singapore. Chapter 16, pages 397-439. [Web-link].
- Lam, T., D.V. Kulp, R. Wang, Z. Lou, J., Taylor, Q. Zhong, Z. Wang, H. Zan, D. Ivanov, G. Zhong, P. Casali* and Z. Xu*. 2016. Small molecule inhibitor of Rab7 impairs B cell class-class switching and plasma cell survival to dampen the autoantibody response in murine lupus [*equal contributors and corresponding authors]. J. Immunol. 197:3792-3805. PMID: 27742832; PMCID: PMC5113143; DOI: 10.4049/jimmunol.1601427
- Zan, H. and P. Casali. 2016. Epigenetic of B cells and antibody responses. Front. Immunol. 6:656. PMID: 26793194; PMCID: PMC4707482; DOI: 10.3389/fimmu.2015.00656
- Zan, H. and P. Casali. 2015. Epigenetics of peripheral B cells differentiation and the antibody response. Front. Immunol. 6:631. PMID: 26697022; PMCID: PMC4677338. http://dx.doi.org/10.3389/fimmu.2015.00631
- Lou, Z., P. Casali and Z. Xu. 2105. Role of intracellular membrane-associated proteins in antibody responses: modulation by microRNAs in B cells. Front. Immunol. 6:537. PMID: 26579118; PMCID: PMC4620719. http://dx.doi.org/10.3389/fimmu.2015.00537
- Shen, T., H.N. Sanchez, H. Zan and P. Casali. 2015. Genome-wide analysis reveals selective modulation of microRNAs and mRNAs by histone deacetylase inhibitor in B cells induced to undergo class-switch DNA recombination and plasma cell differentiation. Front. Immunol. 6:627. PMID: 26697020; PMCID: PMC4677488. http://dx.doi.org/10.3389/fimmu.2015.00627.
- Pone E. J., T. Lam, Z. Lou, R. Wang, Y. Chen, D.-F. Liu, A. L. Edinger, Z. Xu and P. Casali. 2015. B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses. J. Immunol. 194: 3065-3078. PMID: 25740947; PMCID: PMC4643723.
- Pone E. J., Z. Lou, T. Lam, M. L. Greenberg, R. Wang, Z. Xu and P. Casali. 2015. B cell TLR1/2, TLR4, TLR7 and TLR9 interact in induction of class switch DNA recombination: modulation by BCR and CD40, and relevance to T-independent antibody responses. Autoimmunity 48: 1-12. PMID: 25536171; PMCID: PMC4625915.
- White, C.A., E.J. Pone, T. Lam, C. Tat, K.L. Hayama, G. Li, H. Zan & P. Casali. 2014. Histone deacetylase inhibitors upregulate B cell microRNAs that silence AID and Blimp-1 expression for epigenetic modulation of antibody and autoantibody responses. J. Immunol.193:5933-5950. PMID: 25392531; PMCID: PMC4258531.
- Morgado, P., D.M. Sudarshana , L. Gov, K.S. Harker, T. Lam, P. Casali, J.P. Boyle and M.B. Lodoen. 2014. Type II Toxoplasma gondii induction of CD40 on infected macrophages enhances interleukin-12 responses. Infect. Immun. 82:4047-4055. PMID: 25024369; PMCID: PMC4187859.
- Zan, H., C. Tat and P. Casali. 2014. MicroRNAs in lupus. Autoimmunity 47:272-275. PMID: 24826805; PMCID: PMC4239026.
- Casali, P. 2014. DNA recombination and somatic hypermutation in the immune system. In: Lewin’sGENES XI, J.E. Krebs, E.S. Goldstein, S.T. Kilpatrick, Eds. (11th Edition), Jones & Bartlett Publishers. Boston, Toronto, London, Singapore. Chapter 18, pages 459-507. [Web Link]
- Zan, H. and P. Casali. 2014. Immunoglobulin somatic hypermutation and class switch DNA recombination. In: Encyclopedia of Medical Immunology. Vol. 1. Autoimmune Diseases, I.R. Mackay & N.L. Rose, Eds. Springer-Verlag GmbH, Heidelberg, 2014. Pages 517-528. [Web Link]
- Lam, T.S., L.M. Thomas, C.A. White, G. Li, E.J. Pone, Z. Xu and P. Casali. 2013. Scaffold functions of 14-3-3 adaptors in B cell immunoglobuin class switch DNA recombination. PLOS ONE 8: e80414, 1-15. PMID: 24282540; PMCID: PMC3840166.
- Li, G., E.J. Pone, T. Mai, T.S. Lam, C.A. White, K.L. Hayama, H. Zan, Z. Xu and P. Casali. 2013. Combinatorial H3K9acS10ph histone modifications in IgH locus S regions target 14-3-3 adaptors and AID to specify antibody class switch DNA recombination. Cell Rep. 5:702-714. PMID: 24209747; PMCID: PMC3951903.
- Li, G., H. Zan, Z. Xu and P. Casali. 2013. Epigenetics of the antibody response. Trends Immunol. 34:460-470. PMID: 23643790; PMCID: PMC3744588.
- Mai, T., E.J. Pone, G. Li, J. Moehlman, Z. Xu and P. Casali. 2013. Induction of activation-induced cytidine deaminase-targeting adaptor 14-3-3g is mediated by NF-kB-dependent recruitment of CFP1 to the 5’-CpG-3’-rich 14-3-3g promoter and sustained by E2A. J. Immunol. 191:1895-1906. PMID: 23851690; PMCID: PMC3833273.
- Park, S.-R., P.H. Kim, K.S. Lee, S.H. Lee, G.Y. Seo, Y.C. Yoo, J. Lee and P. Casali. 2013. APRIL stimulates NF-kB-mediated HoxC4 induction for AID expression in mouse B cells. Cytokine 61:608-613. PMID: 23178148; PMCID: PMC3723325.
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M.D., University of Milan, School of Medicine & Surgery, 1974.
Specialty Diploma and Board Certification in Allergy and Clinical Immunology, University of Milan, School of Medicine & Surgery, 1976.
Doctorat en Immunologie, University of Geneva, Ecole de Medicine, 1979.
Specialty Diploma and Board Certification in Microbiology and Virology, University of Milan, School of Medicine & Surgery, 1984.