Paolo Casali, M.D.
Zachry Foundation Distinguished Professor
Molecular genetics of 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, we can now extend the analysis of such epigenetic modulation human antibody responses in vivo. Thus, by performing first-class research using cutting-edge technology and open communication, my laboratory continues to train next generation scientists to become future leaders in molecular immunology and epigenetics.
Related diseases: Lupus, Cancer, Allergy, Autoimmunity
Techniques: Deep Sequencing, ATAC-sequencing, humanized mice, cell sorting
(selected publications since 2000)
Complete List of Publications
- Sanchez, H.N., H. Gan, J.B. Moroney, C.C. Daw, D.P. Chupp, J.R. Taylor, H. Zan and P. Casali. 2018. B cell-intrinsic epigenetic modulation of local and systemic antibody responses by gut microbiota through catabolic short-chain fatty acids. Submitted to Nature Immunol.
- Wang, R., H. Yan, M. Fernandez, P. Casali and Z. Xu. 2018. Inhibition of Rab7 by a small molecule compound arrests growth of diffused large B cell lymphoma in vitro and in vivo. Submitted to J. Immunol.
- Yan, H., R. Wang, M. Fernandez, C. E. Rivera, H. N. Sanchez, X.-D. Li, N. Zhang, X.-Z. Meng, C. A. Hunter, Y. Xiang, H. Zan, P. Casali and Z. Xu. 2017. B lymphocytes are a major source of paracrinic IL-27 that signals through re-distributed receptors and collaborates with IFN-gamma to critically drive class-switched antibody responses and anti-viral immunity. Submitted to Cell Rep.
- Catalan-Dibene, J, M.I. Vazquez, V.P. S.P. Luu, Nuccio, A. Karimzadeh, J.M. Kastenschmidt, S.A. Villalta, I. Ushach, E.J. Pone, P. Casali, M. Raffatellu, M. Burkhardt, M. Hernandez-Ruiz, G. Heller, P.A. Hevezi and A. Zlotnik. 2017. Identification of IL-40, a Novel B Cell-Associated Cytokine. J. Immunol. 199:3326-3335; DOI:10.4049/jimmunol.1700534; PMID: 28978694.
- 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. [*equal contributors and corresponding authors]. J. Vis. Exp., 127; PMID: 28994753; DOI:10.3791/55135.
- 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’sGENES 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.
- 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
University of Milan, School of Medicine & Surgery, Specialty Diploma and Board Certification in Allergy and Clinical Immunology, 1976
University of Milan, School of Medicine & Surgery, Specialty Diploma and Board Certification in Microbiology and Virology, 1984