Marilia Cascalho, M.D., Ph.D.
Marilia Cascalho, MD, PhD, is Associate Professor of Surgery and Associate Professor of Microbiology & Immunology. She received her medical training at the University of Lisbon, Portugal and did her graduate studies at the University of California, San Francisco, CA. Most recent research and professional experience includes Assistant Professor in the Departments of Immunology, Surgery and Pediatrics at the Mayo Clinic, Rochester, MN, Chair of the Division of Experimental Surgery at the Mayo Clinic, Rochester, MN and Associate Editor for the Journal of Immunology. She has published more than 50 papers and contributed to several books. Awards and honors include the Juvenile Diabetes Fellowship and Leukemia Research Foundation Fellowship.
Dr. Cascalho’s research focuses on the immunobiology of B cell and T cell responses to microorganisms, transplants and tumors.
Early in her career Dr. Cascalho and collaborators engineered a mouse model with a simplified immune system by targeting the immunoglobulin heavy and light chain loci (1). The “quasi-monoclonal mouse”, as such, proved instrumental in resolving fundamental questions about how the variable regions diversify and impact of B cell V region diversification on B cell and T cell biology. For example, the quasi-monoclonal mice and derivatives were instrumental to our discovery that DNA
mismatch repair contributes to somatic hypermutation of immunoglobulin genes (2) and thus to affinity maturation and generation of B cell memory. The model allowed us to identify the components of the B cell receptor necessary for survival of mature B cells (3). It also led to our connecting B cell receptor diversification development and diversification of the TCR repertoire. Finally, in collaborations with Dr. R. Bram the model advanced understanding of the B cell differentiation and
development of long-lived plasma cells and to the concept that TACI has both inhibitory and stimulatory functions. Recently, we found that paradoxically, in spite of severe hypogammaglobulinemia, TACI-deficient animals have enhanced host defense. This serendipitous finding suggested a mechanism to explain the high prevalence of TACI variant genes in the population (4).
(1) Cascalho M, Ma A, Lee S, Masat L, Wabl M. A quasi-monoclonal mouse. Science 272:1649-52, 1996.
(2) Cascalho M, Wong J, Steinberg C, Wabl M. Mismatch repair co-opted by hypermutation Science 279:1207-1210, 1998.
(3) Geraldes P, Rebrovich M, Herrmann K, Wong J, Jäck H-M, Wabl M, Cascalho M. Ig heavy chain promotes mature B cell survival in the absence of light chain. J Immunol 179: 1659-1668, 2007.
(4) Tsuji S, Stein L, Kamada N, Nunez G, Bram R, Sousa A E, Platt JL, Cascalho M. TACI-deficiency enhances antibody avidity and clearance of an intestinal pathogen. J Clin Invest 2014 124:4857-66, 2014. PMID: 25271628
Research Opportunities for Rotating Students
1. Mechanism of somatic hypermutation and generation of diversity and immunity. Dr. Cascalho first identified the contribution of DNA mismatch repair to immunoglobulin somatic hypermutation, thus resolving a long standing paradox (Science, 1998 cited above). Dr. Cascalho and collaborators then discovered that nuclear localization controls mismatch repair and that the function of activation-induced cytidine deaminase, the enzyme that initiates somatic hypermutation of Ig genes, is regulated by its association with the DNA protein kinase complex. Dr. Cascalho showed that somatic hypermutation diversifies microbial genes and generates variants similar to those found in nature. This finding originated a novel concept of vaccination, the “mutable vaccine,” and a patent “Mutable Vaccines” US Patent No: US 7,776,321 B2. The “mutable vaccine” is a DNA vaccine that encodes a microbial antigen that diversifies in B cells undergoing somatic hypermutation. The variants are secreted from plasma cells and in turn evoke variant-specific immunity in anticipation of variants generated naturally. We hypothesize that exposure to diversifying variants in vaccinated individuals will generate broadly reactive immunity and protection against new strains.
Cascalho M, Wong J, Wabl M. VH gene replacement in hyperselected B cells of the quasi-monoclonal mouse. J Immunol 159:5795-5801, 1997.
Wu X, Platt JL, Cascalho M. Dimerization of MLH1 and PMS2 limits nuclear localization of MutLα. Mol Cell Biol 23: 3320-3328, 2003.
Wu X, Geraldes P, Platt JL, Cascalho M. The double-edged sword of activation-induced cytidine deaminase. J Immunol 174:934-941, 2005.
Balin SJ, Ross TM, Platt JL, Cascalho M. HIV genes diversify in B cells. Curr HIV Res 6:10-18, 2008.
2. B cell diversity and immunoglobulin contribute to T cell development and function. Dr. Cascalho discovered that B cells and the Ig they produce facilitate development and diversification of thymocytes, allowing T cell-dependent control of Pneumocystis murina. This research originated two patent applications: “Methods of assessing biologic diversity.” PCT NO: US04/12058 (Co-inventor) and “Methods for altering T cell diversity.” PCT NO: US05/07101 (Co-inventor). B cell-dependent-T cell immunity, as such, was found to fashion the dimensions and determine the outcome of cell-mediated immune responses in transplantation. Among various implications of this research is understanding how transplant recipients might respond to B cell depletion therapies.
João CM, Ogle BM, Gay-Rabinstein C, Platt JL, Cascalho M. B cell-dependent TCR diversification.
J Immunol 172:4709-4716, 2004. PMID: 15067046
Cascalho M, Platt JL. B cell-dependent T cell development. Acta Paediatr 93(Supplement 445):52-53, 2004. PMID: 15176721
Cascalho M, Platt JL. B cells and B cell products—helping to restore cellular immunity? Transfus Med Hemother 33:45-49, 2006. PMID: 16755301
Balin SJ, Cascalho M. The rate of mutation of a single gene. Nucleic Acids Res. 2010. 38:1575-82. PMID: 20007603
3. Fitness of cellular immunity and T cell receptor diversity. T cell diversity is generally thought to confer immune fitness. However which properties of immunity depend absolutely on TCR receptor diversity and the extent of diversity necessary for optimal function are not fully understood. My research conducted in collaboration with Dr. Platt revealed for the first time that significant contractions of the T cell receptor repertoire do not impair certain functions of cell-mediated immunity, such as defense against intracellular fungi and rejection of grafts disparate for minor transplant antigens, but instead limit T cell-dependent B cell responses.
Ogle BM, West LJ, Driscoll DJ, Strome SE, Razonable RR, Paya CV, Cascalho M, Platt JL. Effacing of the T cell compartment by cardiac transplantation in infancy. J Immunol 176:1962-1967, 2006. PMID: 16424228
AbuAttieh M, Rebrovich M, Wettstein PJ, Vuk-Pavlovic Z, Limper AH, Platt JL, Cascalho M. Fitness of cell-mediated immunity independent of repertoire diversity. J Immunol 178:2950-2960, 2007. PMID: 17312140
AbuAttieh MQ, Bender D, Liu E, Wettstein P, Platt JL, Cascalho M. Affinity maturation of antibodies requires integrity of the adult thymus. Eur J Immunol 42:500-510, 2012. PMID:22105515
4. B cell responses in transplantation. In collaboration with Dr. Platt, I advanced concepts regarding the genesis and impact of donor-specific B cell responses in transplantation, including accommodation.
Cascalho M, Platt JL. The immunological barrier to xenotransplantation. Immunity 14:437-446, 2001. PMID: 11336689.
Platt JL, Tsuji S, Cascalho M. Novel functions of B cells in transplantation. Current Opinion in Organ Transplantation, 16(1):61-68, 2011. PMID:21150607
Lynch R, Chen B, Punch JD, Cascalho M*, Platt JL.* Cryptic B cell response to renal transplantation Am J Transplant. 2013. 13(7):1713-1723, 2013. PMID:23750851. M Cascalho and L Platt are corresponding authors.
Cascalho M*, Chen BJ, Kain M, Platt JL. The Paradoxical functions of B cells in transplantation. Journal of Immunology 190:875-9, 2013. PMID: 23335803. M. Cascalho is the corresponding author.
5. The control of immunity by the “transmembrane activator and CAML interactor” (TACI). Exploring the determinants of immune fitness and control, we discovered that TACI, a receptor expressed by B cells and T cells, regulates expression of Blimp-1, the master transcription factor governing plasma cell differentiation. Consistent with that function, mutants of TACI and related proteins underlie common variable immunodeficiency, the most common primary immunodeficiency disease. Most remarkable, however, we also discovered that while TACI-deficiency causes hypogammaglobulinemia and defective memory, it does not prevent and indeed it promotes production in bursts of high affinity antibodies capable of protecting animals against enteric pathogens. Because human variants of TACI (C104R and A181E) that impair TACI function are frequent, our discovery raises the possibility that TACI variants might in fact be adaptations that confer protection against pathogens common in some populations.
Mantchev GT, Cortesão C, Rebrovich M, Cascalho M*, Bram RJ.* TACI is required for efficient plasma cell differentiation in response to T-independent type 2 antigens. J Immunol 179:2282-2288, 2007. * M. Cascalho and R. Bram are corresponding authors. PMID: 17675489
Tsuji S, Cortesão C, Bram R, Platt JL, Cascalho M. TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow. Blood, 118(22):5832-5839, 2011. PMID: 21984806
Tsuji S, Stein L, Kamada N, Nunez G, Bram R, Sousa A E, Platt JL, Cascalho M. TACI-deficiency enhances antibody avidity and clearance of an intestinal pathogen. J Clin Invest 2014. 124:4857-66. PMID: 25271628