Marilia Cascalho, M.D., Ph.D.
Associate Professor of Surgery
Associate Professor of Microbiology and Immunology
marilia@umich.edu

Research interests:

1. Molecular mechanisms to generate and maintain B cell memory in health and disease, including immunodeficiencies and transplantation.

2. The means by which B cells and/or immunoglobulin diversify the T cell repertoire and how these mechanisms impact on T cell responses to microbes, tumors and transplantation.

3. Another goal of the laboratory is the study of molecular mechanisms of somatic hypermutation of immunoglobulin genes and whether these mechanisms contribute to pathogen diversity and/or tumorigenesis.

Our research investigates human subjects and novel experimental gene-targeted and conditional mouse models.

Current Research Activity:

Our laboratory studies the means by which a B cell memory response is generated from naïve B cells and the requirements for the maintenance of memory responses. We study the contributions of immunoglobulin, somatic hypermutation, thymus and T cells for the generation of long lived B cells.

Another goal of the laboratory is the study of mechanisms by which B cells and/or immunoglobulin contribute to the development and regulation of T cell responses to microbes and in transplantation. To elucidate the elements of B cell memory and the mechanisms of B cell dependent T cell development the laboratory generated novel experimental gene-targeted and conditional mouse models.

Another goal of the laboratory is the study of molecular mechanisms of somatic hypermutation of immunoglobulin genes and whether these mechanisms contribute to pathogen diversity and/or tumorigenesis.

Selected Publications:

Balin SJ, Platt JL, Cascalho M. New insights into the functions of B cells. Pediatr Transplant, 2008 Aug; 12 (5): 510-5.

Balin SJ, Ross TM, Platt JL, Cascalho M. HIV genes diversify in B cells. Curr HIV Res. 6:10-8.2008.

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.

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 179:1962-1967, 2007 (MC: Corresponding Author).

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.

Cascalho M, Platt JL. Novel functions of B cells. Curr Rev Immunol 27:141-151, 2007.

Martin DA, Lu L, Cascalho M, Wu GE. Maintenance of surrogate light chain expression induces developmental delay in early B cell compartment. J Immunol 179:4996-5005, 2007.

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(3):1962-1967, 2006.

Cascalho M, Platt JL. B cells and B cell products-helping to restore cellular immunity? Transfus Med Hemother 33(1):45-49, 2006.

Cascalho M, Platt JL. The immunologic barriers to replacing damaged organs. Curr Immunol Rev 2:65-72, 2006.

Cascalho M, Platt JL. The future of organ replacement: needs, potential applications and obstacles to application. Transplant Proc 38:362-364, 2006.

Wu X, Geraldes P, Platt JL, Cascalho M. The double-edged sword of activation-induced cytidine deaminase. J. Immunol 174:934-941, 2005.

Cascalho M. B cell tolerance: lessons from transplantation. Curr Drug Targets - Cardiovasc & Haematol Disord 5(3):271-5, 2005.

Cascalho M, Platt JL. Basic mechanisms of humoral rejection. Pediatr Transplantation 9:9-16, 2005.

Kanayama N, Cascalho M, Ohmori H. Analysis of marginal zone B cell development in the mouse with limited B cell diversity: role of the antigen receptor signals in the recruitment of B cells to the marginal zone.
J Immunol 174:1438-1445, 2005.

Ogle BM, Cascalho M, Platt JL. Biological implications of cell fusion. Nat Rev Mol Cell Biol 6:567-575, 2005.

João CM, Ogle BM, Gay-Rabinstein C, Platt JL, Cascalho M. B cell-dependent TCR diversification. J Immunol 172(8):4709-4716, 2004.

Cascalho M, Platt JL. B cell-dependent T cell development. Acta Paediatr 93(Supplement 445):52-53, 2004.

Ogle BM, Butters KA, Plummer TB, Ring KR, Knudsen B, Litzow MR, Cascalho M, Platt JL. Spontaneous fusion of cells between disparate species yields transdifferentiation and retroviral DNA transfer in vivo. FASEB J 18:548-550, 2004.

Cascalho M. Advantages and disadvantages of cytidine deamination. J Immunol 172:6513-6518, 2004.

Keshavarzi S, Rietz C, Simões S, Wong J, Shih S, Platt JL, Wong J, Wabl M, Cascalho M. The possibility of B-cell-dependent T-cell development. Scand J Immunol 57:446-452, 2003.

Wu X, Platt JL, Cascalho M. Dimerization of MLH1 and PMS2 limits nuclear localization of MutLα. Mol Cell Biol 23: 3320-3328, 2003.

Kojima H, Sitkovsky MV, Cascalho M. HIF-1α deficiency perturbs T and B cell functions. Curr Pharm Des 9:1827-32, 2003.

Ogle BM, Cascalho M, Joao CM, Taylor W, West LJ, Platt JL. Direct measurement of lymphocyte receptor diversity. Nucleic Acids Res 31:e139, 2003.

O’Connor BP, Cascalho M, Noelle RJ. Short-lived and long-lived bone marrow plasma cells are derived from a novel precursor population. J Exp Med 195(6):737-45, 2002.

Erickson LD, Durell BG, Vogel LA, O’Connor BP, Cascalho M, Yasui T, Kikutani H, Noelle RJ. Short-circuiting long-lived humoral immunity by the heightened engagement of CD40. J Clin Invest 109(5):613-20, 2002.

Magari M, Sawatari T, Kawano Y, Cascalho M, Wabl M, Kanayama N, Hikida M, Ohmori H. Contribution of light chain rearrangement in peripheral B cells to the generation of high affinity antibodies. Eur J Immunol 32(4):957-66, 2002.

Kanayama N, Kimoto T, Todo K, Nishikawa Y, Hikida M, Magari M, Cascalho M, Ohmori H. B cell selection and affinity maturation during an antibody response in the mouse with limited B cell diversity. J Immunol 169:6865-74, 2002.

Golub R, Martin D, Bertrand F, Cascalho M, Wabl M, Wu G. VH-Gene replacement in thymocytes. J Immunol 166: 855-860, 2001.

Cascalho M, Platt JL. The immunological barrier to xenotransplantation. Immunity 14:437-446, 2001.

Cascalho M, Platt JL. Xenotransplantion and other means of organ replacement. Nature Reviews 1:154-160, 2001.

Cascalho M, Wong J, Brown J, Jäck H, Steinberg C, Wabl M. A B220-negative, CD19-negative population of B cells in the peripheral blood of quasimonoclonal mice. Int Immunol 12:29-30, 2000.

Vinuesa C, Cook M, Ball J, Drew M, Sunners Y, Cascalho M, Wabl M, Klaus G, MacLennan I. Germinal centres can form without T cells, but a failsafe mechanism prevents the emergence of autoreactive cells. J Exp Med 191:485-94, 2000.

Erickson L, Vogel L, Cascalho M, Wong J, Wabl M, Durell B, Noelle R. B cell immunopoiesis: visualizing the impact of CD40 engagement on the course of T cell-independent immune responses in an Ig transgenic system. Eur J Immunol 30:3121-31, 2000.

Wabl M, Cascalho M, Steinberg C. Hypermutation in antibody affinity maturation. Curr Opin Immunol 11:186-189, 1999.

Cascalho M, Martin D, Wong J, Lam Q, Wabl M, Wu G. A monoclonal B mouse. Dev Immunol 7:43-50, 1999.

Lopez-Macías C, Kalinke U, Cascalho M, Wabl M, Hengartner H, Zinkernagel R M, Lamarre A. Secondary rearrangements and hypermutation generate sufficient B cell diversity to mount protective antiviral immunoglobulin responses. J Exp Med 189:1791-1798, 1999.

Vinuesa C, Gulbranson-Judge A, Khan M, O’Leary P, Cascalho M, Wabl M, Klaus G, Owen M, MacLennan I. A subset of dendritic cells associated with plasmablast differentiation. Eur J Immunol 29:3712-3721, 1999.

Cascalho M, Wong J, Steinberg C, Wabl M. Mismatch repair co-opted by hypermutation. Science 279:1207-1210, 1998.

Cascalho M, Wong J, Wabl M. VH gene replacement in hyperselected B cells of the quasi-monoclonal mouse. J Immunol 159:5795-5801, 1997.

Cascalho M, Ma A, Lee S, Masat L, Wabl M. A quasi-monoclonal mouse. Science 272:1649-1652, 1996.