WBUR Radio Show Aired on April 9, 2013 Interview done by Darrien Garay
Ronald B. Corley, PhD
Director, Immunology Core; Associate Provost for Research, BUSM; Professor and Chairman of Microbiology
BS, Duke University
PhD, Duke University
Our laboratory is interested in the functions of secretory antibody and in the changing functions of B lymphocytes during their development and differentiation. Our studies on secretory antibody structure and function focus on IgM, the first antibody secreted during adoptive immune responses. IgM is a polymeric antibody that is normally secreted by plasma cells in the pentameric form, but IgM can be secreted in other polymeric forms as well, IgM monomers and IgM hexamers. These latter two polymers are associated with certain disease states, but their role is not understood. We have been interested in the roles of these different polymeric forms, and in understanding the unique features of pentameric IgM that not only make it the “favored” IgM product, but distinguish its function from other Ig isotypes. Using both in vitro and in vivo systems, we have identified the elements that control IgM assembly, defined the subunits that modulate its assembly, and begun to identify the distinct functions of the different polymeric forms of IgM.
Our current efforts focus on the role of IgM in initiation the immune response. Mice that are deficient in secretory IgM give a delayed protective response to pathogens and respond poorly to low doses of antigens. To help to understand the immunodeficient phenotype of these animals, we are investigating the role that IgM plays in facilitating the trapping of antigen in secondary lymphoid organs, and in enhancement of primary and secondary immune responses. We are defining the requirements for antigen trapping in lymphoid follicles, and the transport of immune complexes onto the follicular dendritic cells, cells that sequester antigen and serve as focal points for germinal center responses. As part of these studies, we are constructing mouse models in which complement-fixing and non-fixing secretory IgM is expressed in order to understand more precisely why secretory IgM cannot be entirely compensated by other immunoglobulin isotypes, as well as to understand its function in disease.
As part of our studies of B lymphocyte development and differentiation, we have been analyzing the changing roles of the NF-kB complex of transcription factors at different times during B cell differentiation. Using model B cell lines, we have found that the NF-kB complex is activated differently depending on the differentiation status of the cells. In primary B cells, the activation of NF-kB uses the “classical” pathway, where the IkB kinase (IKK) complex phosphorylates IkBalpha and IkBbeta, resulting in their degradation. However, more differentiated B cells, characterized by expression of the IgG B cell receptor, do not involve this mechanism, but rather may rely on the change in steady state levels of a third IkB component, Ikepsilon. We are determining the role that this “switch” in NF-kB activation plays in the immune system in conventional B cells, and defining the functional consequences of this switch for gene expression in B cells.
- Brewer, J.W. and R.B. Corley. 1997. Late events in assembly regulate the polymeric structure and biological activity of secretory IgM. Mol. Immunol. 34:323–331.
- Reddy, P.S. and R.B. Corley. 1998. Assembly, sorting, and exit of oligomeric proteins from the ER. BioEssays 20: 546–554.
- Hughey, C.T., J.W. Brewer, A. D. Colosia, W. F. Rosse, and R. B. Corley. 1998. Production of IgM hexamers by normal and autoimmune B cells: Implications for the physiologic role of hexameric IgM. J.Immunol. 161:4091–4097.
- Doerre, S. and R.B. Corley. 1999. Constitutive nuclear translocation of NF-kappaB in B cells in the absence of IkappaB degradation. J.Immunol. 163: 269–277.
- Reddy, P.S. and R.B. Corley. 1999. The contribution of ER quality control to the biologic functions of secretory IgM. Immunol. Today 20: 582–588.
- Phillips-Quagliata, J.M., S. Patel, J-.K. han, S. Arakelov, T.D. Rao, M.J. Shulman, S. Fazel, R.B. Corley, M. Everett, M.H. Klein, B.J. Underdown, and B. Corthésy. 2000. The IgA/IgM receptor expressed on a murine B cell lymphoma is poly-Ig receptor. J. Immunol 165: 2544–2555.