John E. Butler, Ph.D.
Ph.D., University of Kansas, 1965 |
Professor of Microbiology Campus address: 3-550 BSB Mailing address: 51 Newton Rd. 3-550 Bowen Science Building Iowa City, IA 52242 Phone: 319-335-7776 Email: |
Antibody and T Cell Repertoire Development in Neonates
The antibody and T cell repertoires develop by combinatorial joining of somatic gene segments mediated by special recombinases. This generates a broad and sometime autoreactive pre-immune repertoire, e.g. the innate natural antibody repertoire. This immature repertoire is refined and diversified by somatic hypermutation and selection to fashion an adaptive immune response/system. This refinement also involves changes in the class or subclass of antibodies used, e.g. IgG, IgA, etc. Four extrinsic factors; diet, maternal regulatory factors, gut flora and pathogens, impact the development of the adaptive immune system during a narrow window of neonatal life. Understanding how these factors promote the transition to adaptive immunity is important in human and animal health. In species like mice and humans, discriminating between repertoire changes generated by intrinsic events versus the extrinsic factors listed above, is difficult. Thus, our studies utilize the isolator piglet model in which all four of theses extrinsic factors can be controlled by the experimenter.
We have shown that contact with microorganism-associated molecular patterns (MAMPs) is required for transition from the pre-immune to the adaptive antibody repertoire. In fact, isolated MAMPs can alone be substituted. Viral pathogens also provide MAMPs for development but some can interfere with the normal transition resulting in immune dysregulation. This can result in immunopathology such as autoimmunity or B cell suppression. Inappropriate neonatal contact with certain bacteria can also upset the development of immune homeostasis and can cause inflammatory bowel disease. The isolator piglet model allows the role of these microorganisms on the development of proper neonatal immunity to be studied.
Monitoring the effect of the changes in T- and B cell repertoires at the molecular level also requires characterization of the antigen receptors on these lymphocytes. Therefore some portion of laboratory effort is devoted to characterizing the porcine T- and B cell antigen receptors.
Current research is focused on a three-virus model in an effort to determine how each virus interacts with normal gut flora, diet and maternal factors to control maturation of the antibody and T cell repertoires during neonatal life.
Recent publications
Butler, J.E., and N. Wertz. 2006. Antibody repertoire development in fetal and neonatal piglets. XVII. IgG subclass transcription revisited with emphasis on new IgG3. J Immunol 177:5480-5489.
Butler, J.E. (Guest editor) 2006. Antibody repertoire development among vertebrates. Development and Comparative Immunology Special Issue 30:1-247.
Butler, J.E., D. Francis, J. Freeling, P. Weber, J. Sun, K.L. Nielsen, and A.M. Krieg. 2005. Antibody repertoire development in fetal and neonatal piglets. IX. Three PAMPs act synergistically to allow germfree piglets to respond to TI-2 and TD antigens. J Immunol 175:6772-6785.