Biao Q. Zheng, M.D., Ph.D.
Associate Professor, Department of Pathology & Immunology
M.D., Zhejiang Medical University
Ph.D., King's College, University of London
Postdoctoral, University of Maryland School of Medicine
Somatic Genetics and Development of Immune Responses; Immunosenescence; Autoimmunity
We are studying the molecular and cellular bases for the fundamental properties of an effective immune response, such as specificity, affinity, and memory using the techniques of cell and molecular biology, and in vitro and in vivo models of immune responses. Also, we are applying similar approaches to understand the pathology of aging and autoimmune diseases. On-going work in this laboratory has focused on the following topics.
Antigen-driven Lymphocyte Differentiation. Antigen-specific T- and B cells interact with each other in complex and dynamic microenvironments, and these interactions regulate their differentiation into different functional cells. Our research focuses on the somatic genetics of antigen-specific lymphocytes, which includes clonal analysis of antigen-receptor repertoires during in vivo immune responses; determination of the relationship between particular phenotypes of lymphocytes and their genotypes; and reconstruction of population structure of immune responses in situ. Using ex vivo and in situ cellular and molecular approaches, we have been able to follow the activation, selection, and differentiation of antigen-specific lymphocytes as an immune response develops in vivo. Further efforts will be made to elucidate the functions of lymphocytes from various compartments in the peripheral lymphoid tissues at distinct stages of immune responses such as memory and tolerance.
Germinal Center Biology. After their activation by antigen in secondary lymphoid tissues, antigen-specific T- and B-lymphocytes form a transient histologic structure known as the germinal center (GC) in the follicular dendritic cell reticulum. GCs represent a remarkable lymphoid microenvironment that functions to expand and diversify antigen-reactive clones. We have been interested in the molecular and cellular processes during the GC reaction, which is a focus of intense cellular proliferation, V(D)J hypermutation, and apoptotic death. Indeed, GCs are microcosms of Darwinian evolution that share many of the processes usually thought to occur only during primary lymphopoiesis , including positive and negative selection, elimination of self-reactive cells, and generation and enrichment of the high affinity, memory compartments. Our work has suggested GC reaction as a new development and differentiation pathway for peripheral lymphocytes. Currently, this laboratory is studying the molecular events that are involved in V(D)J hypermutation, receptor editing, and the development of memory compartments in the GC.
Immunosenescence. Dysfunction of the immune system in aged individuals includes least two important factors: accumulation of immunocytes with reduced function and accumulation of lymphocyte clones with self-reactive potential. One notable alteration during aging is that the germinal center reaction is significantly diminished. This reduced germinal center response is probably the result of age-associated impairment in lymphocyte function, but the reduction of germinal centers may itself make an important contribution to further immunological dysfunction. While progress has been made in defining age-associated alterations in the immune response, little is known about the cellular and molecular mechanisms, which drive these processes. Our laboratory is systemically studying the effect of aging on germinal center response and its immunological consequence.
Autoimmunity. In addition to peripheral lymphoid tissues, the lymphocytic infiltrates present in various autoimmune diseases also form GC-like structures. In patients with rheumatoid arthritis (RA), the synovial membrane or subchondral bone of the arthritic joints is infiltrated with T- and B lymphocytes organized into structures that are similar to the GCs present in peripheral lymphoid tissues. V(D)J hypermutation, development of plasmacytes and generation of memory cells in this GC-like environment indicate that this response is part of the chronic process of this immune-mediated disease. However, the role of GC reaction in the pathogenesis of RA has never been adequately addressed, because GCs formed in the affected joints of RA patients can not be readily studied. This laboratory has, for the first time, induced de novo GC formation in inflamed joints in a mouse model with collagen-induced arthritis (CIA). Our goal is to understand the role of GC reaction in the initiation and progression of autoimmune arthritis. This study will also provide new insight into identification of potential targets for immunological intervention.
Zheng, B., S Brett, J Tite, MR Lifely, TA Brodie, and J Rhodes. (1992) Galactose Oxidation in the Design of Immunogenetic Vaccines. Science, 256:1560.
Rhodes, J., Chen, H., Hall, S. R., Beesley, J. E., Jenkins, D. C., Collins, P. and Zheng, B. (1995) Therapeutic Potentiation of the Immune System by Costimulatory Schiff Base-forming Drugs. Nature, 377:71.
Zheng, B., Han, S., Zhu, Q., Goldsby, R., Kelsoe, G. (1996) Alternative pathways for the antigen-specific selection of peripheral T cells. Nature, 384:263.
Han, S, B Zheng, DG Schatz, E Spanopoulou, G Kelsoe (1996) Neoteny in lymphocytes: Rag1 and Rag 2 expression in germinal center B cells. Science, 274:2094.
Han, S, S-T Cao, R Bheeka-Escure, and B Zheng. (2001) Germinal Center Reaction in the Joints of Mice with Collagen-Induced Arthritis. Arthritis & Rheumatism, 44:1438.
Li, T-T. Han, S., Cubbage, M. and Zheng, B. (2002) Continued RAG-expression and TCR gene recombination in human peripheral CD4+ T cells. European Journal of Immuology, 32:2792.
- Han, S., Yang, K., Ozen, Z., Marinova, K., Peng, W., Kelsoe, G., and Zheng, B. (2003) Enhanced Splenic Differentiation of Splenic Plasma Cell but Diminished Long-lived High-affinity Bone Marrow Plasma Cells in Aged Mice. Journal of Immunology, 170:1267.
Zheng, B., Marinova, E., Han, J., Tan, T-S., and Han, S. (2003) Cutting Edge: gd T Cells Provide Help to B cells with Altered Clonotypes and Are Capable of Inducing Immunoglobulin Gene Hypermutation. Journal of Immunology, 171:4979.
Marinova, E., Han, S., and Zheng, B. (2007) Germinal center helper T-cells are dual functional regulatory cells with suppressive activity to conventional CD4+ T-cells. Journal of Immunology, 178:5010.
Zheng, B., Marinova, E., Switzer. K., Bheekha-Escura., R., Behrens, T., and Han S. (2007). Over-expression of Bcl-XL in B cells promotes Th1 response and exacerbates collagen-induced Arthritis. Journal of Immunology. 179:7087.
For a complete list of Dr. Zheng's publications, visit PubMed.
Lab web site: www.bcm.edu/labs/zhengContact Information:
Biao Q. Zheng, M.D., Ph.D.
Department of Pathology & Immunology
Baylor College of Medicine
One Baylor Plaza, BCM245
Houston, TX 77030 Telephone: 713-798-8796