Professor of Microbiology
Associate Director, Medical Scientist Training Program

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Education

B.A. (Microbiology), Miami University
M.S. (Microbiology), Ohio State University
Ph.D. (Microbiology/Immunology), Ohio State University
Postdoctoral fellow, National Jewish Medical and Research Center in Denver, Colorado

Research Interests

Analysis of the Molecular and Functional Role of the Adaptor Protein HSH2. Studies are ongoing to elucidate the functional role that the adaptor protein HSH2 plays in regulating B cell biology.  HSH2 is selectively expressed in cells of the B lineage and its expression is up-regulated in vitro in response to agonists that promote B cell survival and differentiation, including CD40L, BLyS, LPS and CpG DNA. Recent studies using transgenic mice have revealed that HSH2 plays a critical role in regulating terminal differentiation of B cells into antibody secreting plasma cells.  Constitutive expression of HSH2 in the B lineage results in a significant decrease in serum immunoglobulin (Ig) titers.  Moreover, immunization of HSH2 Tg mice with either T-dependent or T-independent antigens induces only a modest antigen-specific IgM response and very little class-switched Ig production.  Conversely immunization of mice in which HSH2 is expressed at only one fifth the normal amount in B cells (HSH2 hypomorph mice), leads to enhanced production of antigen-specific class switched Ig both in terms of the kinetics and magnitude of the response when compared to wild type mice. Based on these observations, it is likely that HSH2 plays a critical role in regulating Ig class switching and terminal differentiation of B cells.  Future studies will be conducted to:

1. Identify important regions/motifs of HSH2 that are involved in its function
2. Identify the proteins that interact with HSH2 in B lymphocytes and assess their functional importance
3. Characterize the molecular mechanisms that control HSH2 expression in B cells
4. Generate conditional knockout mice to examine the importance of HSH2 in regulation of B cell development, activation and differentiation

Analysis of the Molecular and Functional Role of the Transmembrane Receptor Trem-Like Transcript 2 (TLT2). The genes encoding mouse and human TLT2 were cloned in our laboratory.  Subsequent experiments in mice demonstrated that TLT2 is expressed on B cells, neutrophils and macrophages.  With respect to the B lineage, TLT2 is expressed early during development, prior to the BCR and can be detected on both fetal liver- and bone marrow-derived B cell progenitors.  Although TLT2 is expressed on all B cells in the periphery, its level is higher on transitional, marginal zone and B-1 B cells when compared to follicular B cells.  Expression of TLT2 can be detected on peritoneal and alveolar macrophages but not on monocytes in the blood.  Finally, TLT2 is expressed on neutrophils and neutrophil progenitors.  Importantly, TLT2 is significantly up-regulated on macrophages and neutrophils in response to inflammatory stimuli such as LPS or Staphylococcal superantigens.  Neutrophils also contain large pools or preformed TLT2 in their granules that are rapidly released in response to activating stimuli such as FMLP or PMA.  Recent studies have shown that TLT2 plays an important role as a potentiating receptor that enhances the neutrophil response to agonists that bind to and signal through 7-transmembrane, G protein-coupled receptors.  Specifically, TLT2 cross-linking enhances ROS production, degranulation and migration of neutrophils stimulated with several agonists, including fMLP, and various chemokines.  Thus, TLT2 is likely to play an important role in the innate immune response and is likely to functionally bridge components of the innate response with the adaptive response.  Future studies will be conducted to:

1. Characterize TLT2 expression and function in human immune cells
2. Assess the functional role played by TLT2 in immune responses to infectious organisms and during the inflammatory response; conditional knockout mice will be generated for these studies, as well as Tg mice that conditionally express a soluble form of TLT2.
3. Identify the ligand(s) for TLT2 using several molecular and biochemical approaches
4. Identify interacting signal transduction proteins and their associated pathways that mediate the functional effects of TLT2 on immune cells

Characterization of Molecular Mechanisms that Regulate 1) Marginal Zone Development and Homeostasis and 2) Initiation and Maintenance of the Germinal Center Reaction. CD19 is a B cell transmembrane protein that is required for both the marginal zone (MZ) and germinal center (GC) B cell responses. The MZ provides a rapid response against pathogens that have entered the circulation, which otherwise can be deadly in hours. We have found that MZ macrophages are absent and dendritic cells were abnormally distributed in mice that lack CD19. Despite these structural defects, adoptive transfer studies demonstrate that failure of CD19-/- B cells to enter the MZ is B cell-intrinsic. Reconstitution of MZ B cells was followed by recovery of MZ macrophages and dendritic cells, suggesting that MZ B cells control the organization of other cells in the MZ. Studies will be conducted to:

1. Determine the mechanisms by which CD19 controls differentiation and localization of MZ B cells
2. Determine the mechanisms by which MZ B cells regulate other MZ cells

The GC is the site of affinity maturation and the generation of B cell memory, which are essential for inducing long-lasting immunity with vaccines. Preliminary data indicate that Follicular Dendritic Cell (FDC) activation fails in mice that lack CD19. The lack of FDC activation is likely critical to the failure of the GC pathway, and hence T-dependent antibody responses. CD19 could contribute to FDC activation through effects on activation of follicular B cells, on formation of immune complexes through effects on IgM, and on MZ-dependent trafficking of antigen into the follicle. Studies will be performed to:

1. Determine the role of CD19 in promoting LTb expression of GC B cells and the role of LTb in activation of FDC
2. Determine the role of immune complex formation in the initiation of the GC response
3. Examine the role of the VLA-4:VCAM-1 interaction between B cells and FDCs, respectively for maintenance of the GC response

Personal Interests

When not working he enjoys cooking and gardening, as well as fishing or hiking.