Hiromi Kubagawa, MD
Adjunct Professor of Pathology, Microbiology & Medicine
|Address:||1825 University Blvd
Shelby Bldg, room 506
Birmingham, AL 35294
M.D., Juntendo University, Tokyo, Japan
Residency, Anatomic and Surgical Pathology, Nihon University
Post-doctoral studies, Max Cooper, MD Laboratory, Division of Developmental and Clinical Immunology, UAB
The main goal of my research is to define the development and differentiation of lymphoid- and myeloid-lineage cells in the context of exploring the diseases of the immune system. Several cell surface molecules expressed by these cell types are being studied with regard to their structure and function in adaptive and innate immunity. My colleagues and I are currently focusing on two Fc receptor-related molecules: (i) paired immunoglobulin-like receptors, PIR-A (A for activating) and PIR-B (B for braking or inhibitory), and (ii) the Fc receptor for IgA and IgM (Fcα/µR).
PIR: In 1997, two different laboratories, Dr. Toshiyuki Takai's and mine, independently identified the Pira and Pirb genes in mice on the basis of limited homology with the human IgA Fc receptor (CD89). [The human counterparts are considered to be the activating and inhibitory types of leukocyte Ig-like receptors (LIR/CD85).] It is now evident that Pir is a multigene family and that PIR-A and PIR-B are cell surface glycoproteins with very similar extracellular regions (>92% homology), but having distinctive transmembrane and cytoplasmic regions. There are multiple PIR-A isoforms (>6), each encoded by a different Pira gene. PIR-A associates non-covalently with a signal transducing transmembrane protein called FcRγc that contains tyrosine-based activation motifs in the cytoplasmic tail, to form a cell activation complex. In contrast, PIR-B is encoded by a single gene and contains three functional tyrosine-based inhibitory motifs in its cytoplasmic tail, thereby negatively regulating cellular activity via the SHP-1 and SHP-2 tyrosine phosphatases. PIR-A and PIR-B are expressed by many hematopoietic cell types, including B cells, dendritic cells (DC), leukocytes, mast cells, and megakaryocyte/platelets. In addition to these mature cell types, PIR are expressed by hematopoietic progenitor cells. They are not expressed by T cells, NK cells and erythrocytes. While PIR are suggested to recognize MHC class I antigen, identity of PIR ligands still remains unclear. Several findings suggest that the function of PIR is to regulate the immune system. (i) Co-ligation of PIR with the B cell receptor (BCR) or high-affinity IgE receptor (FcεRI) on mast cells attenuates the BCR-mediated activation and IgE-mediated mast cell responses. (ii) Disruption of Pirb gene results in hyper-responsiveness of B cells and, surprisingly, increased IgG1 and IgE responses to T-dependent antigens, suggesting an enhanced Th2 response due to immaturity of PIR-B deficient DC. (iii) PIR-B deficient mice exhibit an exaggerated graft-versus-host disease. These findings led to the hypothesis that PIR-A and PIR-B play specific regulatory roles in host defense, including inflammatory, coagulative, antigen-presenting, allergic and humoral immune responses. This hypothesis is currently being tested in the following aims: (i) to identify the PIR ligands and (ii) to determine the functional consequences of PIR-B deficiency in a gene-targeted mouse model.
Fcα/μR: Evidence for an IgM Fc receptor (FcμR) on subpopulations of B, T, NK cells and macrophages have been reported from many laboratories including ours for many years. A gene encoding an FcμR, however, defied identification until the serendipitous discovery of a murine cDNA that encodes a protein able to bind the Fc portion of both IgA and IgM, hence its designation as Fcα/μR. The predicted Fcα/μR protein consists of an extracellular region with a single Ig-like domain, an uncharged transmembrane segment, and a cytoplasmic tail. The Ig-like domain contains a sequence motif, which is conserved in the polymeric Ig receptor of various species and is predicted to be the binding site for IgM and IgA. The carboxyl terminal two-thirds of the extracellular region is uncharacteristic in terms of domain nature. The cytoplasmic tail contains no tyrosine residues, but possesses two serine and four threonine residues that are conserved in both human and mouse. A di-leucine motif shown to be involved in receptor internalization is found in the cytoplasmic tail of mouse, but not human, Fcα/μR. The initial characterization of the Fcα/μR gene indicated that it is expressed by B cells and monocyte/macrophages and by unknown cell types in kidney and intestine. Our preliminary findings using receptor specific mAb and RT-PCR analysis indicate an interesting cellular distribution of the human Fcα/μR: germinal centers with the appearance of follicular dendritic cells (FDC) in tonsils, proximal tubular epithelial cells in kidneys and Paneth cells in small intestinal crypts. Another remarkable finding is that human Fcα/μR is expressed by a small subpopulation of B cells that reside in tonsils, but not in the circulation; hence the expression pattern differs from that of mouse Fcα/μR, which is expressed by both circulating and resident B cell populations. A novel splice variant that may encode a soluble form of Fcα/μR has been identified in the kidney. These findings led to the hypothesis that Fcα/μR plays multiple functional roles depending upon the cell types expressing it. Fcα/μR on FDC may trap IgM or IgA immune complexes and present the intact antigens to B cells in germinal centers. Fcα/μR expression by B cells may be closely linked with cellular activation. Fcα/μR in renal tubular epithelial cells and intestinal Paneth cells on the other hand may play a protective role at portals of entry for antigens and microorganisms. This hypothesis is currently tested by the following aims: (i) to determine the function of the membrane-bound Fcα/μR, (ii) to define the newly identified Fcα/μR splice variant as a soluble form of the receptor, and (iii) to employ an Fcα/μR-deficient mouse model to explore the in vivo function of the Fcα/μR.
- Last Updated on November 26, 2014