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Faculty Detail    
Campus Address SHEL 506 Zip 2182
Phone  (20-5) -201
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Faculty Appointment(s)
Appointment Type Department Division Rank
Primary  Pathology   Laboratory Medicine Professor Adjunct

Graduate Biomedical Sciences Affiliations
Cellular and Molecular Biology Program 
Hughes Med-Grad Fellowship Program 
Integrative Biomedical Sciences 
Medical Scientist Training Program 
Molecular and Cellular Pathology Program 

Biographical Sketch 
Hiromi Kubagawa (b. 1946), Professor of the Department of Pathology with secondary appointments in Microbiology and Medicine, received the M.D. degree from Juntendo University (Tokyo, Japan) in 1971, completed a residency in Anatomic and Surgical Pathology at Nihon University, and conducted immunopathological studies in the laboratory of Dr. Yoshihiro Hamashima at Nihon University (1971-1975) and Kyoto University (1975-1976). He performed his postdoctoral studies in the laboratory of Dr. Max D. Cooper on the clonal origin of B cell malignancies using individually specific (idiotype) antibodies and joined the pathology staff in 1983. In 1986 he spent a year with Dr. Martin Weigert in the Fox Chase Cancer Center, Philadelphia where he learned molecular biology. His outside interests include music, reading, cooking, and watching sports (especially, college basketball and football).

Society Memberships
Organization Name Position Held Org Link
The American Association of Immunologists  Member   

Research/Clinical Interest
Molecular Genetics and Immunopathology of Host Defense
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/R).

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.

Selected Publications 
Publication PUBMEDID
15: Kubagawa H, Chen CC, Ho LH, Shimada TS, Gartland L, Mashburn C, Uehara T, Ravetch JV, Cooper MD. Biochemical nature and cellular distribution of the paired immunoglobulin-like receptors, PIR-A and PIR-B. J Exp Med. 189:309-318, 1999  9892613 
16: Alley TL, Cooper MD, Chen M, Kubagawa H. Genomic structure of PIR-B, the inhibitory member of the paired immunoglobulin-like receptor genes in mice. Tissue Antigens. 51:224-231, 1998  9550322 
17: Blery M, Kubagawa H, Chen CC, Vely F, Cooper MD, Vivier E. The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc Natl Acad Sci U S A. 95:2446-2451, 1998  9482905 
72: Kubagawa H, Vogler LB, Capra JD, Conrad ME, Lawton AR, Cooper MD. Studies on the clonal origin of multiple myeloma. Use of individually specific (idiotype) antibodies to trace the oncogenic event to its earliest point of expression in B-cell differentiation.
J Exp Med. 150:792-807, 1979 
18: Bertrand FE 3rd, Billips LG, Burrows PD, Gartland GL, Kubagawa H, Schroeder HW. Ig D(H) gene segment transcription and rearrangement before surface expression of the pan-B-cell marker CD19 in normal human bone marrow. Blood. 90:736-744, 1997  9226174 
20: Mestecky J, Moro I, Moldoveanu Z, Takahashi T, Iwase T, Kubagawa H, Cooper MD. Immunoglobulin J chain. An early differentiation marker of human B cells. Ann N Y Acad Sci. 815:111-113, 1997  9186644 
19: Kubagawa H, Burrows PD, Cooper MD. A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proc Natl Acad Sci U S A. 94:5261-5266, 1997  9144225 
21: Bertrand FE, Billips LG, Gartland GL, Kubagawa H, Schroeder HW. The J chain gene is transcribed during B and T lymphopoiesis in humans. J Immunol. 156:4240-4244, 1996  8666793 
22: Nunez C, Nishimoto N, Gartland GL, Billips LG, Burrows PD, Kubagawa H,
Cooper MD. B cells are generated throughout life in humans. J Immunol. 156:866-872, 1996 
30: Maliszewski CR, VandenBos T, Shen L, Schoenborn MA, Kubagawa H, Beckmann MP, Monteiro RC. Recombinant soluble IgA Fc receptor: generation, biochemical characterization, and functional analysis of the recombinant protein. J Leukoc Biol. 53:223-232, 1993  8454945 
31: Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, Sparkes RS, Kubagawa H, Mohandas T, Quan S, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 72:279-290, 1993  8425221 
26: Monteiro RC, Hostoffer RW, Cooper MD, Bonner JR, Gartland GL, Kubagawa H. Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals. J Clin Invest. 92:1681-1685, 1993  8408621 
28: van den Wall Bake AW, Bruijn JA, Accavitti MA, Crowley-Nowick PA, Schrohenloher RE, Julian BA, Jackson S, Kubagawa H, Cooper MD, Daha MR, et al. Shared idiotypes in mesangial deposits in IgA nephropathy are not disease-specific. Kidney Int. 44:65-74, 1993  8355468 
27: Nakamura T, Sekar MC, Kubagawa H, Cooper MD. Signal transduction in human B cells initiated via Ig beta ligation. Int Immunol. 5:1309-1315, 1993  8268137 
25: Nakamura T, Kubagawa H, Ohno T, Cooper MD. Characterization of an IgM Fc-binding receptor on human T cells. J Immunol. 151:6933-6941, 1993  8258701 
24: Rokhlin OW, Cohen MB, Kubagawa H, Letarte M, Cooper MD. Differential expression of endoglin on fetal and adult hematopoietic cells in human bone marrow. J Immunol. 154:4456-4465, 1995  7722302 
29: Lassoued K, Nunez CA, Billips L, Kubagawa H, Monteiro RC, LeBlen TW, Cooper MD. Expression of surrogate light chain receptors is restricted to a late stage in pre-B cell differentiation. Cell. 73:73-86, 1993  7681728 
23: Billips LG, Lassoued K, Nunez C, Wang J, Kubagawa H, Gartland GL, Burrows PD, Cooper MD. Human B-cell development. Ann N Y Acad Sci. 1764:1-8, 1995   7486507 
71: Amano S, Hazama F, Kubagawa H, Tasaka K, Haebara H, Hamashima Y. General pathology of Kawasaki disease. On the morphological alterations corresponding to the clinical manifestations. Acta Pathol Jpn. 30:681-694, 1980  7446109 
68: Mayumi M, Kubagawa H, Omura GA, Gathings WE, Kearney JF, Cooper MD. Studies on the clonal origin of human B cell leukemia using monoclonal anti-idiotype antibodies. J Immunol. 129:904-910, 1982  6979581 
66: Kubagawa H, Gathings WE, Levitt D, Kearney JF, Cooper MD. Immunoglobulin isotype expression of normal pre-B cells as determined by immunofluorescence. J Clin Immunol. 2:264-269, 1982  6815220 
69: Gandini M, Kubagawa H, Gathings WE, Lawton AR. Expression of three immunoglobulin isotypes by individual B cells during development: implications for heavy chain switching. Am J Reprod Immunol. 1:161-163, 1981  6802006 
65: Cooper MD, Kubagawa H. B-cell malignancies: origin and extent of clonal involvement. Haematol Blood Transfus. 28:425-433, 1983  6602746 
70: Gathings WE, Kubagawa H, Cooper MD. A distinctive pattern of B cell immaturity in perinatal humans. Immunol Rev. 57:107-126, 1981  6458552 
60: Velardi A, Kubagawa H, Kearney JF. Analysis of the reactivity of four anti-mouse IgM allotype antibodies with mu+ B lineage cells at various stages of differentiation. J Immunol. 133:2098-2103, 1984  6432906 
61: Haber PL, Kubagawa H, Cooper MD. Epstein-Barr virus-induced immunoglobulin synthesis by B cells from individuals with late-onset panhypogammaglobulinemia. J Clin Immunol. 3:253-259, 1983  6309895 
63: Mayumi M, Kuritani T, Kubagawa H, Cooper MD. IgG subclass expression by human B lymphocytes and plasma cells: B lymphocytes precommitted to IgG subclass can be preferentially induced by polyclonal mitogens with T cell help. J Immunol. 130:671-677, 1983  6217248 
62: Basta P, Kubagawa H, Kearney JF, Briles DE. Ten percent of normal B cells and plasma cells share A VH determinant(s) (J606-GAC) with a distinct subset of murine VHIII plasmacytomas. J Immunol. 130:2423-2428, 1983  6187856 
64: Kubagawa H, Mayumi M, Crist WM, Cooper MD. Immunoglobulin heavy-chain switching in pre-B leukaemias. Nature. 301:340-342, 1983  6185849 
67: Kubagawa H, Mayumi M, Kearney JF, Cooper MD. Immunoglobulin VH determinants defined by monoclonal antibodies. J Exp Med. 156:1010-1024, 1982  6185604 
58: Maruyama S, Kubagawa H, Cooper MD. Activation of human B cells and inhibition of their terminal differentiation by monoclonal anti-mu antibodies. J Immunol. 135:192-199, 1985   3923101 
59: Haber PL, Kubagawa H, Koopman WJ. Immunoglobulin subclass distribution of synovial plasma cells in rheumatoid arthritis determined by use of monoclonal anti-subclass antibodies. Clin Immunol Immunopathol. 35:346-351, 1985  3886223 
51: Kubagawa H, Bertoli LF, Barton JC, Koopman WJ, Mestecky J, Cooper MD. Analysis of paraprotein transport into the saliva by using anti-idiotype antibodies. J Immunol. 138:435-439, 1987  3794339 
54: Luzi G, Kubagawa H, Crain MJ, Cooper MD. Analysis of IgG subclass production in cell cultures from IgA deficient patients and in normal controls as a function of age. Clin Exp Immunol. 65:434-442, 1986  3791704 
52: Wright JT, Chen CL, Kubagawa H, Cooper MD. Avian B cell diversity examined with monoclonal anti-VH antibodies. Prog Clin Biol Res. 238:81-85, 1987  3496616 
48: Sanders SK, Kubagawa H, Suzuki T, Butler JL, Cooper MD. IgM binding protein expressed by activated B cells. J Immunol. 139:188-193, 1987  3495598 
50: Kiyotaki M, Cooper MD, Bertoli LF, Kearney JF, Kubagawa H. Monoclonal anti-Id antibodies react with varying proportions of human B lineage cells. J Immunol. 138:4150-4158, 1987  3495581 
43: Bertoli LF, Kubagawa H, Borzillo GV, Burrows PD, Schreeder MT, Carroll AJ, Cooper MD. Bone marrow origin of a B-cell lymphoma. Blood. 72:94-101, 1988  3291988 
57: Tedder TF, Crain MJ, Kubagawa H, Clement LT, Cooper MD. Evaluation of lmphocyte differentiation in primary and secondary immunodeficiency diseases. J Immunol. 135:1786-1791, 1985  3160779 
73: Cooper MD, Kubagawa H, Vogler LB, Kearney JF, Lawton AR. Generation of clonal and isotype diversity. Adv Exp Med Biol. 107:9-17, 1978  311144 
53: Burrows PD, Kubagawa H. Immunoglobulin gene rearrangements in pre-B cells. Curr Top Microbiol Immunol. 135:125-138, 1987  3107912 
55: Landay A, Kubagawa H, Cooper MD. Idiotypic analysis of a B cell clone with anti-intermediate filament specificity in a patient with Sjogren's syndrome: involvement of five subpopulations producing different immunoglobulin isotypes. J Immunol. 137:129-136, 1986   3086445 
56: Kubagawa H, Burrows PD, Grossi CE, Cooper MD. Epstein-Barr virus induced differentiation of early B-lineage cells. Curr Top Microbiol Immunol. 132:246-250, 1986  3024917 
46: Borzillo GV, Cooper MD, Kubagawa H, Landay A, Burrows PD. Isotype switching in human B lymphocyte malignancies occurs by DNA deletion: evidence for nonspecific switch recombination. J Immunol. 139:1326-1335, 1987  2886542 
44: Miyawaki T, Kubagawa H, Butler JL, Cooper MD. Ig isotypes produced by EBV-transformed B cells as a function of age and tissue distribution. J Immunol. 140:3887-3892, 1988  2836502 
45: Kubagawa H, Burrows PD, Grossi CE, Mestecky J, Cooper MD. Precursor B cells transformed by Epstein-Barr virus undergo sterile plasma-cell differentiation: J-chain expression without immunoglobulin. Proc Natl Acad Sci U S A. 85:875-879, 1988  2829207 
41: Chevailler A, Monteiro RC, Kubagawa H, Cooper MD. Immunofluorescence analysis of IgA binding by human mononuclear cells in blood and lymphoid tissue. J Immunol. 142:2244-2249, 1989  2647847 
42: Kubagawa H, Cooper MD, Carroll AJ, Burrows PD. Light-chain gene expression before heavy-chain gene rearrangement in pre-B cells transformed by Epstein-Barr virus. Proc Natl Acad Sci U S A. 86:2356-2360, 1989  2538839 
47: Morikawa K, Kubagawa H, Suzuki T, Cooper MD. Recombinant interferon-alpha, -beta, and -gamma enhance the proliferative response of human B cells. J Immunol. 139:761-766, 1987  2439592 
38: Ohno T, Kubagawa H, Sanders SK, Cooper MD. Biochemical nature of an Fc mu receptor on human B-lineage cells. J Exp Med. 172:1165-1175, 1990  2212947 

B cells, antibodies, Fc receptors, immunoglobulin-like receptors, innate immunity, immunopathology