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Mucosal Immunology at Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Richard S. Blumberg
Principal Investigator
RESEARCH SUMMARY, CURRENT ACTIVITIES: BLUMBERG LABORATORY
Current Lab Members
Sebastian Zeissig- Research Fellow
Zhangguo Chen- Research Fellow
Stephane Nancy - Research Fellow
Eric de Muinck- Research Assistant
Brian Chase - Laboratory Technician
Nicolas Kuperwasser - Laboratory Manager
The intestinal epithelial cell surface represents a vast frontier of body surfaces that must be defended by the immune system. The intestinal immune system must defend against the many infectious and toxic assaults that may breach the epithelium and cause intestinal injury. The immune system also must recognize epithelial cell transformation, to which the intestine may be uniquely prone, because toxin exposure and the high proliferation rate of the epithelial cells increase the risk of cytogenetic error and malignant transformation. The intestinal immune system must simultaneously ignore the multitude of commensal organisms and dietary antigens that are not threats to the host.
Because specific immunity is driven by antigen recognition, the components of the immune system that protect the gut are presented with a significant challenge in differentiating foreign or nonself material from self-antigens by responding to the former and ignoring the latter. Except for a few other epithelial surfaces, no other organ system is presented with this combination of problems in such a dramatic fashion. As a result of constant antigenic exposure, the gut possesses abundant lymphoid cells (i.e., B and T lymphocytes) and myeloid cells (i.e., macrophages, neutrophils, eosinophils, mast cells). The mucosal immune system of the gastrointestinal tract represents one of the largest immunologic compartments in the body.
To deal with this challenge, the gut-associated lymphoid tissue (GALT) has evolved several important modifications of antigen processing, humoral immunity, and cellular immunity to cope with its organ-specific responsibilities. These include flattened epithelial microfold (M) cells that transport antigens, the specialized epithelial cells of the domes overlying lymphoid aggregates that sample luminal antigens selectively, unique immunologic functions of the single layer of enterocytes (epithelial cells) that separate the outside from inside worlds, the IgG and IgA systems that helps to exclude and remove foreign antigens, and unique mechanisms of generating local specific secretory immunity in the context of systemic tolerance. The functional segregation of intestinal from systemic compartments reiterates the separate role of the intestine as a unique lymphoid organ that is linked to other mucosal surfaces such as those of the lung, breast, and/or genitourinary tract to create a common mucosa-associated lymphoid tissue (MALT).
The approach that the laboratory has taken to study mucosal immunity is to focus on several molecules that the laboratory believes are operative and especially relevant to the physiologic processes and diseases related to these compartments. As such, the laboratory has a particular interest in the manner in which aberrations of these physiologic processes lead to the development of inflammatory bowel disease, the management of the luminal microbial ecology, intestinal barrier dysfunction and allergy, among others. Particular areas of interest are in the following molecular pathways:
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Characterization of the neonatal MHC class I-related Fc receptor (FcRn). This receptor is responsible for the transport of IgG across the intestinal epithelium in a novel transcytotic pathway that is bidirectional in nature. It has previously been suggested that this molecule is expressed developmentally only during antenatal and neonatal periods of life. The laboratory, however, has shown that rodent and human FcRn is expressed beyond the neonatal period in adult animals in intestinal epithelial cells, dendritic cells and intestinal macrophages. One logical interpretation of these data is that adult expression of FcRn may play a role in the uptake of immune complexes from the intestinal and/or other mucosal surfaces for the purposes of influencing subepithelial B and T cell responses. The laboratory is therefore investigating the cell biologic pathways associated with FcRn transport of IgG across intestinal epithelia and the role that FcRn may have in regulating responses to luminal antigens.
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| Double-staining of Golgi FcRn | Macrophage treated with a-GalCer |
| Claypool JBC 2002.pdf | Nieuwenhuis Nature Medicine 2002.pdf |
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The nonclassical MHC class I-related molecule, CD1d. The laboratory has previously demonstrated the expression of human CD1d constitutively on normal human and rodent intestinal epithelia and the ability of CD1d to function as a restriction element for T cells in this compartment on these cell types. The major goals of the laboratory are to understand and characterize the cell biology (e.g. microsomal triglyceride transfer protein), biosynthesis and function of CD1d on intestinal epithelia and to define the role of CD1d-restricted pathways in regulating mucosal inflammation and responses to mucosal microbiota. The delineation of such knowledge will have important implications in understanding the pathogenesis of inflammatory bowel disease and other related conditions given the importance of the mucosal microbiota to the development of these diseases.
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Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). CEACAM1 has traditionally been viewed as an adhesion molecule associated with signal transduction pathways in epithelial surfaces that is involved in regulating epithelial cell growth and development. Recent work from this laboratory has revealed a role for CEACAM1 in regulating of T cell responses. The laboratory has found that CEACAM1 is expressed on activated T cells and regulates the activity of T cells in vitro and in vivo. This regulation of T cells by CEACAM1 is consistent with the signaling properties of this molecule and the possession of two immune receptor tyrosine-based inhibitory motifs in the cytoplasmic tail of this molecule. The laboratory is interested in defining the molecular mechanisms underlying T cell regulation by CEACAM1 and the manner in which CEACAM1 regulates inflammatory diseases of the intestine.
Bleicher PA, Balk SP, Hagen SJ, Blumberg RS, Flotte TJ, Terhorst, C.
Expression of Murine CD1 on Gastroeintestinal Epithelium.
Balk SP, Ebert EC, Blumenthal RL, McDermott FV, Wucherpfennig KW, Landau SB, Blumberg RS.
Oligonal Expansion and CD1 Recognition by Human Intestinal Intraepithelial Lymphocytes.
Balk SP, Burke S, Polischuk JE, Frantz ME, Yang L, Porcelli S, Colgan SP, Blumberg RS.
β2-Microglobulin-Independent MHC Class lb Molecule Expressed by Human Intestinal Epithelium.
Probert CS, Chott A, Turner JR, Saubermann LJ, Stevens AC, Bodinaku K, Elson CO, Balk SP, Blumberg RS.
Persistent clonal expansions of peripheral blood CD4 lymphocytes in chronic inflammatory bowel disease.
Probert CS, Christ AD, Saubermann LJ, Turner JR, Chott A, Carr-Locke D, Balk SP, Blumberg RS.
Analysis of human common bile duct associated T cells: evidence for oligoclonality, T cell clonal persistence and epithelial cell recognition.
Christ AD, Stevens AC, Koeppen H, Walsh S, Omata F, Devergne O, Birkenbach M, Blumberg RS.
Epstein-Barr virus induced gene 3, a novel, interleukin-12 related cytokine, is expressed in human intestine and upregulated in ulcerative colitis but not in Crohn's disease.
Gastroenterology 1998; 115:307-13.
Kim HS, Garcia J, Exley M, Johnson KW, Balk SP, Blumberg RS.
Biochemical characterization of CD1d expression in the absence of β2-microglobulin.
Saubermann LJ, Probert CS, Christ AD, Chott A, Turner JR, Stevens AC, Balk SP, Blumberg RS.
Evidence of T cell receptor b-chain patterns in inflammatory and noninflammatory bowel disease states.
Somnay-Wadgaonkar K, Nusrat A, Kim HS, Canchis WP, Balk SP, Colgan SP, Blumberg RS.
Immunolocalization of CD1d in human intestinal epithelial cells and identification of a b2-microglobulin associated form.
Morales VM, Christ AD, Watt SM, Kim HS, Johnson KW, Utkan N, Texieira AM, Mizoguchi A, Mizoguchi E, Russell GJ, Russell SE, Bhan AK, Freeman GJ, Blumberg RS.
Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a).
Dickinson BL, Badizadegan K, Wu Z, Ahouse JC, Zhu X, Simister NE, Blumberg RS, Lencer WI.
Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line.
J Clin Invest 1999; 104:903-11.
Colgan SP, Hershberg RM, Furuta GT, Blumberg RS.
Ligation of epithelial CD1d by antibody crosslinking induces bioactive IL-10; critical role of the cytoplasmic tail in autocrine signaling.
Proc Natl Acad Sci USA 1999; 96:13938-43.
Saubermann LJ, Beck P, DeJong YP, Pitman RS, Ryan MS, Kim HS, Exley M, Snapper S, Balk SP, Hagen SJ, Kanauchi O, Motoki K, Sakai T, Terhorst C, Koezuka Y, Podolsky DK, Blumberg RS.
Natural killer-T cells activated by a galactosylceramide in the presence of CD1d provide protection against colitis in mice.
Gastroenterology 2000; 119:119-28.
Kim HS, Colgan SP, Pitman R, Hershberg RM, Blumberg RS.
Human CD1d associates with prolyl-4-hydroxylase during its biosynthesis.
Zhu X, Meng G, Dickinson BL, Li X, Mizoguchi E, Miao L, Wang Y, Robert C, Wu B, Smith PD, Lencer WI, Blumberg RS.
MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, macrophages and dendritic cells.
Nakajima A, Iijima H, Neurath MF, Nagaishi T, Niewenhuis ES, Raychowdhury R, Glickman HJ, Blau DM, Russell S, Holmes KV, Blumberg RS.
Activation-induced expression of carcinoembryonic antigen-cell adhesion molecule 1 regulates mouse T lymphocyte function.
Nakajima A, Wada K, Miki H, Kubota N, Nakajima N, Terauchi Y, Ohnishi S, Saubermann LJ, Kadowaki T, Blumberg RS, Nagai R, Matsuhashi N.
Endogenous PPARγ mediates anti-inflammatory activity in murine ischemia-reperfusion injury.
Gastroenterology 2001; 120:460-469.
Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK.
Chronic intestinal inflammatory condition generates IL-10 producing regulatory B cell subset characterized by CD1d upregulation.
Neurath MF, Weigmann B, Finotto S, Glickman J, Nieuwenhuis E, Iijima H, Mizoguchi A, Mizoguchi E, Mudter J, Galle PR, Bhan A, Autschbach F, Sullivan BM, Szabo SJ, Glimcher LH, Blumberg RS.
The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease.
J Exp Med. 2002; 195:1129–1143.
Nieuwenhuis ES, Matsumoto T, Exley M, Schleipman RA, Glickman J, Bailey DT, Corazza N, Colgan SP, Onderdonk AB, Blumberg, RS.
CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung.
Nature Medicine 2002; 8:588-593.
Claypool SM, Dickinson BL, Yoshida M, Lencer WI, Blumberg RS.
Functional Reconstitution of Human FcRn in MDCK Cells Requires Co-Expressed Human β2m.
Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, Lencer WI.
Receptor-mediated Immunoglobulin G Transport Across Mucosal Barriers in Adult Life: Functional Expression of FcRn in the Mammalian Lung.
J. Exp. Med. 2002; 196: 281-292. Supplement
Zhu X, Peng J, Chowdhurry R, Nakajima A, Lencer WI, Blumberg RS.
The heavy chain of neonatal Fc receptor for IgG is sequestered in endoplasmic reticulum by forming oligomers in the absence of 2-microglobulin association.
Biochemical Journal 2002; 367:703-14.
Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W.
Oxazolone Colitis, a Th2 Colitis Model Resembling Ulcerative Colitis, Is Mediated by IL-13 Producing NK-T Cells.
Nieuwenhuis EE, Neurath MF, Corazza N, Iijima H, Trgovcich J, Wirtz S, Glickman J, Bailey D, Yoshida M, Galle PR, Kronenberg M, Birkenbach M, Blumberg RS.
Disruption of T helper 2-immune responses in Epstein–Barr virus-induced gene 3-deficient mice.
van de Wal Y, Corazza N, Allez M, Mayer LF, Iijima H, Ryan M, Cornwall S, Kaiserlian D, Hershberg R, Koezuka Y, Colgan SP, Blumberg RS.
Delineation of a CD1d-Restricted Antigen Presentation Pathway Associated With Human and Mouse Intestinal Epithelial Cells.
Gastroenterology 2003; 124:1420-31.
Katayama K, Wada K, Nakajima A, Mizuguchi H, Hayakama T, Nakagawa S, Kadowaki T, Nagai R, Kamisaki Y, Blumberg RS, Mayumi T.
A Novel PPARγ Gene Therapy to Control Inflammation Associated Whith Inflammatory Bowel Disease in a Murine Model.
Gastroenterology 2003; 124:1315-1324.
Colgan SP, Pitma n RS, Nagaishi T, Mizoguchi A, Mizoguchi E, Mayer LF, Shao L, Sartor RB, Subjeck JR, Blumberg RS.
Intestinal heat shock protein 110 regulates expression of CD1d on intestinal epithelial cells.
J. Clin. Invest. 2003; 112: 745-754.
Nicchitta CV.
Come forth CD1d: Hsp110 in the regulation of intestinal epithelial CD1d expression.
J. Clin. Invest. 2003; 112: 646-648.
Iijima H, Neurath MF, Nagaishi T, Glickman JN, Nieuwenhuis EE, Nakajima A, Chen D, Fuss IJ, Utku N, Lewicki DN, Becker C, Gallagher TM, Holmes KV, Blumberg RS.
Specific Regulation of T Helper Cell 1-mediated Murine Colitis by CEACAM1.
J. Exp. Med. 2004; 199:471-482.
Chen D, Iijima H, Nagaishi T, Nakajima A, Russell S, Raychowdhury R, Morales V, Rudd CE, Utku N, Blumberg RS.
Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 Isoforms Alternatively Inhibit and Costimulate Human T Cell Function.
J. Immunol 2004; 172:3535-3543.
Claypool SM, Dickinson BL, Wagner JS, Johansen FE, Venu N, Borawski JA, Lencer WI, Blumberg RS.
Bidirectional Transepithelial IgG Transport by a Strongly Polarized Basolateral Membrane Fcg-Receptor.
Mol. Biol. Cell 2004; 15:1746-1759. Supplemental Figure
Brozovic S, Nagaishi T, Yoshida M, Betz S, Salas A, Chen D, Kaser A, Glickman J, Kuo T, Little A, Morrison J, Corazza N, Kim JY, Colgan SP, Young SP, Exley M, Blumberg RS.
CD1d function is regulated by microsomal triglyceride transfer protein.
Nature Medicine 2004; 1:535-9. Supplemental Figure Supplemental Table
Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W.
Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis.
J. Clin. Invest. 2004; 113:1490-7.
Hokama A, Mizoguchi E, Sugimoto K, Shimomura Y, Tanaka Y, Yoshida M, Rietdijk ST, de Jong YP, Snapper SB, Terhorst C, Blumberg RS, Mizoguchi A.
Induced Reactivity of Intestinal CD4+ T Cells with an Epithelial Cell Lectin, Galectin-4, Contributes to Exacerbation of Intestinal Inflammation.
Immunity 2004; 20: 681-693. Supplemental TableS1 Supplemental FigureS1
Yoshida M, Claypool SM, Wagner JS, Mizoguchi E, Mizoguchi A, Roopenian DC, Lencer WI, Blumberg RS.
Human Neonatal Fc Receptor Mediates Transport of IgG into Luminal Secretions for Delivery of Antigens to Mucosal Dendritic Cells.
Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella VJ, Stattel JM, Lu Y, Tan CA, Song JJ, Garcia AM, Simister NE, Spiekermann GM, Lencer WI, Blumberg RS.
Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway.
Wada K, Nakajima A, Takahashi H, Yoneda M, Fujisawa N, Ohsawa E, Kadowaki T, Kubota N, Terauchi Y, Matsuhashi N, Saubermann LJ, Nakajima N, Blumberg RS.
Protective effect of endogenous PPARg against acute gastric mucosal lesions associated with ischemia-reperfusion.
Am. J. Physiol. Gastrointest. Liver Physiol. 2004; 287: G452-8.
Utku N, Boerner A, Tomschegg A, Bennai-Sanfourche F, Bulwin G, Heinemann T, Loehler J, Blumberg RS, Volk H.
TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response. J Immunol 173 (4): 2342-52
J. Immunol. 2004; 173: 2342-2352
Stirling CMA, Charleston B, Takamatsu H, Claypool SM, Lencer WI, Blumberg RS, Wileman TE.
Characterization of the porcine neonatal Fc receptor -- potential use for trans-epithelial protein delivery.
Immunology 2005; 114: 542-553.
Arita M, Yoshida M, Hong S, Tjonagen E, Glickman JN, Petasis NA, Blumberg RS, Serhan CN.
Resolvin E1, an Endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6 trinitrobenzene sulfonic acid-induced colitis.
Nieuwenhuis EE, Gillessen S, Scheper RJ, Exley MA, Taniguchi M, Balk SP, Strominger JL, Dranoff G, Blumberg RS, Wilson SB.
CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity.
Exp. Dermatology 2005; 14: 250-258
Zhu X, Peng J, Chen D, Liu X, Ye L, Iijima H, Kadavil K, Lencer WI, Blumberg RS.
Calnexin and ERp57 Facilitate the Assembly of the Neonatal Fc Receptor for IgG with b2- Microglobulin in the Endoplasmic Reticulum.
J. Immunology 2005; 175: 967-976
Dougan SK, Salas A, Rava P, Agyemang A, Kaser A, Morrison J, Khurana A, Kronenberg M, Johnson C, Exley M, Hussain MM, Blumberg RS.
Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells.
J. Exp. Med. 2005; 202: 529-39.
Utku N, Heinemann T, Winter M, Bulwin CG, Schlawinsky M, Fraser MP, Nieuwenhuis EE, Volk HD, Blumberg RS.
Antibody targeting of TIRC 7 results in significant therapeutic effects on collagen-induced arthritis in mice.
Clinical Expt. Immunololgy 2006; 144: 142-151
Nagaishi T, Pao L, Lin SH, Iijima H, Kaser A, Qiao SW, Chen Z, Glickman J, Nijjar SM, Nakajima A, Neel BG, Blumberg RS.
SHP1 Phosphatase-Dependent T Cell Inhibiton by CEACAM1 Adhesion Molecule Isoforms.
Yoshida M, Kobayashi K, Kuo T, Bry L, Glickman JN, Claypool SM, Kaser A, Nagaishi T, Higgins DE, Mizoguchi E, Wakatsuki Y, Roopenian DC, Mizoguchi A, Lencer WI, Blumberg RS.
Neonatal Fc receptor for IgG Regulates Mucosal Immune Responses to Luminal Bacteria.
Dougan SK, Rava P, Hussain MM, Blumberg, RS.
MTP regulated by an alternate promoter is essential for NKT cell development.
J. Exp. Med. 2007; 204: 533-545
Kaser A, Blumberg RS.
The other way round: Colitis regulates regulatory T cells.
Gastroenterology 2004; 126: 1903-1906
Strober W, Fuss IJ, Blumberg RS.
The Immunology of Mucosal Models of Inflammation.
Annu. Rev. Immunology 2002; 20: 495-549
Blumberg RS, Saubermann LJ, Strober W.
Animal Models of Mucosal Inflammation and Their Relation to Human Inflammatory Bowel Disease.
Current Opinions in Immunology 1999; 11: 648-656
Blumberg RS, Strober W.
Prospects for Research in Inflammatory Bowel Disease.
Blumberg RS, Friedman S.
Chapter on IBD in
Harrison's Online; Chapter 287: Inflammatory Bowel Disease, Page 1-34 (Harvard ID Required)