The overall goals of our laboratory are to understand why the immune system causes autoimmune diseases and to devise methods to predict and treat them. We develop and use mouse strains that provide models for human diseases such as lupus, rheumatoid arthritis, and epidermolysis bullosa. We use a combination of genetics, molecular biological and cellular immunological tools to dissect the molecular and cellular processes that cause these diseases. Finally, we study the mechanisms that affect the persistence of antibodies and antibody-based therapeutics. The information gained from all of these approaches is then used to devise possible therapeutic approaches with a keen eye on those that can be translated to humans.
Autoimmune disease and antibody therapeutics
Mechanisms of systemic lupus erythematosus (SLE) and related autoimmune disorder
SLE is a poorly understood, highly variable autoimmune disorder in which B lymphocytes play a key role. They produce autoantibodies that attack multiple tissues, including the joints, skin, lungs, blood vessels, heart, liver, nervous system and kidneys. Its current treatments remain primitive, typically involving high dose corticosteroids and other immunosuppressive agents that are encumbered with significant side effects. More efficacious therapies that specifically target key mediators of SLE hinge on the basic research needed to better understand this disease.
There is increasing appreciation of the importance of Toll-like receptors (TLRs) in the immunological defense against infection. Unfortunately, these same TLRs can also function aberrantly to promote autoimmune diseases. In particular, the Toll-like receptor 7 is proving to be important for initiating SLE-like autoimmune diseases. An important goal of our laboratory is to understand the mechanism by which TLR7 causes autoimmunity. We are studying a mouse model that that spontaneously develops an SLE-like autoimmune disorder because of a mutation that results in excess expression of TLR7. We are using a number of approaches to investigate how excessive TLR7 signaling causes B lymphocytes to become autoreactive and to ultimately produce the pathogenic autoantibodies that result in SLE.
In a related line of investigation, we and our collaborators discovered that a certain cytokine, Interleukin 21 (IL-21), was considerably elevated our mouse model for SLE, the BXSB-Yaa mouse. This recently discovered cytokine is a strong potentiator of many types of immunological cell types, including B cells, but its role in SLE-like autoimmune disease was not known. Through the analysis of BXSB-Yaa mice genetically engineered to lack the IL-21 receptor, we showed that IL-21 signaling was absolutely required for the severe SLE disease that BXSB-Yaa mice normally develop. This result provides very strong support for the importance of IL-21 in SLE. Our subsequent experiments are dedicated towards characterizing the cellular mechanisms by which IL-21 promotes SLE and potentially other related forms of autoimmune disease.
Our final line of investigation is directed toward the development of "vaccines" that can counteract SLE. Through the introduction of engineered mutations that inactivate CD8 T cells and natural killer cells, we have found that CD8 T cells and natural killer cells normally prevent BXSB-Yaa mice from developing an even more severe form of autoimmune disease. We are seeking to characterize these regulatory cells and the mechanisms by which they counteract SLE. Our longer term goal is to develop ways to develop immunization strategies that augment the activity of these regulatory cells as a method of therapy.Development of improved biological therapeutics
The biology and pathobiology of FcRn (a.k.a. Fcgrt), a distant member of the major histocompatibility complex (MHC) class I protein family, is particularly interesting. While most class I members present peptide antigens to cytotoxic T cells, FcRn has acquired a distinct function. Rather than binding peptides and presenting them on the plasma membrane to T cells, FcRn binds antibodies of the IgG class, but only at a pH less than ~6.5. This pH is found in the intestinal lumen, and intracellularly in endosomes. FcRn was originally shown to be responsible for transport of IgG across the rodent gut, but more recent evidence suggests that FcRn is expressed in many tissues. In addition to maternal IgG transport, FcRn plays a critical role in IgG homeostasis by protecting IgG from normal protein catabolism, which results in a substantial increase in the half-life of IgG. Recent collaborative studies have shown that FcRn binds not only IgG, but also albumin, which is the dominant serum protein. In doing so, FcRn plays a critical role in both IgG and albumin homeostasis. A focus of our laboratory is to understand the biology of FcRn. Antibody-based therapeutics are emerging as a major treatment for a wide range of disorders, including autoimmune disease and cancer. One avenue of investigation is to improve the efficacy of antibody-based therapeutics by exploiting the interaction between antibodies and FcRn to extend (or shorten) the pharmokinetics of the antibodies. We have developed mouse models that are particularly valuable in evaluating the pharmacokinetics of therapeutic antibodies. These studies have shown that it is possible to substantially increase the lifespan of therapeutic antibodies by enhancing their interaction with FcRn. Finally, there are many gaps in our understanding of the cell biology of FcRn, which, if resolved, will aid in exploiting its medical potential. We are therefore seeking to identify the cell types in which FcRn normally functions in vivo.
The genetic basis of epidermolysis bullosa
Epidermolysis bullosa is a single-gene Mendelian human disorder characterized by a weakened dermal/epidermal junction. Any form of mechanical trauma leads to blister formation, inflammation and scar formation. We identified a spontaneous mutation that is a remarkable mimic of the human disorder. We have shown that the mutation is in the laminin gamma 2 (Lamc2) gene, recapitulating the genetic defects found in certain affected humans. With our institutional collaborator, John Sundberg, DVM, Ph.D., we are characterizing this disease model and determining whether the severity of the disease can be modified by genes distinct from Lamc2. Prior to our study, there were no viable mouse models for this devastating disease. Our ongoing characterization of this model opens the road to develop therapies to treat epidermolysis bullosa.
Principal Investigator: Derry Roopenian, Ph.D.
High School Intern: Liam Torrey, Mount Desert High School
Graduate student: Elisabeth Adkins- Tufts Program
Postdoctorial Asscociate: Giljun Park, Ph.D., Victor Sun, Ph.D.
Senior Professional Assistants: Gregory Christianson, B.S., Thomas Sproule, B.A.
Senior Laboratory Assistant: Shari Roopenian
RAF Primary Room Technician: Bruce Carpenter
Research Administrative Assistant: Ashley Stanton
2006 to present
Andersen JT, Foss S, Kenoanova VE, Olafesen T, Leikfoss IS, Roopenian DC, Wu AM, Sandie I. 2012. Anti-carcinoembryonic antigen single-chain variable fragment antibody variants bind mouse and human neonatal Fc receptor with differen t affinities that reveal distinct cross-species differences in serum half-life. J Biol Chem Jun 29:287(27):22927-37.
Sproule TJ, Roopenian DC, Sundberg JP. 2012. A direct method to determine stregth of the dermal-epidermal junction in a mouse for epidermolysis bullosa. Exp Dermatol March 5. [Epub ahead of print]
Christianson GJ, Sun VZ, Akilesh S, Pesavento E, Proetzel G, Roopenian DC. 2012. Monoclonal antibodies directed against human FcRn and their applications. MAbs 1;4(2) [Epub ahead of print]
Ryu SJ, Jeon JY, Chang J, Sproule TJ, Roopenian DC, Choi EY. 2012. A single amino acid variant of the H60 CD8 epitope generates specific immunity with diverse TCR recruitment. Mol Cells March 21 [Epub ahead of print]
McPhee CG, Duncan FJ, Silva KA, King LE, Hogenesch H, Roopenian DC, Everts HB, Sundberg JP. 2012. Increased Expression of Cxcr3 and Its Ligands, Cx110 and Cxc110, duringthe dDevelopment of Alopecia areata in the Mouse. J Invest Dermatol Feb 23 [epub ahead of print]
Stein C, Kling L, Proetzel G, Roopenian DC, de Angelis MH, Wolf E, Rathkolb B. 2012. Clinical chemistry of human FcRn transgenic mice. Mamm Genome. Apr 23(3-4):259-69.
Bai Y, Ye L, Tesar DB, Song H, Zhao D, Bjorkman PJ, Roopenian DC, Zhu X. 2011. Intracellular neutralization of viral infection in polarized epithelial cells by neonatal Fc receptor (FcRn)-mediated IgG transport. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18406-11. Epub 2011 Oct 31.
Lindfors C, Nilsson IA, Garcia-Roves PM, Zuberi AR, Karimi M, Donahue LR, Roopenian DC, Mulder J, Uhlén M, Ekström TJ, Davisson MT, Hökfelt TG, Schalling M, Johansen JE. 2011. Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse. Proc Natl Acad Sci U S A. Nov 1; 108(44):18108-13.
McPhee CG, Sproule TJ, Shin DM, Bubier JA, Schott WH, Steinbuck MP, Avenesyan L, Morse HC 3rd, Roopenian DC. 2011. MHC class I family proteins retard systemic lupus erythematosus autoimmunity and B cell lympphomagenesis. J Immunol. Nov 1;187(9):4695-704. Epub 2011 Sep 30.
Lu L, Palaniyandi S, Zeng R, Bai Y, Liu X, Wang Y, Pauza CD, Roopenian DC, Zhu X. 2011. A Neonatal Fc receptor-targeted mucosal vaccine strategy effectively induces HIV-1 antigen-specific immunity to genital infection. J Viro. Oct;85(20):10542-53.
Li N, Matte-Martone C, Zheng H, Cui W, Venkatesan S, Tan HS, McNiff J, Demetris AJ, Roopenian D, Kaech S, Shlomchik. WD. 2011. Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improves GVL and immune reconstitution. Blood. Nov 24;118(22):5965-76.
Dragovic SM, Hill T, Christianson GJ, Kim S, Elliott T, Scott D, Roopenian DC, Van Kaer L, Joyce S. 2011. Proteasomes, TAP, and Endoplasmic, Reticulum-Associated Aminopeptidase with Antigen Processing Control CD4+ Th Cell Responses by Regulating Indirect Presentation of MHC Class 11-Restrited Cytoplasmic Antigens. J Immunol. May 13. [Epub ahead of print]
Derbyshire K, Addey C, Coe D, Stuckey DW, Muezzin H, Bubier JA, Shaffer DJ, Roopenian DC, Chai JG, Scott DM. 2011. Molecular mechanisms of induction of antigen-specific allograft tolerance by intranasal Peptide administration. J Immunol. May 15;186(10):5719-28. Epub 2011 Apr 13.
Liu X, Lu L, Yang Z, Palaniyandi S, Zeng R, Gao LY, Mosser DM, Roopenian DC, Zhu X. 2011. The neonatal FcR-mediated presentation of immune-complexed antigen is associated with endosomal and phagosomal pH and antigen stability in macrophages and dendritics cells. J Immunol. Apr 15;186(8):4674-86. Epub 2011 Mar 14.
Russell PS, Chase CM, Madsen JC, Hirohashi T, Cornell LD, Sproule TJ, Colvin RB, Roopenian DC. 2011. Cornonary artery disease from isolated non-h2-determined incompatiblites in transplanted mouse hearts.
Transplantation. Apr 27;91(8):847-52.
Li Z, Palaniyandi S, Zeng R, Tuo W, Roopenian DC, Zhu X. 2011. Transfer of IgG in the female genital tract by MHC class 1-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection. Proc Natl Acad Sci U S A. Mar 15;108(11):4388-93. Epub 2011 Feb 28.
Kim HJ, Wang X, Radfar S, Sproule TJ, Roopenian DC, Cantor H. 2011. CD8+ T regulatory cells express the Ly49 Class 1 MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci U S A. Feb 1;108(5):2010-5. Epub 2011 Jan 13.
Ye L, Zeng R, Bai Y, Rooneian DC, Zhu X. 2011. Effecient mucosal vaccination mediated by the neonatal Fc receptor. Nat Biotechnol Feb;29(2):158-63. Epub 2011 Jan 16
Kim HJ, Wang X, Radfar S, Sproule TJ, Roopenian DC, Cantor H. 2011. CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci USA Feb 1;108(5):2010-5.
Sproule TJ, Sled JG, Wentzellj, Wang B, Henkelman RM, Roopenian DC, Burgess RW. 2010. A mouse model of heritable cerebrovascular disease. PLoS One. Dec 31;5(12):e15327.
Sundberg JP, Taylor DK, Lorch G, Miller J, Silva KA, Sundberg BA, Roopenian DC, Sperling LC, Ong D, King LE, Everts HB. 2010. Primary Follicular Dystrophy with Sacrring Dermatitis in C57BL/6 Mouse substrains resembles Central Centrifugal Cicatricial Alopecia in Humans. Vet Pathol. 2010 Sept 22 Epub ahead of print.
Roopenian DC, Sun VZ. 2010. Clinical ramifications of the MHC family Fc receptor FcRn. J Clin Immunol. Nov;30(6):790-7.
Wu B, Potter CS, Silva KA, Liang Y, Reinholdt LG, Alley LM, Rowe LB, Roopenian DC, Awgulewitsch A, Sundberg JP. 2010. Mutations in sterol O-acyltansferase 1 (Soat 1) result in hair interior defects in AKR/J mice. J Invest Dermatol. Nov;130(11);2666-8.
Morse III, HC , Janz S, Qi CF, Shin DM, Davidson WF, Wang H, Li Z, Roopenian DC, Hartley J, Fredrickson TN, Kovalchuk A, Potter M. 200_. Features of plasma cell-related neoplasms in mice. National Institute of Allergy and Infectious Diseases. NIH: Volume 3. Humana Press.
Bubier JA, Sproule TJ, Petell L, Fine JD, Roopenian DC, Sundberg JP. 2010. A Mouse Model of Generalized non-Herlitz Junctional Epidermolysis Bullosa. J Invest Dermatol. Jul;130(7): 1819-28.
Roopenian DC, Christianson GJ, Sproule TJ. 2010. Human FcRn transgenic mice for pharmacokinetic evaluation of therapeutic antibodies. Methods Mol Biol. 602:93-104.
Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IW, Sproule TJ, Lazar GA, Roopenian DC, Desjarlais JR. 2010. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol. 2010 Feb;28(2):157-9. Epub 2010 Jan 17.
Bleich A, BŸchler G, Beckwith J, Petell LM, Affourtit JP, King B, Shaffer DJ, Roopenian DC, Hedrich HJ, Sundberg, Leiter EH. Cdcs1 a major colitis susceptibility locus in mice; subcongenic analysis reveals genetic complexity. Inflamm Bowel Dis, in press.
Shin DM , Shaffer DJ, Roopenian DC, Morse HC 3rd. 2008. Identification of Notch as a component of the transcriptional networks regulating cell growth and survival in mouse plasmacytomas. Cancer Res. 68(22):9202-11.
Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, Milford E, Roopenian DC, Lencer WI, Blumberg RS. 2008. Dependence of antibody-mediated presentation of antigen on FcRn. Proc Natl Acad Sci 105(27):9337-9342.
Petkova SB, Yuan R, Tsaih SW, Schott W, Roopenian DC, Paigen B. 2008. Genetic influence on immune phenotype revealed strain-specific variations in peripheral blood lineages. Physiol Genomics. 34(3):304-314.
Serreze DV, Choisy-Rossi CM, Grier AE, Holl TM, Chapman HD, Gahagan JR, Osborne MA, Zhang W, King BL, Brown A, Roopenian D, Marron MP. 2008. Through regulation of TCR expression levels, an Idd7 region gene(s) interactively contributes to the impaired thymic deletion of autoreactive diabetogenic CD8+ T cells in nonobese diabetic mice. J Immunol. 180(5):3250-3259.
Akilesh S, Huber TB, Wu H, Wang G, Hartleben B, Kopp JB, Miner JH, Roopenian DC, Unanue ER, Shaw AS. 2008. Podocytes use FcRn to clear IgG from the glomerular basement membrane. Proc Natl Acad Sci 105(3):967-972.
Bubier JA, Bennet SM, Sproule TJ, Lyon BL, Olland S, Young DA, Roopenian DC. 2007. Treatment of BXSB-Yaa mice with Il21-Fc fusion protein minimally attenuates SLE disease. NY Acad Sci Sept;1110:590-601.
Akilesh S, Christianson GJ, Roopenian DC, Shaw AS. 2007. Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism. J Immunol 179(7):4580-4588.
Roopenian DC, Akilesh S. 2007. FcRn: The neonatal Fc receptor comes of age. Nat Rev Immunol 7(9):715-725.
Liu X, Ye, L, Christianson GJ,Yang JQ, Roopenian DC, Zhu X. 2007. NF-kappaB signaling regulates functional expression of the MHC class I-related neonatal Fc receptor for IgG via intronic binding sequences. J Immuno 179(5):2999-3011.
Woo Y, Wright SM, Maas SA, Alley TL, Caddle LB, Kamdar S, Affourtit J, Foreman O, Akeson EC, Shaffer D, Bronson RT, Morse HC 3rd, Roopenian D, Mills KD. 2007. The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity. Oncogene 26(41):6010-6020.
Shatry AM, Roopenian DC, Levy RB. Survival and Function of MiHA Epitope-Specific Host CD8 TM Cells Following Ablative Conditioning and HCT. Biol Blood Marrow Transplant 13:293-298.
Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC, Sundberg JP. 2007. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun 8(5):416-21.
Ostrov DA, Barnes CL, Smith LE, Binns S, Brusko TM, Brown AC, Quint PS, Litherland SA, Roopenian DC, Iczkowski KA. 2007. Characterization of HKE2: an ancient antigen encoded in the major histocompatibility complex. Tissue Antigens 69:181-188.
Qi CF, Zhou JX, Lee CH, Naghashfar Z, Xiang S, Chattopadhyay SK, Fredrickson TN, Hartley JW, Roopenian DC, Davidson WF, Janz S, Morse HC 3rd. 2007. Anaplastic, plasmablastic and plasmacytic plasmacytomas of mice: relationships to human plasma cell neoplasms and late stage differentiation of normal B cells. Cancer Research 67, 2439-2447.
Brown AC, Lerner CP, Graber JH, Shaffer DJ, Roopenian, DC. 2006. Pooling and PCR As a Method to Combat Low Frequency Gene Targeting in ES Cells. Cytotechnology 51:81-88.
Petkova SB, Akilesh S, Sproule TJ, Christianson GJ, Al Khabbaz H, Brown AC, Presta LG, Meng YG, Roopenian DC. 2006. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 2006 18:1759-1769.
Yoshida M, Kobayashi K, Kuo TT, Bry L, Glickman JN, Claypool SM, Kaser A, Nagaishi T, Higgins DE, Mizoguchi E, Wakatsuki Y, Roopenian DC, Mizoguchi A, Lencer WI, Blumberg RS. 2006. Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria.
J Clin Invest 116(8):2142-2151.
Liu XY, Pop LM, Roopenian DC, Ghetie V, Vitetta ES, Smallshaw JE. 2006. Generation and characterization of a novel tetravalent anti-CD22 antibody with improved antitumor activity and pharmacokinetics. Int Immunopharmacol 6(5):791-799.
Yan J, Parekh VV, Mendez-Fernandez Y, Olivares-Villagómez D, Dragovic SM, Hill T, Roopenian DC, Joyce S, Van Kaer L. 2006. In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules. J Exp Med. 203(3):647-659.
Petkova SB; Konstantinov KN; Sproule TJ; Lyons BL; Awwami MA; Roopenian DC. 2006. Human antibodies induce arthritis in mice deficient in the low-affinity inhibitory IgG receptor FcgRIIB. J Exp Med 203(2):275-280.
Kim J, Bronson CL, Hayton WL, Radmacher MD, Roopenian DC, Robinson JM, Anderson CL. 2006. Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. Am J Physiol Gastrointest Liver Physiol 290: G352-60.