Research interests

Autoimmune disease, antibody therapeutics, and transplantation biology

The biology and pathobiology of FcRn (a.k.a. Fcgrt), a distant member of the major histocompatibility complex (MHC) class I protein family, is a particularly interesting protein. 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. Additional collaborative work has also shown that FcRn is able to transport IgG/antigen complexes across the intestinal wall of adult mice, and in doing so, could play an important role in protective immunity to intestinal pathogens and other infectious organisms.

A major focus of our laboratory is to understand the biology of FcRn, both in health and disease. 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 therapeutic efficacy of IgG-based, 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. A second area hinges on the fact that IgG autoantibodies contribute substantially to a number of autoimmune diseases. We are devising ways to prevent IgG autoantibodies from being stabilized by FcRn, and in that way, to reduce the number of antibodies that can inflict autoimmune damage. 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 functionsin vivo.

 

Analysis of systemic lupus erythematosus (SLE)

A strain of mice, BXSB/MpJ, develops a very severe autoimmune disease with considerable similarity to human SLE. We are using this model to understand the genetic and mechanistic basis of this disease. These studies involve the genetic analysis of a locus called the Y linked autoimmune accelerator, Yaa, with the goal of understanding how this locus promotes SLE. The studies also involve the mechanistic dissection of the disease process using gene-targeted mutations to remove key molecules from BXSB/MpJ mice, and then to evaluate the impact on disease genesis.

 

Transplantation immunology

Transplant rejection is a complex genetic trait in both humans and mice. The genes responsible for rejection are histocompatibility (H) genes. While the H genes associated with the MHC on mouse Chromosome 17 have been well characterized, most H genes map to other chromosome locations. We are continuing to characterize the genetic basis for the H antigens encoded by these genes. Using MHC tetramer technology, we are able to track immune responses to specific H antigens in "real" time. This approach is providing original insights into the dynamics of the response of T cells to specific antigens in complex antigenic settings. We have shown that not all H antigens are equal, in that certain immunodominant ones prevail over many others. We are using a combination genetic and immunobiological approach to understand the dynamics of T-cell responses in solid and bone marrow transplant situations. These studies include the analysis of solid tissue transplantation and bone marrow transplantation, investigating which H antigens contribute to transplant rejection.

 

The genetic basis of epidermolysis bullosa

Epidermolysis bullosa is a devastating inherited human disorder characterized by blister formation caused by mechanical trauma. We have shown that the mutation is in the laminin 2 gene, recapitulating the genetic defects found in certain affected humans. With our institutional collaborator, Dr. John Sundberg, we are characterizing this disease model and determining whether the severity of this disease can be modified by genes distinct from laminin 2. Up to now, there have been no good models for studying this disease. Its characterization opens the road to develop therapies to treat epidermolysis bullosa.

 

 

 

Publications

• Bubier JA, Sproule TJ, Foreman O, Spolski R, Shaffer, DJ Morse HC 3rd, Leonard WJ, Roopenian DC 2009. A Critical Role for IL21 Receptor Signaling in the Pathogenesis of Systemic Lupus Erythematosus in BXSB-Yaa Mice. Proc Natl Acad Sci, Feb 3;106(5):1518-23
• 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. PNAS 105(3):967-972.
• Serreze DV, Choisy-Rossi CM, Grier A, Holl M, Chapman HD, Gahagan JR, Osborne MA, Zhang W, King BL, Brown A, Roopenian DC, 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 NOD mice1. J Immunol 180(5):3250-9.
• Petkova SB, Yuan R, Tsaih SW, Schott W, Roopenian DC, Paigen B. 2008. Physiol Genomics. Genetic influence on immune phenotype revealed strain-specific variations in peripheral blood lineages. Physiol Genomics. 34(3):304-314.
• Shin DM, Shaffer DJ, Wang H, 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 S-W, Kobayashi K, Johansen, Sollid LM, Andersen JT, Milford E, Roopenian DC, Lencer WI, Blumberg RS Dependence of antibody-mediated presentation of antigen on FcRn. Proc Natl Acad Sci, Jul 8;105(27):9337-42
• Liu X, Ye, L, Christianson GJ,Yang JQ, Roopenian DC, Zhu X. 2007. NF-kB signaling regulates functional expression of the MHC class I-related neonatal Fc receptor for IgG via intronic binding sequences. J Immuno Sept 1;179(5):2999-3011.
• 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 Oct 1:179(7):4580-8.
• 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.
• 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 Feb;69(2):181-8.
• Qi CF, Zhou JX, Lee CH, Naghashfar Z, Xiang S, Chattopadhyay SK, Fredrickson TN, Hartley JW, Roopenian DC, Davidson WF, Janz S, Morse III HC. 2007. Anaplastic, plasmablastic and plasmacytic plasmacytomas of mice: relationships to human plasma cell neoplasms and late stage differentiation of normal B cells. Cancer Res March15:67(6):2439-47.
• Roopenian DC, Akilesh S. 2007. FcRn: The neonatal Fc receptor comes of age. Nat Rev Immunol Sept;7(9):715-25.
• 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 Jul;8(5):416-21.
• Shatry AM, Roopenian DC, Levy RB. 2007. Survival and Function of MiHA Epitope-Specific Host CD8 TM Cells Following Ablative Conditioning and HCT. Biol Blood Marrow Transplant March;13(36):2439-47.
• 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 Sept 6;26(41):6010-20.
• 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.
• Crowley H, Alroy J, Sproule TJ, Roopenian D, Huber BT. 2006. The MHC class I-related FcRn ameliorates murine Lyme arthritis. Int Immunol Mar;18(3):409-14.
• 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(2):G352-60.
• 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 6:791-799.
• 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 Dec;18(12):1759-69.
• 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 Fc gamma RIIB. J Exp Med 203:275-280.
• Yan J, Parekh VV, Mendez-Fernandez Y, Olivares-Villagomez D, Dragovic S, 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 203:647-659.
• 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.
• Brown AC, Olver W. Donnelly C, May M, Naggert J, Shaffer DJ, Roopenian DC. 2005. Searching QTL by Gene Expression: Analysis of Diabesity. BMC Genet 6(1):12.
• Chen Y-G, Choisy-Rossi CM, Holl TM, Chapman HD, Besra GS, Procelli SA, Shaffer DJ, Roopenian DC, Wilson SB, Serreze DV. 2005. Activated NKT-cells Inhibit Autoimmune Diabetes Through Tolerogenic Recruitment of Dendritic Cells to Pancreatic Lymph Nodes. J Immunol 174:1196-1204.
• Kim J, Bronson CL, Hayton WL, Radmacher MD, Roopenian DC, Robinson JM, Anderson CL. 2005. Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. Epub ahead of print. PMID: 16210471. Am J Physiol Gastrointest Liver Physiol.
• Oh K, Kim S, Park SH, Gu H, Roopenian DC, Chung DH, Kim YS, Lee DS. 2005. Direct regulatory role of NKT cells inallogeneic graft survival is dependent on the quantitative strength of antigenicity. J Immunol 174:2030-2036.
• Ueno M, Lyons BL, Burzenski LM, Gott B, Shaffer DJ, Roopenian DC, Shultz LD. 2005. Accelerated Wound Healing of Alkali-Burned Corneas in MRL Mice Is Associated with a Reduced Inflammatory Signature. Invest Ophthalmol Vis Sci 46(11):4097-4106.
• Akilesh S, Petkova SB, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian DC. 2004. The MHC class I-like Fc Receptor (FcRn) promotes humorally-mediated autoimmune disease. J Clin Invest 113:1328-1333.
• Brown AC, Kai K, May ME, Brown DC, Roopenian DC. 2004. ExQuest, a novel method fordisplaying quantitative gene expression from ESTs. Genomics 83(3):528-539.
• Hart GT,Shaffer DJ, Akilesh S, Brown AC, Moran L, Roopenian DC, Baker PJ. 2004. Quantitative gene expression profiling implicates genes for susceptibility and resistance to alveolar bone loss. Infect Immun 72(8):4471-4479.
• Ozaki K, Spolski R, Ettinger R, Kim H-Pyo, Wang G, Qi C-F, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, Morse HC, Lipsky PE, Leonard WJ. 2004. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 173(9):5361-5371.
• Serreze DV, Roopenian DC. 2004. Was there type 1 diabetes in the Olduvai Gorge? Adv Exp Med Biol 552:322-325.
• Yoshida M, Claypool SM, Mizoguchi E. Mizoguchi A, Roopenian DC, Lencer WI, Blumberg RS. 2004. Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20:769-783:
• Yoshimura Y, Yadav R, Christianson GJ, Ajayi WU, Roopenian DC, Joyce S. 2004. Duration of alloantigen presentation and avidity of T cell antigen recognition correlate with immunodominance of CTL response to minor histocompatibility antigens. J Immunol 170-6666-6674.
• Zhang JQ, Okumura C, McCarty T, Shin MS, Mukhopadhyay P, Hori M, Torrey TA, Naghashfar Z, Zhou JX, Lee CH, Roopenian DC, Morse HC III, Davidson WF. 2004. Evidence for selective transformation of autoreactive immature plasma cells in mice deficient in Fasl. J Exp Med 200(11):1467-1478.
• Akilesh S, Shaffer DJ, Roopenian DC. 2003. Customized molecular phenotyping by quantitative gene expression and pattern recognition analysis. Genome Res 13:1719-172
• Brown AC, Kai K, May ME, Brown Dc, Roopenian DC. 2003. A novel method for deciphering and displaying quantitative gene expression from ESTs. Genomics 83:528-539
• Chadhury C, Mehanz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL. 2003. The MHC-related Fc Receptor (FcRn) binds albumin and prolongs its lifespan, J Exp Med 197:315-322.
• Haskova Z, Sproule TJ, Roopenian DC, Ksander AB. 2003. An immunodominant minor histocompatibility alloantigen that initiates corneal allograft rejection. Transplantation 75(8):1368-1374.
• Luedtke B, Pooler LM, Choi EY, Tranchita AM, Reinbold C, Brown AC, Shaffer DJ, Roopenian DC, Malarkannan S. 2003. A single nucleotide polymorphism in the Emp3 gene defines the H4 minor histocompatibility antigen. Immunogenetics 55:284-295.
• Roopenian DC, Christianson, GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, Petkova S, Avanessyan L, Choi, EY, Shaffer DJ, Eden PA, Anderson CL. 2003. The MHC class I-like IgG receptor (FcRn) controls perinatal IgG transport, IgG homostasis and the fate of IgG-Fc coupled drugs. J Immunol 170(7):3528-3533.
• Stanic AK, Shashidharamurthy R, Bezbradica JS, Matsuki N, Yoshimura Y, Miyake S, Choi EY, Schell TD, Van Kaer L, Tevethia ST, Roopenian DC, Yamamura T, Joyce S. 2003. Another view of T cell antigen recognition: Co-operative engagement of glycolipid antigens by Va14Ja18 natural T cell receptor. J Immunol 171:4539-4551.
• Yadav R, Yoshimura Y, Boesteanu A, Christianson GJ, Ajayi WU, Shashidharamurthy R, Stanic AK, Roopenian DC, Joyce S. 2003. The H4b minor histocompatibility antigen is caused by a combination of genetically determined and posttranslational modifications. J Immunol 170:5133-5142.
• Baker PJ, Howe L, Garneau J, Roopenian DC. 2002. T cell knockout mice have diminished alveolar bone loss after oral infection with Porphyromonas gingivalis. FEMS Immunol Med Microbiol 34:45-50.
• Baker PJ, Roopenian DC. 2002. Genetic susceptibility to chronic periodontal disease. Microbes Infect 4:1157-1167.
• Cerwenka A, O'Callaghan CA, Hamerman JA, Yadav R, Ajayi W, Roopenian DC, Joyce S, Lanier LL. 2002. The minor histocompatibility antigen H60 peptide interacts with both H-2Kb and NKG2D. J Immunol 168:3131-3134.
• Choi EY, Christianson GJ, Sproule TS, Yoshimura Y, Jung N, Joyce S, Roopenian DC. 2002. Immunodominance of H60 is caused by an abnormally high precursor T cell pool directed against its unique minor histocompatibility antigen peptide. Immunity 17:593-603.
• Choi EY, Christianson GJ, Yoshimura Y, Jung N, Sproule TJ, Malarkannan S, Joyce S, Roopenian DC. 2002. Real-time T cell profiling identifies H60 as a major minor histocompatibility antigen in murine graft vs. host disease. Blood 100:4259-4264.
• Ostrov DA, Roden MM, Shi W, Palmieri E, Christianson GJ, Mendoza L, Villaflor G, Tilley D, Shastri N, Grey H, Almo SC, Roopenian D, Nathenson SG. 2002. How H13 histocompatibility peptides differing by a single methyl group and lacking conventional MHC binding anchor motifs determine self-nonself discrimination. J Immunol 168:283-289.
• Roopenian DC. 2002. The immunogenomics of minor histocompatibility antigens. Immunol Rev 190:86-94.
• Serreze DV, Roopenian DC. 2002. Was there type 1 diabetes in the Olduvai Gorge? In: Immunology of type 1 diabetes, Eisenbarth G, [ed], Landes Bioscience, Austin, Texas, in press.
• Simpson E, Roopenian DC. 200_. Much progress but a long road ahead. In: HLA 2002, Immunobiology of the Human MHC. Vol 2. IHWG Press, Seattle, WA, (in press)