Research interests

Autoimmune Disease and Transplantation Biology

Our laboratory is currently focused on three broad questions. What is the function of the IgG antibody receptor FcRn in biology and in autoimmune disease? How does genetic variation among individuals lead to tissue transplant rejection? What is the transcriptional basis of normal and pathological biological processes?

The Biology and Pathobiology of FcRn

FcRn (a.k.a. FcRp and 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. Finally, our 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.

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. 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 functions in vivo.

Transplantation Immunology

Transplant rejection is a complex genetic trait in both humans and in 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. With our collaborators, 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.

Gene Expression Profiling In Silico and In Vivo

The mouse and human genome sequences are now assembled into chromosomes punctuated with an increasing number of known or hypothesized genes organized in linear fashion. This provides the roadmap for understanding the genetic basis of mammalian biology and disease. Major opportunities now arise to connect the genome to the biology that it confers, and a logical first step is to elucidate the pattern of expression of each gene. We have developed a novel bioinformatic tool, ExQuest, that greatly facilitates this process. As its foundation, ExQuest catalogues publicly available expressed sequence tags (ESTs), which are sequences derived from RNA isolated from specific tissue types (e.g., liver, lung, adipose tissue). It then organizes and pools these EST libraries hierarchically into tissue groups of increasing complexity, an organized database resulting in a "virtual" gene expression model. We have automated this procedure such that users can examine entire chromosomes and view the tissue expression pattern of each gene in the context of the mouse genome. These transcriptome maps should help clarify key issues regarding the influence of chromosomal position on gene expression patterns. They also provide an improved tool to help identify genes that are candidates for genetic diseases.

While the above in silico data-mining tool provides a first approximation of gene-expression patterns, high-throughput, reliable methods for gene expression analysis are critically needed for empirical analysis of gene expression patterns coincident with normal and pathological processes. Because all pathological processes are logically associated with changes in gene expression, the expression changes during disease progression should suggest a molecular phenotype that provides clues regarding the nature of the disease. We have developed a highly reliable quantitative gene expression platform that allows users to track the molecular progression of autoimmune disease and better define the nature of the pathological processes involved. To provide this capacity, we have designed a customized gene expression array that focuses on a set of genes of known immunological importance. The method is high-throughput, quantitative, and requires no sophisticated equipment other than a Real-Time® PCR machine. We have additionally developed a novel, robust analytical program termed "Global Pattern Recognition" to extract meaningful expression data. Our current experiments are focused on determining the gene expression patterns that precede and correlate with severity of graft-versus-host disease, systemic lupus erythematosus, rheumatoid arthritis, and periodontal disease.

Publications

• 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.
• 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.
• 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.
• 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.
• 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)

[Edit my profile]