Our laboratory focuses on defining the mechanisms of the human autoimmune rheumatic diseases, including myositis, scleroderma, SLE, Sjogren’s syndrome and Rheumatoid Arthritis. We investigate the human model of these diseases, and utilize samples and tissues from patients with well-defined clinical phenotypes followed longitudinally in the Disease-specific Centers for our work. One of the major challenges to the investigation of the human autoimmune rheumatic diseases is their extraordinary complexity. In spite of this complexity, specific phenotypes are associated with unique autoantibody signatures, implying a potential mechanistic connection between the targeting of specific molecules and particular forms of tissue damage. This phenotype-specific immune response provides important tools to interrogate the basis for this specificity, and hence the events underlying initiation and propagation of rheumatic diseases.We are currently pursuing studies in many areas, including understanding the relevance of autoantigen cleavage and modification on their immunogenicity, quantitation of antigen-specific immune responses in patients with a variety of diseases and the ability to monitor activity and predict outcomes. We have also taken a new approach to defining amplification-specific autoantibodies in rheumatic diseases, and will use these to identify important amplification pathways. We also have projects aimed at understanding the reasons underlying specific targeting of apparently ubiquitously expressed antigens in unique diseases. Several areas are very exciting at present. These include our class="msoDel"recent demonstration class="msoIns"finding that myositis-specific autoantigens are expressed at low levels in normal healthy muscle, but at elevated levels in muscle obtained from patients with autoimmune myositis. Strikingly, we showed that autoantigen expression is highest in regenerating cells in the diseased muscle. The data suggests that regenerating cells may be the targets of the immune response in autoimmunity, with ongoing tissue damage the proximate cause of increased autoantigen expression, and a basic mechanism underlying the patchy and self-sustaining nature of these diseases. Interdicting such pathways may provide new therapeutic opportunities, and may be relevant to many of the diseases in this spectrum. Faculty associated with our laboratory are listed below.
I am a Ph#D# student in the Immunology Graduate Program and am one of the newer additions to the Rosen Lab# I received a B#S# in Biology from Ursinus College and subsequently worked as a lab technician studying synaptic transmission in C# elegans# Upon entering graduate school at the Johns Hopkins University School of Medicine, I rotated in the Rosen Lab and explored the role of barrier-to-autointegration factor #BAF# as an autoantigen in the pathogenesis of lupus. I am currently investigating the roles of perforin and granzyme B in granule-mediated cell death# Specifically, I am interested in the interplay between granule components as well as their trafficking within target cells.
I am studying the altered structure and immunogenicity of nucleophosmin #NPM1#, a tumor antigen in hepatocellular carcinoma that is targeted by autoantibodies in these patients. We have observed that NPM1 was not only over-expressed in tumor tissue, but also behaved differently by biochemical analyses than NPM1 from normal or cirrhotic liver tissues. Specifically, tumor NPM1 formed SDS stable oligomeric complexes and was highly susceptible to cleavage by granzyme B, a very fastidious serine protease. Similar properties were observed with a mutant form of this protein beginning at the seventh methionine instead of the first #M7-NPM#, making M7-NPM a good model for the tumor protein. Using a variety of techniques, we are currently investigating the conformational and functional differences between wild-type NPM1 and M7-NPM.
Michelle Harris, Ph.D.
The cytotoxic lymphocyte granule protease, granzyme B #GrB#, appears to play a role in autoantigen selection in systemic autoimmunity. In rheumatoid arthritis #RA#, the noncoded amino acid, citrulline, is a frequent and specific target of autoantibodies. Citrulline is formed by the post-translational deimination of arginine in a reaction catalyzed by peptidylarginine deiminases PADs, one of which, PAD4, has been genetically associated with RA. We have made the exciting discoveries that PADs can be cleaved by GrB and that PAD4 is itself a highly specific autoantigen in RA. To gain a better understanding of disease pathogenesis, we are characterizing anti-PAD4 as a disease marker, and are investigating the interaction between PAD4, GrB, and anti-PAD4 autoantibodies.
Katy Roberts Marron
As a graduate student in the Graduate Training Program in Cellular and Molecular Medicine, my research interest has been focused on the study of what happens to the Golgi apparatus during apoptosis. We are interested both in the overall fate of the Golgi apparatus, as well as in specific proteolysis of the golgin family of autoantigens localized to the Golgi apparatus during cell death. Since the Golgi apparatus is central in the secretory pathway, and many viruses rely on the host cell secretory pathway for the production of new virions, we are particularly focused on apoptosis mediated by cytotoxic lymphocyte granule exocytosis as this pathway of inducing apoptosis is critical in the elimination of many types of viral infections. We hypothesize that rapid disruption of the secretory pathway in virally infected cells killed as part of the immune response to viral infection could be a potent antiviral activity, helping to reduce the spread of virus to neighboring healthy cells.
After graduation I am going to be a secondary school biology teacher. In addition to teaching my long term interests include future involvement in science education policy and/or curriculum design and implementation.
Tomeka Suber, MD/PhD Candidate
I am an MD/PhD student in the Cellular and Molecular Medicine Graduate Program. I graduated from the University of North Carolina with a BS in Chemistry in 2002. I am currently studying how various physiologic states of specific cell populations affect the expression and modification of common autoantigens. I am exploring developmental, proliferative, and proinflammatory pathways to understand how autoantigen levels are attenuated in vitro and in lupus mouse models. Understanding these mechanisms will also help clarify the connection between autoimmune disease and cancer. Along with my research interests, I also mentor minority premedical undergraduate students, and I am active in the Student National Medical Association. After completing the MD/PhD Program, I plan to enter into an internal medicine residency program and to specialize in oncology or rheumatology.
Toni is a technician working with Drs. Livia Casciola-Rosen and Antony Rosen.
|Marissa Mullins |
Marissa is a technician working with Drs.Livia Casciola-Rosen and Stuart Levine.