Christiane Hampe, PhD

Background:

Chris Hampe received her PhD at the Weizmann Institute of Science in Israel in 1997. She did her post-doctoral training in Dr. Åke Lernmark’s laboratory at the University of Washington, Seattle and is currently a Research Associate Professor at the Diabetes and Obesity Center of Excellence at the University of Washington.

Focus:

Dr. Hampe's research interests center on human autoimmune diseases and the role of autoantibodies in disease pathogenesis with particular interest in Type 1 diabetes and Stiff Person Syndrome.  More specifically, areas of focus are as follows.

Identification of autoantibodies and their epitopes in different forms of diabetes, and during progression to type 1 diabetes
The major autoantibodies in type 1 diabetes are defined as being specific to insulin (IAA), the tyrosine-phosphatase-like protein IA-2 (IA2Ab), and the 65kDa isoform of glutamate decarboxylase (GAD65Ab). GAD65Ab in type 1 diabetes are especially dependent on the conformational integrity of the antigen.  Traditional epitope mapping assays using deletion mutation, fusion proteins etc often compromise the conformation and lead to biased results. We developed a novel epitope mapping assay that depends on competition of the serum antibodies with recombinant Fab derived from GAD65-specific monoclonal antibodies. Using this novel technique, we were able to identify disease-specific GAD65Ab epitopes. We also succeeded to detect antibody maturation towards these epitopes during progression of disease.
 
The studies encompass the following areas:
• Characterization of the molecular aspects autoantigen-autoantibody interaction (Drs. M, Rowley, G. Fenalti, I.R. Mackay, P.J. Banga).
• Identification of disease-specific autoantibodies and their epitopes in different forms of autoimmune diabetes to aid in diagnosis and classification (Drs. A. Balasubramanyam, I. Hirsch, S. Kahn, T. Maruyama, O. Rolandsson, J. Palmer).
• Identification of disease-specific autoantibodies and their epitopes in Stiff Person Syndrome to aid in better diagnosis.
• Analysis of genetic and environmental effects in autoimmune diabetes (M. Metzker, Z. Laron).
• Identification of autoantibodies and their epitopes during progression to type 1 diabetes (A. Lernmark, M. Schlosser, M. Pietropaolo, J. Ludvigsson).

Anti-idiotypic antibodies
Recently we identified the presence of masked GAD65Ab in the majority of healthy individuals. These autoantibodies are not detected in the regular radioligand binding assay, because they are masked by anti-idiotypic antibodies. Removal of the anti-idiotypic antibodies allows their detection. Currently we investigate the role of anti-idiotypic antibodies in the disease pathogenesis both in humans and in animal models for type 1 diabetes.
 
The studies encompass the following projects:
• Monoclonal GAD65Ab and their anti-idiotypic antibodies in type 1 diabetes of the NOD mouse (Drs. H. Reijonen, X. Wang)
• GAD65Ab-specific anti-idiotypic antibodies in the progression to type 1 diabetes.

Role of GAD65Ab in disease pathogenesis
The central hypothesis is that autoantibody modulation of T cell mediated autoimmunity plays a key role in the pathogenesis of type 1 diabetes. It is well established  that antibodies can modulate T cell responses either by enhanced  antigen uptake (receptor-mediated endocytosis) or alteration of  antigen processing, or both.  Antibodies can both suppress or boost the presentation of certain peptides, hence the analysis of  heterogeneous GAD65Abs, as present in patients’ sera, will be  difficult.  We use GAD65-B cell lines to test how they deviate the T cell response  (H. Reijonen).
 
A potential role of GAD65Ab on the pathogenesis of Stiff Person Syndrome has been suggested based on the finding that GAD65Ab in this disease inhibit the enzymatic activity of GAD65 and that SPS patients have decreased levels of GABA. In collaboration with Drs. Manto and Honnorat rats were intracerebellar injected with monoclonal GAD65Ab. Only GAD65Ab that are SPS specific induced significant changes in the neurophysiology and the behavior of these animals. These findings strongly support a pathogenic role of GAD65Ab in the pathogenesis (Drs. Manto (Belgium) and Honnorat (France)).

Representative Publications:

Ortqvist E, Brooks-Worrell B, Lynch K, Radtke J, Bekris LM, Kockum I, Agardh CD, Cilio CM, Lethagen AL, Persson B, Lernmark A, Reichow J, Oak S, Palmer JP, Hampe CS. Changes in GAD65Ab-specific anti-idiotypic antibody levels correlate with changes in C-peptide levels and progression to islet cell autoimmunity. J Clin Endocrinol Metab. 2010 [Epub ahead of print].
 
Vaziri Sani F, Oak S, Radtke J, Lernmark A, Lynch K, Agardh CD, Cilio CM, Lethagen AL, Örtqvist E, Landin-Olsson M, Törn C, Hampe CS. ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset. Autoimmunity. 2010 [Epub ahead of print].
 
Chéramy M, Skoglund C, Johansson I, Ludvigsson J, Hampe CS, Casas R. GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD(65) enzyme activity and humoral response. Clin Immunol. 137:31-40, 2010.
 
Rizzi M, Knoth R, Hampe CS, Lorenz P, Gougeon ML, Lemercier B, Venhoff N, Ferrera F, Salzer U, Thiesen HJ, Peter HH, Walker UA, Eibel H. Long-lived plasma cells and memory B cells produce pathogenic anti-GAD65 autoantibodies in Stiff person syndrome. PLoS One. 26;5:e10838, 2010.
 
Oak S, Gilliam LK, Landin-Olsson M, Törn C, Kockum I, Pennington CR, Rowley MJ, Christie MR, Banga JP, Hampe CS. The lack of anti-idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxylase, defines type 1 diabetes. Proc Natl Acad Sci USA. 105:5471-5476, 2008. 
 
Hall T R, Bogdani M, LeBoeuf R, Kirk, E, Maziarz M, Banga J P, Oak, S, Pennington C, Hampe CS. Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies. Immunology. 123:547-554, 2008.
 
 
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Current Collaborations:

Within the Diabetes and Obesity Center of Excellence and its Affiliated Members
Irl Hirsch, MD
Jay Taborsky, PhD
Ian Sweet, PhD
Jerry Palmer, MD
Jerry Nepom, MD, PhD
 
Outside the Diabetes and Obesity Center of Excellence
Ake Lernmark, Sweden
Olav Rolandsson, Sweden
Johnny Ludvigsson,  Sweden
Ashok Balasubramanyam, Houston
Taro Maruyama, Japan
Paul Banga, UK
Merrill Rowley, Australia
Massimo Pietropaolo, Michigan
Mario Manto, Belguim
Jerome Honnorat, France
Xin Wang, China

Lab Members:

Jared Radtke, Lab Manager