Immunopathology and Cell Biology of Autoantigens STBA-GROUP
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Laboratory of Immunopathology and Cell Biology of Autoantigens (laboratory closed in April 2017)
Research Program
Type 1 Diabetes (T1D) in humans develops following an autoimmune destruction of pancreatic beta-cells in the islets of Langerhans. In earlier work, we and others identified three intracellular beta cell membrane proteins which are targeted by autoantibodies associated with beta cell destruction in humans. These include GAD65, the smaller isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and a tyrosine phosphatase, IA-2. Autoantibodies to those proteins can be detected in the blood long before clinical onset of T1D and they identify individuals at risk. Although T1D can be prevented in inbred animal models by development of antigen specific immune tolerance, such methods are currently not available in humans.
GAD65, IA-2, and ZnT8 are also expressed in CNS neurons, which, in contrast to beta cells, are protected behind the blood brain barrier. Never-the-less, GAD65 in CNS can become a target of autoimmunity resulting in a rare neurological disorder, stiff-man syndrome that affects GABA-ergic neurons. In contrast, the highly homologous isoform of GAD, GAD67, is not a target antigen in either disease. The two isoforms differ mainly in the N-terminal region that controls membrane targeting and trafficking of the proteins, suggesting that this region in GAD65 plays a role in its susceptibility to be targeted by the immune system.
GAD65 is synthesized in the cytosol as a hydrophilic cytosolic molecule, which undergoes a series of hydrophobic post-translational modifications in the N-terminal domain to become membrane anchored at the cytosolic face of endomembranes. The modifications, include a reversible palmitoylation of cysteines 30 and 45. A palmitoylation-depalmitoylation cycle controls the spatial distribution of GAD65 in endomembranes and thus the localization of GABA synthesis.
Pancreatic beta cells have a well developed, extensive, and highly active ER, reflecting their role in synthesizing and secreting large amounts of insulin. Beta cells are unusually sensitive to ER stress. There is evidence to suggest that induction of ER-stress by cytokines secreted by inflammatory cells and other ER stressors play a role in the loss of beta cells that precedes clinical onset of Type 1 diabetes.
Research in the Baekkeskov Lab, aims at elucidating the mechanisms of early events leading to autoimmunity towards the beta cell and how they can be prevented. The focus of current projects is:
- Understanding how the release of the autoantigens GAD65, IA-2 and proinsulin in exosomes may initiate autoimmunity associated with beta cell destruction
- Testing the hypothesis that ER stress is an important factor in inducing autoimmunity to GAD65, IA2, and proinsulin
- Understanding the role of GABA-ergic signalling in islets of Langerhans
Research Themes
Type 1 Diabetes
Autoimmunity
Beta Cell Autoantigens
Intracellular Membrane Proteins
Protein Targeting and Trafficking
Endoplasmic Reticulum Stress
GAD65, GAD67, IA-2, GABA
Contact
Head of Laboratory
Visiting Prof. Steinunn Baekkeskov
SV-3826
steinunn.baekkeskov@epfl.ch
Phone : +41 21 69 30983
Mailing Address
EPFL
SV-IBI-GR-STBA
Station 19
CH-1015 Lausanne
News
New Publication: E. A. Phelps*, C. Cianciaruso*, J. Santo-Domingo, M. Pasquier, G. Galliverti, L. Piemonti, E. Berishvili, O. Burri, A. Wiederkehr, J. A. Hubbell and S. Baekkeskov. Advances in pancreatic islet monolayer culture on glass surfaces enable super-resolution microscopy and insights into beta cell ciliogenesis and proliferation. Scientific Reports in press
*co-first authors
Congratulations to Chiara Cianciaruso, who successfully defended her doctoral dissertation on December 13, 2016 and was awarded her Ph.D. diploma following a public thesis lecture on March 17, 2017
Congratulations to Edward Phelps, who has moved on to a faculty position at the University of Florida in January 2017
New Publication: C. Cianciaruso, E. A. Phelps, M. Pasquier, R. Hamelin, D. Demurtas, M. Alibashe Ahmed, L. Piemonti, S. Hirosue, M. A. Swartz, M. De Palma, J. A. Hubbell and S. Baekkeskov. Primary human and rat beta cells release the intracellular autoantigens GAD65, IA-2 and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes 66, 460-473, 2017. http://dx.doi.org/10.2337/db16-0671
News Article: http://actu.epfl.ch/news/protein-packaging-may-cause-the-immune-attacks-o-2/
News Article: http://bioengineering.epfl.ch/page-139264.html
New Publication: E. A. Phelps, C. Cianciaruso, I. P. Michael, M. Pasquier, J. Kanaani, R. Nano, V. Lavallard, N. Billestrup, J. A. Hubbell and S. Baekkeskov. Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of ER stress and autoimmunity. Diabetes 65, 2686-2699, 2016. http://dx.doi.org/10.2337/db16-0180