The smaller form of the biosynthesizing enzyme for the inhibitory neurotransmitter GABA, glutamic acid decarboxylase (GAD65), is expressed at comparable levels in GABA-ergic neurons in the central nervous system and in pancreatic (3-cells. This protein is a major autoantigen in two human diseases that affect its sites of expression, insulin dependent diabetes mellitus (IDDM), which results from an autoimmune destruction of the (3-cell, and stiff-man syndrome (SMS), a rare neurological disorder caused by a dysfunction of GABA-ergic neurons. Although there is a high coincidence of IDDM in SMS patients, very few IDDM patients develop SMS. The major hypothesis to be tested are i) that SMS is caused by autoantibodies to a distinct epitope in GAD65 ii) that IDDM is caused by GAD65 specific cytotoxic T-cells which destroy the (3-cell, and iii) that B-cells play a role as antigen presenting cells in IDDM. The overall objective of the work proposed here is to understand the molecular mechanisms of autoimmunity to GAD65 and its role in each disease. The first and second aims propose to characterize the human B-cell and T-cell epitopes in GAD65 and their correlation with each disease and with HLA-susceptibility and protective haplotypes in humans. The larger form of the enzyme, GAD67, which is highly homologous to GAD65 and yet does not play a role as an autoantigen in either disease, provides an important reference molecule for those studies.
The third aim i s to study mechanisms of autoimmunity and tolerance to GAD65 in animal models. If autoimmunity to GAD65 is causative for either disease, the results will be important for development of antigen specific methods of immuno prevention. If autoimmunity to GAD65 is not pathogenic but rather a marker of disease development, the results are important for diagnosis and prediction in each disease and for mechanisms of tolerance and autoimmunity to peripheral antigens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047043-04
Application #
2391475
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Akolkar, Beena
Project Start
1994-04-01
Project End
1999-03-31
Budget Start
1997-06-05
Budget End
1999-03-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Nunez, Jacques; Celi, Francesco S; Ng, Lily et al. (2008) Multigenic control of thyroid hormone functions in the nervous system. Mol Cell Endocrinol 287:1-12
Hayakawa, N; Premawardhana, L D K E; Powell, M et al. (2002) Isolation and characterization of human monoclonal autoantibodies to glutamic acid decarboxylase. Autoimmunity 35:343-55
Wolfe, Tom; Bot, Adrian; Hughes, Anna et al. (2002) Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL-4 increases safety. Eur J Immunol 32:113-21
Roll, U; Turck, C W; Gitelman, S E et al. (2000) Peptide mapping and characterisation of glycation patterns of the glima 38 antigen recognised by autoantibodies in Type I diabetic patients. Diabetologia 43:598-608
O'Rourke, R W; Kang, S M; Lower, J A et al. (2000) A dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet allograft survival. Transplantation 69:1440-6
Shi, Y; Kanaani, J; Menard-Rose, V et al. (2000) Increased expression of GAD65 and GABA in pancreatic beta-cells impairs first-phase insulin secretion. Am J Physiol Endocrinol Metab 279:E684-94
Kanaani, J; Lissin, D; Kash, S F et al. (1999) The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to membranes and nerve terminals independent of dimerization with the hydrophobic membrane-anchored isoform, GAD65. J Biol Chem 274:37200-9
Schwartz, H L; Chandonia, J M; Kash, S F et al. (1999) High-resolution autoreactive epitope mapping and structural modeling of the 65 kDa form of human glutamic acid decarboxylase. J Mol Biol 287:983-99
Kang, S M; Schneider, D B; Lin, Z et al. (1997) Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med 3:738-43