The gamma-aminobutyrate-synthesizing enzyme glutamate decarboxylase (GAD; L-glutamate 1-carboxy-lyase, EC 4.1.1.15) is a major target of autoantibodies associated with both early and late stages of pancreatic beta-cell destruction and development of type 1 diabetes. We have used five monoclonal anti-islet-cell antibodies (MICAs 1,2,3,4, and 6) derived from a newly diagnosed diabetic patient to ...

Gamma-aminobutyric acid (GABA)ergic neurons have been postulated to compose an important component of local circuits in the adult spinal cord, yet their identity and axonal projections have not been well defined. We have found that, during early embryonic ages (E12-E16), both glutamic acid decarboxylase 65 (GAD65) and GABA were expressed in cell bodies and growing axons, whereas at older ages (...

The generation of human monoclonal autoantibodies is critical for understanding humoral immune responses in autoimmunity. In this study, we isolated the first human recombinant antibodies to glutamate decarboxylase (rGAD65ab) by IgG repertoire cloning, phage display of Fab fragments, and biopanning from two patients at onset of type 1 diabetes. We demonstrate that natural Ig heavy- and light-ch...

Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65 isoform of the GABA synthesizing enzyme glutamic...

To study the antigens involved in the islet cell antibody (ICA) reaction we selected 30 patient serum samples (ten in each group) positive for ICA and one other additional autoantibody, such as glutamic acid decarboxylase antibodies (GADA), thyrosine phosphatase antibodies (IA-2A) or insulin autoantibodies (IAA). The serum samples were incubated with the specific antigen (GAD65, IA-2 or insulin...

T cell recognition of autoantigens is critical to progressive immune-mediated destruction of islet cells, which leads to autoimmune diabetes. We identified a naturally presented autoantigen from the human islet antigen glutamic acid decarboxylase, 65-kDa isoform (GAD65), by using a combination of chromatography and mass spectrometry of peptides bound by the type I diabetes (insulin-dependent di...

The localizations and functions of glutamate and GABA, the major amino acid neurotransmitters in the central nervous system, are still unclear in the peripheral nervous system. We immunohistochemically double-stained mouse superior cervical ganglia with antibodies for the vesicular acetylcholine transporter (VAchT), GAD65, the vesicular glutamate transporters 1-3 (VGluTs1-3), the marker of the ...

Identifying beta cell autoantigen-reactive T cells that are involved in the pathogenesis of type 1 diabetes has been troublesome for many laboratories. Disease-relevant autoreactive T cells should be in vivo Ag experienced. The aim of this study was to test this hypothesis and then use this principle as a strategy for identifying diabetes-relevant autoreactive T cells. In this study, a CSFE dil...

The spinal dorsal horn (SDH) is the first step in the integration of primary nociceptive information, which is controlled by the descending serotonin (5-HT) system as well as the principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA). However, the influence exerted by 5-HT on GABA synthesis remains poorly understood. The major pathway for GABA synthesis is the enzymatic decarboxyl...

In this issue of Diabetes, Zhou et al. (1) report on the prevalence and characteristics of latent autoimmune diabetes in adults (LADA) in China. Findings from this study underscore the profound need for a new definition of LADA. LADA, a slowly progressive form of autoimmune diabetes that develops in adults and does not require insulin therapy for some time after diagnosis, was first described o...