Статті в журналах: "Human GAD65"

1

Trier, Nicole Hartwig, Niccolo Valdarnini, Ilaria Fanelli, Paolo Rovero, Paul Robert Hansen, Claus Schafer-Nielsen, Evaldas Ciplys, et al. "Peptide Antibody Reactivity to Homologous Regions in Glutamate Decarboxylase Isoforms and Coxsackievirus B4 P2C." International Journal of Molecular Sciences 23, no. 8 (April 17, 2022): 4424. http://dx.doi.org/10.3390/ijms23084424.

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Two isoforms of the glutamate decarboxylase (GAD) enzyme exist, GAD65 and GAD67, which are associated with type 1 diabetes (T1D) and stiff-person syndrome (SPS), respectively. Interestingly, it has been reported that T1D patients seldom develop SPS, whereas patients with SPS occasionally develop T1D. In addition, coxsackievirus B4 (CVB4) has previously been proposed to be involved in the onset of T1D through molecular mimicry. On this basis, we aimed to examine antibody cross-reactivity between a specific region of GAD65 and GAD67, which has high sequence homology to the nonstructural P2C protein of CVB4 to determine potential correlations at antibody level. Monoclonal peptide antibodies generated in mice specific for a region with high similarity in all three proteins were screened for reactivity along with human sera in immunoassays. In total, six antibodies were generated. Two of the antibodies reacted to both GAD isoforms. However, none of the antibodies were cross-reactive to CVB, suggesting that antibody cross-reactivity between GAD65 and CVB, and GAD67 and CVB may not contribute to the onset of T1D and SPS, respectively.

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2

Schwab, Claudia, Sheng Yu, Winnie Wong, Edith G. McGeer, and Patrick L. McGeer. "GAD65, GAD67, and GABAT Immunostaining in Human Brain and Apparent GAD65 Loss in Alzheimer's Disease." Journal of Alzheimer's Disease 33, no. 4 (January 21, 2013): 1073–88. http://dx.doi.org/10.3233/jad-2012-121330.

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3

Schwab, Claudia, Sheng Yu, Winnie Wong, Edie McGeer, and Patrick McGeer. "P2-417: GAD65, GAD67 and GABAT immunoreactivity in human brain and GAD65 loss in Alzheimer's disease." Alzheimer's & Dementia 8, no. 4S_Part_11 (July 2012): P410. http://dx.doi.org/10.1016/j.jalz.2012.05.2042.

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4

Schlosser, Michael, Uwe Walschus, Ingrid Klöting, and Reinhard Walther. "Determination of Glutamic Acid Decarboxylase (GAD65) in Pancreatic Islets and ItsIn VitroandIn VivoDegradation Kinetics in Serum Using a Highly Sensitive Enzyme Immunoassay." Disease Markers 24, no. 3 (2008): 191–98. http://dx.doi.org/10.1155/2008/961421.

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Glutamic acid decarboxylase GAD65 autoantibodies (GADA) are an established marker for autoimmune diabetes. Recently, the autoantigen GAD65 itself was proposed as biomarker of beta-cell loss for prediction of autoimmune diabetes and graft rejection after islet transplantation. Therefore, the GAD65 content in pancreatic islets of different species and its serum degradation kinetics were examined in this study using a sensitive immunoassay. GAD65 was found in quantities of 78 (human), 43.7 (LEW.1A rat) and 37.4 (BB/OK rat) ng per 1,000 islets, respectively, but not in mouse islets. Thein vitrohalf-life of porcine GAD65 and human recombinant GAD65 ranged from 1.27 to 2.35 hours at 37°C in human serum, plasma and blood, and was unaffected by presence of GAD65 autoantibodies. After injecting 2,000 ng recombinant human GAD65 into LEW.1A rats, thein vivohalf-life was 2.77 hours. GAD65 was undetectable after 24 hours in these animals, and for up to 48 hours following diabetes induction by streptozotocin in LEW.1A rats. Estimated from these data, at least 13 islets in rat and 1,875 in human must be simultaneously destroyed to detect GAD65 in circulation. These results should be taken into consideration in further studies aimed at examining the diagnostic relevance of GAD65.

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5

Shi, Yuguang, Jamil Kanaani, Virginie Menard-Rose, Yan Hui Ma, Pi-Yun Chang, Douglas Hanahan, Allan Tobin, Gerold Grodsky та Steinunn Baekkeskov. "Increased expression of GAD65 and GABA in pancreatic β-cells impairs first-phase insulin secretion". American Journal of Physiology-Endocrinology and Metabolism 279, № 3 (1 вересня 2000): E684—E694. http://dx.doi.org/10.1152/ajpendo.2000.279.3.e684.

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The functional role of glutamate decarboxylase (GAD) and its product GABA in pancreatic islets has remained elusive. Mouse β-cells express the larger isoform GAD67, whereas human islets express only the smaller isoform GAD65. We have generated two lines of transgenic mice expressing human GAD65 in pancreatic β-cells (RIP7-hGAD65, Lines 1 and 2) to study the effect that GABA generated by this isoform has on islet cell function. The ascending order of hGAD65 expression and/or activity in β-cells was Line 1 heterozygotes < Line 2 heterozygotes < Line 1 homozygotes. Line 1 heterozygotes have normal glucose tolerance, whereas Line 1 homozygotes and Line 2 heterozygotes exhibit impaired glucose tolerance and inhibition of insulin secretion in vivo in response to glucose. In addition, fasting levels of blood glucose are elevated and insulin is decreased in Line 1 homozygotes. Pancreas perfusion experiments suggest that GABA generated by GAD65 may function as a negative regulator of first-phase insulin secretion in response to glucose by affecting a step proximal to or at the KATP +channel.

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6

Hampe, C. S., E. Örtqvist, O. Rolandsson, M. Landin-Olsson, C. Törn, Å Ågren, B. Persson, D. B. Schranz, and Å Lernmark. "Species-Specific Autoantibodies in Type 1 Diabetes1." Journal of Clinical Endocrinology & Metabolism 84, no. 2 (February 1, 1999): 643–48. http://dx.doi.org/10.1210/jcem.84.2.5503.

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GAD65 autoantibodies (GAD65Ab) are important markers for type 1 (insulin-dependent) diabetes mellitus. Although most patients have GAD65Ab at the time of clinical diagnosis, there are also GAD65Ab-positive individuals in the population at low risk of developing type 1 diabetes. The aim of this study was to test the hypothesis that the GAD65Ab reactivity to GAD65 cloned from human, mouse, and rat in newly diagnosed type 1 diabetic patients differ from antibody-positive healthy individuals. Sera from 254 new-onset 0- to 34-yr-old type 1 diabetic patients and 270 controls were assayed for their reactivity to human, mouse, and rat GAD65. Among the type 1 diabetic patients there was a significant better binding of human GAD65 compared to either mouse (P = 0.03) or rat GAD65 (P = 0.0005). The preference for human GAD65 increased with increasing age at onset (P = 0.0002). This differentiation was not observed in 88 GAD65Ab-positive control subjects. Our data indicate that recognition of epitopes by GAD65Ab in type 1 diabetes is different from that in nontype 1 diabetes, GAD65Ab-positive individuals.

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7

Aulanni’am, Aulanni’am, Djoko Wahono Soeatmadji, and Sutiman Bambang Sumitro. "KONFIRMASI SPESIFITAS GAD65 TERHADAP ANTI-GAD65 PADA TIKUS DM DAN PASIEN DM TIPE 1." Berkala Penelitian Hayati 11, no. 2 (June 30, 2006): 125–28. http://dx.doi.org/10.23869/bphjbr.11.2.20065.

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The use of glutamic acid decarboxylase (GAD65) from bovine brain has been studied to obtain basic knowledge and diagnosis and prediction of Type 1 Diabetes Mellitus (DM) patients. The importance of GAD65 in DM diagnosis based on its patogenesis. One of the autoimmune marker that can be used to detect beta-pancreas destruction in Diabetes Type I is the antibody to glutamic acid decarboxylase (GAD65). Most of the pre-diabetic patients indicate the reactive autoantibody to GAD65. For early detection of anti-GAD65 in the serum of the patient, human recombinat GAD65 has been succeed to be used. However this is not economical, therefore, it is necessary to find the alternative source of cheaper GAD65. The aim of this research is to develop an early detection kit of Type 1 DM based on antibody-GAD65, since the longest patient suffering from DM has higher probability to be complicated, especially for uncured patients. The anti- GAD65 antibodies induced by anti-GAD65 synthetized and labelled by alkaline phosphatase can be used as reagent detection early DM patients. The ten patients of DM as samples (positive of anti-GAD65) and five rats of DM were positive with western blott technique using reagents as result of this research. It can be concluded, GAD65 enzyme isolated from bovine brain induced anti-GAD65 production and have possibilities to be packaged in a diagnostic kit for patient pre DM.

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8

Reijonen, Helena, John F. Elliott, Peter van Endert, and Gerald Nepom. "Differential Presentation of Glutamic Acid Decarboxylase 65 (GAD65) T Cell Epitopes Among HLA-DRB1*0401-Positive Individuals." Journal of Immunology 163, no. 3 (August 1, 1999): 1674–81. http://dx.doi.org/10.4049/jimmunol.163.3.1674.

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Abstract Glutamic acid decarboxylase 65 (GAD65) is one of the major autoantigens in type 1 diabetes. We investigated whether there is variation in the processing of GAD65 epitopes between individuals with similar HLA backgrounds and whether the processing characteristics of certain immunogenic epitopes are different in distinct APC subpopulations. Using DR401-restricted T cell hybridomas specific for two immunogenic GAD65 epitopes (115–127 and 274–286), we demonstrate an epitope-specific presentation pattern in human B-lymphoblastoid cell lines (B-LCL). When pulsed with the GAD protein, some DRB1*0401-positive B-LCL, which presented GAD65 274–286 epitope efficiently, were unable to present the GAD65 115–127 epitope. However, all B-LCL presented synthetic peptides corresponding to either GAD epitope. In addition, when pulsed with human serum albumin, all cell lines gave equal stimulation of a DR4-restricted human serum albumin-specific T hybridoma. GAD65-transfected cell lines displayed the same presentation phenotype, showing that lack of the presentation of the 115–127 epitope was not due to inefficient uptake of the protein. Blood mononuclear adherent cells, B cells, or dendritic cells derived from the same individual displayed the same presentation pattern as observed in B cell lines, suggesting that the defect most likely is genetically determined. Therefore, individual differences in Ag processing may result in the presentation of distinct set of peptides derived from an autoantigen such as GAD65. This may be an important mechanism for the deviation of the immune response either into a regulatory pathway or into an inflammatory autoimmune reactivity.

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9

Kim, J., W. Richter, H. J. Aanstoot, Y. Shi, Q. Fu, R. Rajotte, G. Warnock, and S. Baekkeskov. "Differential Expression of GAD65 and GAD67 in Human, Rat, and Mouse Pancreatic Islets." Diabetes 42, no. 12 (December 1, 1993): 1799–808. http://dx.doi.org/10.2337/diab.42.12.1799.

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10

Kim, J., W. Richter, H. J. Aanstoot, Y. Shi, Q. Fu, R. Rajotte, G. Warnock, and S. Baekkeskov. "Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets." Diabetes 42, no. 12 (December 1, 1993): 1799–808. http://dx.doi.org/10.2337/diabetes.42.12.1799.

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11

Tarbell, Kristin V., Mark Lee, Erik Ranheim, Cheng Chi Chao, Maija Sanna, Seon-Kyeong Kim, Peter Dickie, Luc Teyton, Mark Davis, and Hugh McDevitt. "CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer." Journal of Experimental Medicine 196, no. 4 (August 19, 2002): 481–92. http://dx.doi.org/10.1084/jem.20011845.

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Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

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12

Bedi, Suhana, Tiffany M. Richardson, Baofeng Jia, Hadeel Saab, Fiona S. L. Brinkman, and Monica Westley. "Similarities between bacterial GAD and human GAD65: Implications in gut mediated autoimmune type 1 diabetes." PLOS ONE 17, no. 2 (February 23, 2022): e0261103. http://dx.doi.org/10.1371/journal.pone.0261103.

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A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65 or GAD), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing in silico analyses, we show that 25 GAD sequences from human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that most gut GAD sequences contain the pyroxical dependent decarboxylase (PDD) domain of human GAD65, which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T cell receptor epitopes, which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities we found between human and bacterial GAD, these deputized immune cells may then target human beta cells leading to the development of T1D.

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13

Robert, S., K. Van Huynegem, C. Gysemans, C. Mathieu, P. Rottiers, and L. Steidler. "Trimming of two major type 1 diabetes driving antigens, GAD65 and IA-2, allows for successful expression in Lactococcus lactis." Beneficial Microbes 6, no. 4 (August 2015): 591–601. http://dx.doi.org/10.3920/bm2014.0083.

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Type 1 diabetes (T1D) is a chronic autoimmune disease characterised by excessive immune reactions against auto-antigens of pancreatic β-cells. Restoring auto-antigen tolerance remains the superior therapeutic strategy. Oral auto-antigen administration uses the tolerogenic nature of the gut-associated immune system to induce antigen-specific tolerance. However, due to gastric degradation, proper mucosal product delivery often imposes a challenge. Recombinant Lactococcus lactis have proven to be effective and safe carriers for gastrointestinal delivery of therapeutic products: L. lactis secreting diabetes-associated auto-antigens in combination with interleukin (IL)-10 have demonstrated therapeutic efficacy in a well-defined mouse model for T1D. Here, we describe the construction of recombinant L. lactis secreting the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and tyrosine phosphatase-like protein ICA512 (IA-2), two major T1D-related auto-antigens. Attempts to secrete full size human GAD65 and IA-2 protein by L. lactis were unsuccessful. Trimming of GAD65 and IA-2 was investigated to optimise antigen secretion while maintaining sufficient bacterial growth. GAD65370-575 and IA-2635-979 showed to be efficiently secreted by recombinant L. lactis. Antigen secretion was verified by immunoblotting. Plasmid-derived GAD65 and IA-2 expression was combined in single strains with human IL-10 expression, a desired combination to allow tolerance induction. This study reports the generation of recombinant L. lactis secreting two major diabetes-related auto-antigens: human GAD65 and IA-2, by themselves or combined with the anti-inflammatory cytokine human IL-10. Prohibitive sequence obstacles hampering antigen secretion were resolved by trimming the full size proteins.

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Syren, K., L. Lindsay, B. Stoehrer, K. Jury, F. Lühder, S. Baekkeskov, and W. Richter. "Immune reactivity of diabetes-associated human monoclonal autoantibodies defines multiple epitopes and detects two domain boundaries in glutamate decarboxylase." Journal of Immunology 157, no. 11 (December 1, 1996): 5208–14. http://dx.doi.org/10.4049/jimmunol.157.11.5208.

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Abstract Autoreactive islet cell Abs (ICA) accompany the pathogenic destruction of pancreatic beta cells in insulin-dependent diabetes mellitus (IDDM). Human monoclonal ICA (MICA 1-6), previously derived from a DR1/DR7-positive newly diagnosed diabetic patient, recognized the islet cell autoantigen glutamate decarboxylase 65 (GAD65) and defined two distinct conformational (MICA 1/3 and MICA 4/6) and one linear (MICA 2) autoimmune epitopes in this molecule. We have isolated 4 new ICA-reactive B cell lines, one from a DR4/DR11-positive newly diagnosed IDDM patient (MICA 7) and three from a DR3 homozygous patient with both IDDM and Graves' disease (MICA 8-10). Like MICA 1-6, MICA 7-10 are specific for GAD65, suggesting that GAD65-reactive B cells dominate the ICA response in IDDM. Comparative analysis of MICA 1-6 and MICA 7-10, using GAD65 mutants and blocking experiments, showed that MICA 7-10 define three novel conformational autoimmune epitopes in GAD65. Further structural analysis of the MICA 1-10 epitopes revealed two distinct and one overlapping region of epitope clusters. Thus, the C-terminal region, defined by amino acids 450 to 570, harbors the conformational MICA1/3 and MICA 7 epitopes as well as the linear epitope of MICA 2 (amino acids 506-531). The MICA 4/6 and MICA 10 epitopes are located in the middle region of the molecule defined by amino acids 245 to 449, whereas the N-terminal region contributes only to the MICA 8/9 epitopes (encompassed in amino acids 39-585). MICA 1-6, 7, and 8-10, derived from three IDDM patients of different HLA haplotypes, define six different epitopes in GAD65 and represent tools to determine the spectrum, possible HLA association, and temporal order of epitope recognition in IDDM.

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15

Costa, Olivier R., Geert Stangé, Katrijn Verhaeghen, Benedicte Brackeva, Ellen Nonneman, Christiane S. Hampe, Zhidong Ling, Daniel Pipeleers, Frans K. Gorus та Geert A. Martens. "Development of an Enhanced Sensitivity Bead-Based Immunoassay for Real-Time In Vivo Detection of Pancreatic β-Cell Death". Endocrinology 156, № 12 (2 жовтня 2015): 4755–60. http://dx.doi.org/10.1210/en.2015-1636.

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There is a clinical need for plasma tests to detect and quantify the in vivo destruction of pancreatic β-cells in type 1 diabetes. We previously developed a time-resolved fluorescence immunoassay (TRFIA) to glutamate decarboxylase 65 kDa (GAD65) (GAD65-TRFIA) that was able to detect the synchronous necrotic destruction of transplanted β-cells in the hours after their infusion in the liver. This GAD65-TRFIA, however, lacked sensitivity to detect continued β-cell rejection beyond this acute phase. The aim of present study was to gain at least an order of magnitude in analytical sensitivity by switching to Becton Dickinson cytometric bead array (CBA) (GAD65-CBA) enhanced sensitivity format, using the same couple of monoclonal antibodies. We compared the performances of GAD65-CBA and GAD65-TRFIA using Clinical and Laboratory Standards Institute protocols for linearity, imprecision, specificity, limit of detection, and functional sensitivity. We conducted a method comparison and assessed the biologic potential on samples from human recipients of islet grafts. The GAD65-CBA showed acceptable linearity and imprecision. Switching from TRFIA to CBA lowered functional sensitivity by a factor 35 and lowered limit of detection by a factor 11 with minimal need for method optimization. The enhanced sensitivity greatly expands the application domain of our biomarker and allowed for the first time to detect ongoing β-cell destruction up to at least 1 day after islet transplantation. We conclude that the GAD65-CBA is suitable for biological and clinical assessment of the real-time destruction of β-cells in intraportal transplantation.

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Wei, Jianning, and Jang-Yen Wu. "Structural and functional analysis of cysteine residues in human glutamate decarboxylase 65 (GAD65) and GAD67." Journal of Neurochemistry 93, no. 3 (May 2005): 624–33. http://dx.doi.org/10.1111/j.1471-4159.2005.03046.x.

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17

Kim, J., M. Namchuk, T. Bugawan, Q. Fu, M. Jaffe, Y. Shi, H. J. Aanstoot, et al. "Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin-dependent diabetes mellitus." Journal of Experimental Medicine 180, no. 2 (August 1, 1994): 595–606. http://dx.doi.org/10.1084/jem.180.2.595.

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The smaller form of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD65) is a major autoantigen in two human diseases that affect its principal sites of expression. Thus, destruction of pancreatic beta cells, which results in insulin-dependent diabetes mellitus (IDDM), and impairment of GABA-ergic synaptic transmission in Stiff-Man syndrome (SMS) are both characterized by circulating autoantibodies to GAD65. Anti-GAD65 autoantibodies in IDDM are predominantly directed to conformational epitopes. Here we report the characterization of humoral autoimmune responses to GAD65 in 35 SMS patients, of whom 13 (37%) also had IDDM. All SMS patients immunoprecipitated native GAD65 and the main titers were orders of magnitude higher than in IDDM patients. Furthermore, in contrast to the situation in IDDM, autoantibodies in 35 of 35 (100%) of SMS patients recognized denatured GAD65 on Western blots. Two major patterns of epitope specificity were identified on Western blots. The first pattern, detected in 25 of 35 SMS patients (71%), of whom 11 had IDDM (44%), was predominantly reactive with a linear NH2-terminal epitope residing in the first eight amino acids of GAD65. Nine of nine individuals who were HLA-haplotyped in this group carried an IDDM susceptibility haplotype and HLA-DR3, DQw2 was particularly abundant. The second pattern, detected in 10 of 35 patients (29%) of whom two had IDDM (20%), included reactivity with the NH2-terminal epitope plus strong reactivity with one or more additional epitope(s) residing COOH-terminal to amino acid 101. The second epitope pattern may represent epitope spreading in the GAD65 molecule, but may also include some cases of epitope recognition associated with IDDM resistant HLA-haplotypes. The principal NH2-terminal linear epitope in GAD65 distinguishes the reactivity of SMS and IDDM autoantibodies and may be a determinant of pathogenicity for GABA-ergic neurons. The greater magnitude and distinct specificity of the humoral response to GAD65 in SMS may reflect a biased involvement of the T helper cell type 2 (Th2) subset of CD4+ T cells and antibody responses, whereas IDDM is likely mediated by the Th1 subset of CD4+ T cells and cytotoxic T cell responses.

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Falorni, Alberto, Eva Örtqvist, Bengt Persson, and Åke Lernmark. "Radioimmunoassays for glutamic acid decarboxylase (GAD65) and GAD65 autoantibodies using 35S or 3H recombinant human ligands." Journal of Immunological Methods 186, no. 1 (October 1995): 89–99. http://dx.doi.org/10.1016/0022-1759(95)00139-2.

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19

Rosso, Pamela, Elena Fico, Louise A. Mesentier-Louro, Viviana Triaca, Alessandro Lambiase, Paolo Rama, and Paola Tirassa. "NGF Eye Administration Recovers the TrkB and Glutamate/GABA Marker Deficit in the Adult Visual Cortex Following Optic Nerve Crush." International Journal of Molecular Sciences 22, no. 18 (September 16, 2021): 10014. http://dx.doi.org/10.3390/ijms221810014.

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Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.

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Marre, Meghan L., Eddie A. James та Jon D. Piganelli. "ER stress generates immunogenicity in human pancreatic β cells". Journal of Immunology 196, № 1_Supplement (1 травня 2016): 124.49. http://dx.doi.org/10.4049/jimmunol.196.supp.124.49.

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Abstract Type 1 diabetes (T1D) is an autoimmune disease in which autoreactive T cells target and destroy pancreatic islet β cells. The key events that break peripheral tolerance in patients genetically predisposed to autoimmunity remain poorly understood. Many physiological and environmental triggers associated with T1D cause endoplasmic reticulum (ER) stress, which may increase abnormal protein post-translational modification (PTM). We hypothesized that β cell ER stress generates neo-antigens that can activate autoreactive T cells in T1D. Chemical (Thapsigargin) induction of ER stress in human islets or insulinomas increased their recognition (135–360 fold) by human T cells known to preferentially recognize deamidated GAD65, as measured by IFNγ secretion. This increased immunogenicity was accompanied by increased activation of the PTM enzyme tissue transglutaminase 2 (Tgase2; 2 fold). We will confirm the role of this enzyme in ER stress-induced human β cell immunogenicity with shRNA. We are also working to validate this pathway as a therapeutic target as follows: First, we are measuring calcium dynamics to determine if cytosolic calcium is crucial to ER stress-dependent immunogenicity. Second, we are assessing whether other triggers of ER stress, such as cytokines and glucose, also generate GAD65 PTM in human β cells. β cell ER stress generated through a variety of sources may be an opportunity for therapeutic intervention to prevent the destruction of β cells. Our on-going work will define the ER stress-induced pathways and PTM that contribute to recognition of GAD65. These findings will also have implications for the recognition of other autoantigens and for the development of T1D.

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Hong, A. Ram, Young A. Kim, Jae Hyun Bae, Hye Sook Min, Jung Hee Kim, Chan Soo Shin, Seong Yeon Kim, and Sang Wan Kim. "A Possible Link Between Parathyroid Hormone Secretion and Local Regulation of GABA in Human Parathyroid Adenomas." Journal of Clinical Endocrinology & Metabolism 101, no. 6 (June 1, 2016): 2594–601. http://dx.doi.org/10.1210/jc.2015-4329.

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Abstract Context: γ-Aminobutyric acid-B receptor 1 (GABABR1) forms a heterodimeric complex with calcium-sensing receptor (CaSR) in human brain tissue. However, the expression and implication of GABABR1 in human parathyroid adenoma has not yet been examined. Objective: The objective of the study was to examine a possible link between GABABR1 and PTH secretion in human parathyroid adenoma Design and Methods: Sixty-five patients who underwent parathyroidectomy for primary hyperparathyroidism (PHPT) and 29 control patients with normal parathyroid glands were retrospectively included. All patients diagnosed with PHPT had parathyroid adenomas. We evaluated the protein expression of GABABR1, glutamic acid decarboxylase 65/67 (GAD65/67), and various factors proposed as regulators of PTH secretion including CaSR, vitamin D receptor (VDR), CYP24A1, CYP27B1, fibroblast growth factor, and α-klotho in parathyroid tissues from patients with parathyroid adenomas using immunohistochemistry. Results: Expressions of CaSR, GABABR1, and VDR were significantly lower in PHPT patients than in control subjects (P < .001 for CaSR and GABABR1; P = .006 for VDR). Protein expression of GAD65/67, which indicates local production and regulation of GABAergic pathway, was significantly increased in PHPT (P < .001). There were no significant differences in CYP24A1, CYP27B1, fibroblast growth factor, and α-klotho expression between the two groups. Expression of GAD65/67 was significantly correlated with VDR, CYP24A1, CYP27B1, and α-klotho in PHPT (all P < .01) but not in the control groups. CaSR expression was positively associated with serum phosphorus level (r = 0.274, P = .029) and GAD65/67 was negatively correlated with serum PTH level (r = −0.342, P = .005). Conclusions: Local production and action of GABA may be regulated in human parathyroid adenomas. This suggests a possible link between PTH secretion and local regulation of GABA in parathyroid adenomas.

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Cram, D. S., B. Faulkner-Jones, J. Kun, and L. C. Harrison. "Glutamic acid decarboxylase-67 (GAD67): expression relative to GAD65 in human islets and mapping of autoantibody epitopes." Endocrinology 136, no. 3 (March 1995): 1111–19. http://dx.doi.org/10.1210/endo.136.3.7532577.

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Mitoma, Hiroshi, Mario Manto, and Christiane S. Hampe. "Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias." Journal of Immunology Research 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/2913297.

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Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum.

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Ronkainen, Matti S., Sanna Hoppu, Sari Korhonen, Satu Simell, Riitta Veijola, Jorma Ilonen, Olli Simell, and Mikael Knip. "Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes." European Journal of Endocrinology 155, no. 4 (October 2006): 633–42. http://dx.doi.org/10.1530/eje.1.02271.

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Objective: The pattern of the humoral immunity to disease-associated autoantigens may reflect the severity of the autoimmune disease process. The purpose of this study was to delineate the maturation of the humoral immunity to one of the main autoantigens in type 1 diabetes (T1D), glutamic acid decarboxylase (GAD65). Design and methods: Serum samples were obtained for the detection of epitope- and isotype-specific antibodies sequentially with short intervals from 36 young children with HLA-conferred genetic susceptibility to T1D starting from the first appearance of GAD65Ab. During prospective observation, ten children developed T1D. Antibodies were analyzed using biotinylated anti-human immunoglobulin (Ig) antibodies and chimeric GAD molecules in radio-binding assays. Results: The immune response to GAD65 started as reactivity to the middle region and spread rapidly to the C-terminal region. IgG1 antibodies dominated among the isotypes from the first appearance of GAD65Ab, while other IgG subclasses were observed to a lesser extent. IgG4 antibodies emerged clearly as the last IgG subclass. A broad initial response comprising three to four IgG subclasses and the lack of an emerging IgG4 response during follow-up was associated with increased risk for progression to clinical diabetes (P<0.05). Conclusions: The humoral response to GAD65 epitope clusters is relatively uniform in young children, whereas there is conspicuous individual variation in IgG subclass responses except for IgG1. A narrow initial IgG subclass response to GAD65 and the emergence of IgG4 antibodies were characteristic of those who remained non-diabetic over the first few years of GAD65 autoimmunity.

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Chujo, Daisuke, Akitsu Kawabe, Maya Matsushita, Nobuyuki Takahashi, Chiharu Tsutsumi, Fumitaka Haseda, Akihisa Imagawa, et al. "Distinct Phenotypes of Islet Antigen-Specific CD4+ T Cells Among the 3 Subtypes of Type 1 Diabetes." Journal of Clinical Endocrinology & Metabolism 105, no. 10 (July 11, 2020): 3141–51. http://dx.doi.org/10.1210/clinem/dgaa447.

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Abstract Context Type 1 diabetes (T1D) is classified into 3 subtypes: acute-onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). The differences in the type of cellular autoimmunity within each subtype remain largely undetermined. Objective To determine the type and frequency of islet antigen-specific CD4+ T cells in each subtype of T1D. Participants Twenty patients with AT1D, 17 with SP1D, 18 with FT1D, and 17 persons without diabetes (ND). Methods We performed an integrated assay to determine cellular immune responses and T-cell repertoires specific for islet antigens. This assay included an ex vivo assay involving a 48-hour stimulation of peripheral blood mononuclear cells with antigen peptides and an expansion assay involving intracytoplasmic cytokine analysis. Results The results of the ex vivo assay indicated that glutamic acid decarboxylase 65 (GAD65)-specific interleukin-6 and interferon-inducible protein-10 (IP-10) responses and preproinsulin (PPI)-specific IP-10 responses were significantly upregulated in AT1D compared with those of ND. Furthermore, GAD65- and PPI-specific granulocyte colony-stimulating factor responses were significantly upregulated in FT1D. Expansion assay revealed that GAD65- and PPI-specific CD4+ T cells were skewed toward a type 1 helper T (Th1)- cell phenotype in AT1D, whereas GAD65-specific Th2 cells were prevalent in SP1D. GAD65-specific Th1 cells were more abundant in SP1D with human leukocyte antigen-DR9 than in SP1D without DR9. FT1D displayed significantly less type 1 regulatory T (Tr1) cells specific for all 4 antigens than ND. Conclusions The phenotypes of islet antigen-specific CD4+ T cells differed among the three T1D subtypes. These distinct T-cell phenotypes may be associated with the manner of progressive β-cell destruction.

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Marcovina, S. M., M. Landin-Olsson, A. Essen-Möller, J. P. Palmer, and Å. Lernmark. "Evaluation of a novel radioimmunoassay using125I-labelled human recombinant GAD65 for the determination of glutamic acid decarboxylase (GAD65) autoantibodies." International Journal of Clinical & Laboratory Research 30, no. 1 (March 2000): 21–26. http://dx.doi.org/10.1007/s005990070029.

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Bjork, E. "Glucose regulation of the autoantigen GAD65 in human pancreatic islets." Journal of Clinical Endocrinology & Metabolism 75, no. 6 (December 1, 1992): 1574–76. http://dx.doi.org/10.1210/jc.75.6.1574.

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Björk, E., O. Kämpe, F. A. Karlsson, D. G. Pipeleers, A. Andersson, C. Hellerström, and D. L. Eizirik. "Glucose regulation of the autoantigen GAD65 in human pancreatic islets." Journal of Clinical Endocrinology & Metabolism 75, no. 6 (December 1992): 1574–76. http://dx.doi.org/10.1210/jcem.75.6.1464667.

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Rasche, Sarah, Michele Phillips, and Anthony Quinn. "IL-13 Mediated Regulation of Islet-Reactive T Cells (143.44)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 143.44. http://dx.doi.org/10.4049/jimmunol.184.supp.143.44.

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Abstract Immunotherapy with the beta cell antigen glutamic acid decarboxylase (GAD65) or GAD65 peptides delays the onset of type 1 diabetes (T1D) in NOD mice, while alum formulated rGAD65 may be therapeutic in human T1D; nevertheless, the regulatory mechanisms involved in each therapy may be distinct. Here, we sought to discover the factors that contribute to GAD65 peptide 524-538 (p524)-mediated protection from T1D in NOD mice and to determine if IL-13 produced by p524-specific T cells could regulate pathogenic islet-reactive T cells. IL-13 produced by p524-reactive T cells directly modulated IFN-g production by spontaneously arising GAD65 530-543-specific Th1 cells in NOD mice and rIL-13 inhibited proliferative responses of islet-reactive BDC2.5 clonotypic T cells. Contrary to previous observations, both CD4+ and CD8+ T cells in the peripheral lymphoid compartment of NOD and C57BL/6 mice expressed the receptor subunit required for IL-13 signaling, IL-13Rα1. Interestingly, the number of IL13Rα1+ T cells was highest in pancreatic lymph nodes, as compared to inguinal lymph node or splenic T cells, and this expression was uniquely diminished in pancreatic lymph nodes of older prediabetic NOD. Thus, IL-13 may be an important mechanism for regulation of autoreactive T cells in the early stages of insulitis. The loss of IL-13Rα1 expression on T cells in the draining nodes of the pancreas may reflect fading regional immune regulation and progression from insulitis to overt T1D.

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Skelin, Marta, Danijel Bursać, Viviana Kozina, Tristan Winters, Marija Macan, and Marija Ćurlin. "Key molecules in the GABA signalling pathway are present in mouse and human cervical tissue." Reproduction, Fertility and Development 30, no. 9 (2018): 1267. http://dx.doi.org/10.1071/rd17333.

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Cervical mucus modulates fertility by cyclical changes of its biophysical and functional properties. Based on an analogy with bronchial goblet cells we set out to investigate the possible role of the gamma-aminobutyric acid (GABA) signalling pathway in the mediation of oestrogen-induced mucus secretion from endocervical secretory cells. The aim of the study was to examine the existence of GABAA receptor (GABAAR), glutamic acid decarboxylase 65/67 (GAD65/67) and vesicular GABA transporter (VGAT) in human and mouse cervical tissue. The mouse cervical tissue expressed GabaAR mRNA transcripts throughout the oestrous cycle. GABAAR-positive immunolabelling was present in the superficial layer of the mouse cervico–vaginal epithelium in pro-oestrus. Human cervical tissue showed the presence of GABAAR, GAD67 and VGAT mRNA transcripts and clear immunofluorescent signals of all three molecules were detected in the endocervical secretory epithelium. The results of this study confirmed that elements of the GABA signalling pathway are present in the secretory epithelium of mouse and human cervical tissue and that GABA signalling pathway could be considered a possible mediator in oestrogen regulation of mucus secretion in the endocervical glands.

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Elagin, Raya B., Sadguna Balijepalli, Maria J. Diacovo, Steinunn Baekkeskov, and Juan C. Jaume. "Homing of GAD65 specific autoimmunity and development of insulitis requires expression of both DQ8 and human GAD65 in transgenic mice." Journal of Autoimmunity 33, no. 1 (August 2009): 50–57. http://dx.doi.org/10.1016/j.jaut.2009.02.004.

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Imam, Shahnawaz. "OR22-4 Homing of Antigen-specific Engineered Regulatory T Cells To Human Pancreatic Islets." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A456. http://dx.doi.org/10.1210/jendso/bvac150.949.

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Abstract The therapeutic application of regulatory T cells (Tregs) for the treatment of autoimmune disorders, although efficacious, has been limited by the scarcity of antigen-specific Tregs. If antigen-specific Tregs, capable of reaching the desired autoimmune target, could be produced on demand, antigen-specific immune suppression of autoimmune diseases would be achievable. One approach to endow T cells with a desired antigen-specificity uses chimeric T cell antigen-receptors (CAR) with antibody-type specificity. Adoptive cell transfer therapies with CAR-re-directed cytotoxic T cells, have shown impressive efficacy in the treatment of hematologic malignancies. Accordingly, employing such technology to re-direct Tregs to sites of autoimmune attack may be a useful therapeutic approach to alleviate a broad spectrum of diseases in which uncontrolled auto and alloimmune responses play a major role. We recently developed pancreatic beta-cell, antigen-specific, CAR Tregs (1) and explored their therapeutic potential against T1D in our humanized mouse model (2). Ours is the first successful, antigen-specific CAR-Treg treatment of T1D in a humanized mouse model that closely resembles the human disease. Based on our mice data, we believe treatment with pancreatic beta-cell, antigen-specific CAR-Tregs will allow for recovery and reconstitution of beta cells in human T1D patients as well. The purpose of this study was to determine if antigen-specific human CAR Tregs could also identify target and home to human pancreatic islets in culture as they do in mice. The study involved drawing 10 cc of blood 1-2 weeks prior to pancreas surgery; followed by collection of a small piece of pancreas (5 cc wedge) once the pancreas was removed for a clinical indication (cancer, pancreatitis). We first isolated Tregs from peripheral blood of these human donors and expanded them in vitro. Treg cells were genetically modified to express either a beta-cell antigen-specific (GAD65) CAR or an irrelevant (EPCAM) CAR construct together with GFP marker. CAR Tregs were selectively expanded in the presence of rhGAD65 antigen. Once pancreas tissue became available, it was processed for islet separation using the collagenase method. Pancreatic islets were then co-cultured with syngeneic CAR Tregs for 7 days. IncuCyte S3 Live-cell System (Sartorius) is a real-time system that automatically acquires and analyzes HD, phase and fluorescent images of cell cultures, around the clock, for 7 days, while cells remain undisturbed. Live immunofluorescence microscopy demonstrated the distinct homing of GAD65 CAR Tregs to islets as compared to control EPCAM CAR Tregs as early as 24 hours of co-culture. Importantly, proliferation of GAD65 CAR Tregs was clearly demonstrated within 72 hours. GAD65 CAR Treg cytokine profile from co-culture supernatant was characteristic of activated Tregs. 1 PATENT #WO2020097546 2 PATENT #US20200037586 Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.

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Lühder, Fred, Klaus-Peter Woltanski, Ludwig Mauch, Heinz Haubruck, Klaus-Dieter Kohnert, Ilona Rjasanowski, Dietrich Michaelis, and Manfred Ziegler. "Detection of autoantibodies to the 65-kD isoform of glutamate decarboxylase by radioimmunoassay." European Journal of Endocrinology 130, no. 6 (June 1994): 575–80. http://dx.doi.org/10.1530/eje.0.1300575.

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Lühder F, Woltanski K-P, Mauch L, Haubruck H, Kohnert K-D, Rjasanowski I, Michaelis D, Ziegler M. Detection of autoantibodies to the 65-kD isoform of glutamate decarboxylase by radioimmunoassay. Eur J Endocrinol 1994:130:575–80. ISSN 0804–4643 Autoantibodies (AAb) to glutamate decarboxylase (GAD) occur with a high prevalence in sera of newly diagnosed type I (insulin-dependent) diabetic patients. The aim of this study was to establish a GAD-AAb radioimmunoassay using 125I-labelled GAD65 and to evaluate this assay in a cross-sectional study with newly diagnosed type I diabetic patients (diabetes duration < 6 weeks). Furthermore, subjects at high risk of developing type I diabetes and individuals suffering from other autoimmune diseases were examined in this assay. For GAD-AAb detection, 125I-labelled GAD65 was incubated with 10 μl of human serum overnight on ice. Thirty of 51 (59%) type I diabetic patients but none of the 54 healthy blood donors tested were found to be positive. A displacement step using 100 000 g supernatant from rat brain containing or not containing GAD showed the specificity of the binding of 125I-GAD65. Concerning the individuals at high risk of developing diabetes, 9/12 (75%) islet cell antibody (ICA)-positive non-diabetic and 4/34 (12%) ICA-negative subjects with metabolic abnormalities were GAD-AAb positive. These results show the association between type I (insulin-dependent) diabetes mellitus and the occurrence of GAD65-AAb, which possibly predicts a risk of developing the disease. F Lühder, Department of Immunochemistry, Institute of Diabetes "Gerhardt Katsch", Greifswalder Str. I la, D-17495 Karlsburg, Germany

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Kareem, Ahmed S., Ghanim A. Almola, and Oday J. Alsalihi. "The Correlation between Anti-GAD65 and Coxsackievirus B-IgG (CVB-IgG) in Type 1 Diabetes-Coxsackievirus B (T1D-CVB) Patients." INTERNATIONAL JOURNAL OF PHARMACEUTICAL QUALITY ASSURANCE 11, no. 02 (June 25, 2020): 208–13. http://dx.doi.org/10.25258/ijpqa.11.2.2.

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Coxsackieviruses are one of the main causes of type 1 diabetes, due to the sequence similarity between the protein 2 C (P2-C) in the structure of the virus and the glutamic acid decarboxylase (GAD65) autoantigen in human beta-cells. The study aims to detect the anti-GAD65 and specific anti-CVB IgG in Type 1 Diabetes (T1D) patients to study the correlation between the levels of the GAD65 autoantigen and CVB- IgG autoantibody in T1D-CVB patients. A hospital-based cross-sectional study was carried out from November 2018 to July 2019 at Babylon Diabetic Center in Marjan Teaching city, Babylon teaching hospital for maternity and children and college of medicine at the University of Babylon. A total of 150 samples were obtained from diabetic patients and 50 samples from non-diabetic individuals as control. Diabetic mellitus (DM) patients diagnosed by clinical features, RBS test (above 200 mg/dL) and HbA1c test (above 6.5%). Anti-Gad and CVB-IgG detected by indirect enzyme-linked immunosorbent assays (ELISA) . The study showed the age group A2 (1-5 years), the females group (B1), and rural group (C1) more susceptible to T1D-CVB infection. The study exhibited a positive correlation between anti-gad and anti-CVB-IgG (r = 0.644**) in T1D-CVB patients.

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Konidaris, C., P. G. Mitlianga, and G. K. Papadopoulos. "No Specific Reactivity to E. Coli Glutamic Acid Decarboxylase from Sera of Newly-Diagnosed Insulin Dependent Diabetic Patients." International Journal of Immunopathology and Pharmacology 16, no. 2 (May 2003): 129–38. http://dx.doi.org/10.1177/039463200301600206.

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The 65 kD isoform of Glutamic Acid Decarboxylase (GAD), is one of the major autoantigens in human type 1 diabetes mellitus. This enzyme shares aminoacid identity, in select regions already determined as antigenic with its counterpart from E. coli. We tested the reactivity of diabetic and normal sera and an E. coli GAD-specific monoclonal antibody (2D9) to E. coli GAD by solid phase and competition ELISA, as well as immunoblotting to check for cross-reactivity of autoantibodies to the two antigens. Specific antibodies for E. coli GAD are present in diabetics and normal subjects without any differences in frequency and titer. The reactivity of such antibodies in ELISA could be blocked in a dose-dependent manner by the addition of excess antigen in the liquid phase. Furthermore, the monoclonal antibody against E. coli GAD does not recognise human recombinant GAD65 in an ELISA. We conclude that there is no basis for cross-reactivity between the two antigens, and antibody reactivity to GAD65 in man cannot arise from cross-reactivity to the E. coli enzyme.

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Akamine, H., I. Komiya, T. Shimabukuro, T. Asawa, H. Tanaka, N. Yagi, T. Taira, et al. "High prevalence of GAD65(and IA-2) antibodies in Japanese IDDM patients by a new immunoprecipitation assay based on recombinant human GAD65." Diabetic Medicine 14, no. 9 (September 1997): 778–84. http://dx.doi.org/10.1002/(sici)1096-9136(199709)14:9<778::aid-dia461>3.0.co;2-7.

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Khalifa, D., H. Gabr, H. Fathy, H. Abdou, and M. Batrawy. "Cognitive Impairment and the correlation with genetic Expression of GAD67, Gad65 and GABA beta2 Using Human Induced Pluripotent Stem Cells." European Psychiatry 65, S1 (June 2022): S314. http://dx.doi.org/10.1192/j.eurpsy.2022.801.

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Introduction Alteration of GABergic neurotransmission is accused to be sharing in the cognitive impairment in schizophrenia. Exploring the relation between the neuronal expression of GABergic genes and cognitive impairment in living patients through modeling of schizophrenia is an important step to know more about the core of the pathophysiology of this disorder Objectives Altered genetic expression of GAD 67 may have an important role in the pathophysiology of cognitive impairment in schizophrenia Methods . Reprogramming of human fibroblasts into human induced pluripotent stem cells (hIPSc) then neuronal differentiation was performed in 20 patients presenting with schizophrenia and 20 matched controls. Real time Polymerase chain reaction was done for measurement of genetic expression of GAD 65, GAD 67 and GABA beta 2. The Digit Symbol task, block design, block design task and similarities tasks from the Wechsler Adult Intelligence Scale., Trail A and Trail B making tests in addition to Rey-Osterrieth Complex Figure Test (ROCF) were applied to measure cognitive functions . Results There were lower means of GAD65, GAD67 and GABA beta2genetic expression in the patients group with significant statistical difference between the 2 groups. The down regulation of GAD 67 in patients presenting with schizophrenia is positively correlated with impairment in executive functions. Conclusions GAD 67 gene expression had the most significant correlations with the cognitive assessment in both patients and controls. The presence of those statistically significant correlations in both groups points to the possible role of GAD 67 gene functioning in the pathophysiology of cognitive impairment in schizophrenia Disclosure No significant relationships.

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Tian, J., P. V. Lehmann, and D. L. Kaufman. "T cell cross-reactivity between coxsackievirus and glutamate decarboxylase is associated with a murine diabetes susceptibility allele." Journal of Experimental Medicine 180, no. 5 (November 1, 1994): 1979–84. http://dx.doi.org/10.1084/jem.180.5.1979.

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Limited regions of amino acid sequence similarity frequently occur between microbial antigens and host proteins. It has been widely anticipated that during infection such sequence similarities could induce cross-reactive T cell responses, thereby initiating T cell-mediated autoimmune disease. However, the nature of major histocompatibility complex (MHC)-restricted antigen presentation confers a number of constraints that should make this type of T cell cross-reactivity a rare, MHC allele-dependent event. We tested this prediction using two insulin-dependent diabetes mellitus (IDDM)-associated antigens, coxsackievirus P2-C (Cox P2-C) protein and glutamate decarboxylase (GAD65), which share a prototypic sequence similarity of six consecutive amino acids within otherwise unrelated proteins. We surveyed a panel of 10 murine MHC class II alleles that encompass the spectrum of standard alleles for the ability to cross-reactively present Cox P2-C and GAD65. Out of the 10 restriction elements tested, the sequence similarity regions were both dominant determinants and were cross-reactively displayed after the natural processing of whole antigens, only in the context of I-Anod. These data show that cross-reactive T cell recognition of sequence similarity regions in unrelated proteins is confined to certain MHC alleles, which may explain MHC association with autoimmune disease. It is striking that these two diabetes-associated antigens were cross-reactively recognized only in the context of a diabetes susceptibility allele. Since the human and the murine class II alleles associated with IDDM share conserved features, cross-reactive T cell recognition of GAD65 and Cox P2-C may contribute to the pathogenesis of human IDDM and account for the epidemiological association of coxsackievirus with IDDM.

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Panina-Bordignon, P., R. Lang, P. M. van Endert, E. Benazzi, A. M. Felix, R. M. Pastore, G. A. Spinas, and F. Sinigaglia. "Cytotoxic T cells specific for glutamic acid decarboxylase in autoimmune diabetes." Journal of Experimental Medicine 181, no. 5 (May 1, 1995): 1923–27. http://dx.doi.org/10.1084/jem.181.5.1923.

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Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that results in the destruction of the pancreatic islet beta cells. Glutamic acid decarboxylase (GAD) has been recently indicated as a key autoantigen in the induction of IDDM in nonobese diabetic mice. In human diabetes, the mechanism by which the beta cells are destroyed is still unknown. Here we report the first evidence for the presence of GAD-specific cytotoxic T cells in asymptomatic and recent diabetic patients. GAD65 peptides displaying the human histocompatibility leukocyte antigen (HLA)-A*0201 binding motif have been synthesized. One of these peptides, GAD114-123, binds to HLA-A*0201 molecules in an HLA assembly assay. Peripheral blood mononuclear cells from individuals with preclinical IDDM, recent-onset IDDM, and from healthy controls were stimulated in vitro with the selected peptide in the presence of autologous antigen-presenting cells. In three cases (one preclinical IDDM and two recent-onset IDDM), we detected specific killing of autologous antigen-presenting cells when incubated with GAD114-123 peptide or when infected with a recombinant vaccinia virus expressing GAD65. These patients were the only three carrying the HLA-A*0201 allele among the subjects studied. Our finding suggests that GAD-specific cytotoxic T lymphocytes may play a critical role in the initial events of IDDM.

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Capitani, Guido, Daniela De Biase, Heinz Gut, Shaheen Ahmed, and Markus G. Grütter. "Structural model of human GAD65: Prediction and interpretation of biochemical and immunogenic features." Proteins: Structure, Function, and Bioinformatics 59, no. 1 (February 2, 2005): 7–14. http://dx.doi.org/10.1002/prot.20372.

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Eugster, Anne, Annett Lindner, Mara Catani, Anne-Kristin Heninger, Andreas Dahl, Sylvia Klemroth, Denise Kühn, et al. "High Diversity in the TCR Repertoire of GAD65 Autoantigen-Specific Human CD4+ T Cells." Journal of Immunology 194, no. 6 (February 13, 2015): 2531–38. http://dx.doi.org/10.4049/jimmunol.1403031.

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GarcÃa, Ernesto, and Rubens LÃ³pez. "Streptococcus pneumoniaetype 3 encodes a protein highly similar to the human glutamate decarboxylase (GAD65)." FEMS Microbiology Letters 133, no. 1-2 (November 1995): 113–18. http://dx.doi.org/10.1111/j.1574-6968.1995.tb07870.x.

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Cousens, Leslie P., Yan Su, Elizabeth McClaine, Xin Li, Frances Terry, Robert Smith, Jinhee Lee, William Martin, David W. Scott, and Anne S. De Groot. "Application of IgG-Derived Natural Treg Epitopes (IgG Tregitopes) to Antigen-Specific Tolerance Induction in a Murine Model of Type 1 Diabetes." Journal of Diabetes Research 2013 (2013): 1–17. http://dx.doi.org/10.1155/2013/621693.

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HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called “Tregitopes”) have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigensex vivoand on the modulation of type 1 diabetes (T1D) in a murine modelin vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4+T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. Inex vivostudies of human T cells, peripheral blood mononuclear cells’ (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopesex vivoby Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.

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Imam, Shahnawaz, Raghavendra G. Mirmira, and Juan C. Jaume. "Eukaryotic translation initiation factor 5A inhibition alters physiopathology and immune responses in a “humanized” transgenic mouse model of type 1 diabetes." American Journal of Physiology-Endocrinology and Metabolism 306, no. 7 (April 1, 2014): E791—E798. http://dx.doi.org/10.1152/ajpendo.00537.2013.

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Therapeutic options for treatment of type 1 diabetes (T1D) are still missing. New avenues for immune modulation need to be developed. Here we attempted at altering the diabetes outcome of our humanized model of T1D by inhibiting translation-initiation factor eIF5A hypusination in vivo. Double-transgenic (DQ8-GAD65) mice were immunized with adenoviral vectors carrying GAD65 for diabetes induction. Animals were subsequently treated with deoxyhypusine synthase (DHS) inhibitor GC7 and monitored for diabetes development over time. On one hand, helper CD4+ T cells were clearly affected by the downregulation of the eIF5A not just at the pancreas level but overall. On the other hand, the T regulatory cell component of CD4 responded with activation and proliferation significantly higher than in the non-GC7-treated controls. Female mice seemed to be more susceptible to these effects. All together, our results show for the first time that downregulation of eIF5A through inhibition of DHS altered the physiopathology and observed immune outcome of diabetes in an animal model that closely resembles human T1D. Although the development of diabetes could not be abrogated by DHS inhibition, the immunomodulatory capacity of this approach may supplement other interventions directed at increasing regulation of autoreactive T cells in T1D.

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Zanone, Maria M., Enrica Favaro, Ilaria Miceli, Giorgio Grassi, Elisa Camussi, Cristiana Caorsi, Antonio Amoroso, Mirella Giovarelli, Paolo Cavallo Perin, and Giovanni Camussi. "Human Mesenchymal Stem Cells Modulate Cellular Immune Response to Islet Antigen Glutamic Acid Decarboxylase in Type 1 Diabetes." Journal of Clinical Endocrinology & Metabolism 95, no. 8 (August 1, 2010): 3788–97. http://dx.doi.org/10.1210/jc.2009-2350.

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Context: Mesenchymal stem cells (MSCs) exert an immunosuppressive effect on the immune system. However, studies on the immunomodulatory potential of MSCs in type 1 diabetes are lacking. Objective: We aimed to evaluate whether human MSCs may inhibit in vitro pancreatic islet antigen-specific T cell activation in type 1 diabetes. Design: Human MSCs were isolated and characterized. Peripheral blood mononuclear cells (PBMCs) were obtained from nine type 1 diabetic patients at disease onset and 13 healthy control subjects. IFN-γ, IL-10, and IL-4 enzyme-linked immunospot responses of lymphocytes incubated with glutamic acid decarboxylase 65 (GAD65) were investigated in PBMC cultures and PBMC/MSC cocultures. Levels of prostaglandin E2 (PGE2), IFN-γ, IL-4, and IL-10 in supernatants were measured by ELISA. PGE2 inhibition experiments with NS-398 and indomethacin were also performed. Results: Five diabetic patients were identified with a positive PBMC IFN-γ response to GAD65 and negative IL-10 and IL-4 response. PBMC/MSC cocultures resulted in a significant decrease in the number of spots and in detection of IL-4-secreting cells. PGE2 inhibitors abrogated the immune-suppressive effect, indicating an involvement of PGE2 production, and the constitutive production of PGE2 by MSCs was enhanced in PBMC/MSC coculture. Moreover, in GAD-responder patients, GAD-stimulated PBMC/MSC cocultures significantly decreased secretion of IFN-γ and IL-10 and increased secretion of IL-4. Conclusions: These results provide evidence that human MSCs abrogate in vitro a proinflammatory T helper type 1 response to an islet antigenic stimulus in type 1 diabetes. MSCs induce IL-4-producing cells, suggesting a possible switch to an antiinflammatory T helper type 2 signaling of T cells.

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García, E. "Streptococcus pneumoniae type 3 encodes a protein highly similar to the human glutamate decarboxylase (GAD65)." FEMS Microbiology Letters 133, no. 1-2 (November 1, 1995): 113–18. http://dx.doi.org/10.1016/0378-1097(95)00346-7.

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Stayoussef, Mouna, Jihen Benmansour, Fayza A. Al-Jenaidi, Hichem B. Said, Chiheb B. Rayana, Touhami Mahjoub, and Wassim Y. Almawi. "Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus." Clinical and Vaccine Immunology 18, no. 6 (April 13, 2011): 990–93. http://dx.doi.org/10.1128/cvi.00073-11.

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ABSTRACTThe frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age- and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in theDRB1*030101allele (P< 0.001), together with theDRB1*030101/DQB1*0201(P< 0.001) andDRB1*040101/DQB1*0302(P= 0.002) haplotypes, while lower anti-GAD titers were associated with theDRB1*070101(P= 0.001) andDRB1*110101(P< 0.001) alleles andDRB1*070101/DQB1*0201(P= 0.001) andDRB1*110101/DQB1*030101(P= 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in theDRB1*040101allele (P= 0.007) andDRB1*040101/DQB1*0302(P= 0.001) haplotypes but were lower in theDRB1*110101allele (P= 0.010) and theDRB1*110101(P< 0.001) andDRB1*110101/DQB1*030101(P= 0.025) haplotypes. Multinomial regression analysis confirmed the positive association ofDRB1*030101and the negative association ofDRB1*110101andDQB1*030101, along with theDRB1*070101/DQB1*0201andDRB1*110101/DQB1*030101haplotypes, with anti-GAD levels. In contrast, only theDRB1*040101/DQB1*0302haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D.

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Masewicz, Susan A., Niecey Meldrum, Vivian Gersuk, Lakshmi Gaur, William Hagopian, Lori Moriarity, and Gerald T. Nepom. "Complexity of Human Immune Response Profiles for CD4+T Cell Epitopes from the Diabetes Autoantigen GAD65." Autoimmunity 34, no. 4 (January 2001): 231–40. http://dx.doi.org/10.3109/08916930109014692.

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Hansen, Niels, Benedikt Grünewald, Andreas Weishaupt, Maria Nandini Colaço, Klaus V. Toyka, Claudia Sommer, and Christian Geis. "Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats." Experimental Neurology 239 (January 2013): 202–9. http://dx.doi.org/10.1016/j.expneurol.2012.10.013.

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Ott, Patrick A., Marcus T. Dittrich, Bernhard A. Herzog, Robert Guerkov, Peter A. Gottlieb, Amy L. Putnam, Ivana Durinovic-Bello, Bernhard O. Boehm, Magdalena Tary-Lehmann, and Paul V. Lehmann. "T Cells Recognize Multiple GAD65 and Proinsulin Epitopes in Human Type 1 Diabetes, Suggesting Determinant Spreading." Journal of Clinical Immunology 24, no. 4 (July 2004): 327–39. http://dx.doi.org/10.1023/b:joci.0000029120.77824.41.

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