Inhibition of γ‐aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff‐man syndrome

Aims/hypothesis. Conformation-dependent autoantibodies directed against GAD65 are markers of Type 1 diabetes. In this study we aimed to determine whether the substitution of GAD65 with GAD67 amino acids would affect the binding of conformation-dependent GAD65 autoantibodies. Methods. We used PCR-based site-directed mutagenesis to generate a series of mutated GAD65 cDNA constructs in which specific GAD65 coding sequences for regions of the protein critical for autoantibody binding were replaced with GAD67 coding sequences. Results. The introduction of a point mutation at position 517, substituting glutamic acid with proline, markedly reduced the binding of disease-associated GAD65 antibodies. The binding of GAD65 antibodies to the E517P mutant was reduced in the sera of all newly diagnosed Type 1 diabetes patients (n=85) by a mean of 72% (p<0.0001) compared with binding to wild-type GAD65. Patients with latent autoimmune diabetes in adults (n=24) showed a similar reduction

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“…3b). This observation supports previous studies indicating that the GAD65Ab epitopes in SMS are distinct from those in Type 1 diabetes [34,36].…”

Section: Discussionsupporting

confidence: 93%

Conformation-dependent GAD65 autoantibodies in diabetes

et al. 2004

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“…The role of anti-GAD antibodies in neurological diseases is still elusive due to the lack of experimental animal models (9). It has been postulated that the humoral immune response to GAD could lead to functional impairment of GABAnergic synaptic transmission in SPS and cellebellar ataxia, possibly due to the reduction by anti-GAD antibodies of GABA synthesis and/or the interference with exocytosis of GABA (16,17). Therefore, it can be speculated that the autoimmunity against GAD may in part contribute to the development of drug-resistant epilepsy as in the present case.…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

Yoshimoto¹,

Doi²,

Fukai³

et al. 2005

Intern. Med.

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A 55-year-old man who was diagnosed as having type 1 diabetes mellitus (DM) at the age of 50 years was started on insulin therapy. At 54 years old of age, he suddenly developed complex partial seizures, which frequently occurred despite intensive anti-epileptic drug therapy. Neurological examination on admission revealed hyporeflexia in bilateral upper and lower extremities without any muscle rigidity, painful spasm or cerebellar ataxia. Laboratory examination showed poor glycemic control with increased glycated hemoglobin levels. Positive anti-thyroglobulin antibodies and anti-thyroid peroxidase (TPO) antibodies and slight elevation of TSH levels are consistent with subclinical hypothyroidism due to Hashimoto's thyroiditis. A high titer of anti-glutamic acid decarboxylase (GAD) antibodies was detected in the patient's serum and cerebrospinal fluid (CSF). Electroencephalography showed temporal spikes, consistent with complex partial seizure. This is a very rare case presenting with concomitant type 1 diabetes and drugresistant epilepsy associated with high titers of circulating and CSF anti-GAD antibodies.

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“…IgG antibodies from SPS patients, and not from T1D patients, can reversibly inhibit GABAergic transmission in rat cerebellar slices (Dinkel 1998;Ishida 1999;Vianello 2008).…”

Section: Gad65 Igg Antibodies and Gad65-specific T Cells In Spsmentioning

confidence: 93%

MS and clinically isolated syndromes: Shared specificity but diverging clonal patterns of virus‐specific IgG antibodies produced in vivo and by CSF B cells in vitro

Skorstad

Vandvik

Vartdal

et al. 2009

Euro J of Neurology

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Background: Intrathecal synthesis of oligoclonal IgG antibodies against measles virus (MeV), varicella zoster virus (VZV) and herpes simplex virus type‐1 (HSV‐1) is a characteristic feature multiple sclerosis (MS). Methods: We have used isoelectric focusing‐immunoblot to define the clonal patterns of IgG and of IgG antibodies to MeV, VZV and HSV‐1 in supernatants of in vitro cultures of peripheral blood lymphocytes (PBL) and cerebrospinal fluid (CSF) cells and in sera and CSF from three patients with MS and three patients with clinically isolated syndromes (CIS) suspective of demyelinating disease. Results: In vitro synthesis of IgG by PBL was not detected in any patient. In contrast, in vitro synthesis by CSF cells of oligoclonal IgG and oligoclonal IgG antibodies to one or two of the three viruses tested was observed in all six patients. The clonal patterns of the in vitro synthesized IgG and virus specific IgG differed to varying extent from those synthesized intrathecally in vivo. However, in each patient, the in vitro and in vivo intrathecally produced antibodies displayed specificity for the same viruses. The addition of B cell activating factor (BAFF) had no effect on the amounts or clonal patterns of either total IgG or virus‐specific IgG produced by CSF cells in vitro. Conclusion: Virus specific B cells capable of spontaneous IgG synthesis are clonally expanded in the CSF of patients with MS. The B‐cell repertoire in CSF samples is only partially representative of the intrathecal B‐cell repertoire.

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Inhibition of γ‐aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff‐man syndrome

Cited by 215 publications

References 32 publications

Conformation-dependent GAD65 autoantibodies in diabetes

Conformation-dependent GAD65 autoantibodies in diabetes

Type 1 Diabetes Mellitus and Drug-resistant Epilepsy: Presence of High Titer of Anti-Glutamic Acid Decarboxylase Autoantibodies in Serum and Cerebrospinal Fluid

MS and clinically isolated syndromes: Shared specificity but diverging clonal patterns of virus‐specific IgG antibodies produced in vivo and by CSF B cells in vitro

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