Abstract
Stiff person syndrome (SPS) is a highly-disabling neurological disorder of the CNS characterized by progressive muscular rigidity and spasms. In approximately 60–80% of patients there are autoantibodies to glutamic acid decarboxylase (GAD), the enzyme that synthesizes gamma-amino butyric acid (GABA), the predominant inhibitory neurotransmitter of the CNS. Although GAD is intracellular, it is thought that autoimmunity to GAD65 may play a role in the development of SPS. To test this hypothesis, we immunized mice, that expressed enhanced green fluorescent protein (EGFP) under the GAD65 promoter, with either GAD65 (n = 13) or phosphate buffered saline (PBS) (n = 13). Immunization with GAD65 resulted in autoantibodies that immunoprecipitated GAD, bound to CNS tissue in a highly characteristic pattern, and surprisingly bound not only to GAD intracellularly but also to the surface of cerebellar neurons in culture. Moreover, immunization resulted in immunoglobulin diffusion into the brainstem, and a partial loss of GAD-EGFP expressing cells in the brainstem. Although immunization with GAD65 did not produce any behavioral abnormality in the mice, the induction of neuronal-surface antibodies and the trend towards loss of GABAergic neurons in the brainstem, supports a role for humoral autoimmunity in the pathogenesis of SPS and suggests that the mechanisms may involve spread to antigens expressed on the surface of these neurons.
Highlights
Stiff person syndrome (SPS), first described by Moersch and Woltman in 1956, is a highly disabling, progressive disorder of the central nervous system (CNS) characterized by muscle rigidity and spasms [1], and recently reviewed by Duddy and Baker [2]
The presence of glutamic acid decarboxylase (GADAbs) in patients with stiff person syndrome has been known for almost three decades but because glutamic acid decarboxylase (GAD) is an intracellular enzyme the pathogenic significance of these antibodies has been in doubt
Immunization against GAD, which induced very high GADAb levels similar to those found in patients with SPS, resulted in IgG reactivity against the intracellular compartment of the GAD-enhanced green fluorescent protein (EGFP) expressing neurons, where GAD65 is located, and against the extracellular surface of unpermeabilized GAD-EGFP positive and negative cerebellar neurons in both mouse and rat cultures
Summary
Stiff person syndrome (SPS), first described by Moersch and Woltman in 1956, is a highly disabling, progressive disorder of the central nervous system (CNS) characterized by muscle rigidity and spasms [1], and recently reviewed by Duddy and Baker [2]. Autoimmune neurological diseases of the peripheral nervous system, such as myasthenia gravis, have been replicated in animal models by immunizing against the acetylcholine receptor [10], there have been relatively few reports of active immunization against CNS antigens. This may partly reflect resistance in believing that a CNS disease can be caused by autoantibodies due to the potential constraints on antibody entry into the CNS imposed by the blood brain barrier (BBB). To date, there have been no reports of attempts to develop SPS by active immunization against GAD65
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