Antibodies to Neuronal Structures
Innocent bystanders or neurotoxins?
- Aaron I. Vinik, MD, PHD12,
- Dharshan Anandacoomaraswamy, MD1 and
- Jagdeesh Ullal, MD, MS1
- 1Department of Internal Medicine, The Strelitz Diabetes Institutes, Norfolk, Virginia
- 2Department of Pathology and Neurobiology, Eastern Virginia Medical School, Norfolk, Virginia
- Address correspondence and reprint requests to Aaron I. Vinik, MD, PhD, The Diabetes Institute, Eastern Virginia Medical School, 855 W. Brambleton Ave., Norfolk, VA 23510. E-mail: vinikai{at}evms.edu
Diabetic neuropathies are a group of clinical syndromes that affect distinct regions of the nervous system, singly or combined, and markedly affect quality of life (1) and activities of daily living and increase morbidity and mortality (2). Therapy directed at the basic pathogenesis is sorely needed. Neurologic complications occur equally in type 1 and type 2 diabetes and additionally in various forms of acquired diabetes (3). Diabetic neuropathies may be diffuse somatic and involve proximal or distal nerves, occur as focal mononeuritides, and involve the autonomic nervous system (4,5).
The pathogenesis of diabetic neuropathies is multifactorial. Hyperglycemia causes nerve damage by inducing the activation of the polyol, protein kinase C, and hexosamine pathways and the accumulation of advanced glycation end products. Hyperglycemia also induces oxidative stress by enhancement of mitochondrial respiration, redox alteration, and uncoupling proteins, which leads to elevated superoxide anions (6,7). Oxidative stress depletes nitric oxide within the peripheral nerves and endothelium of the microvasculature by reducing endothelial nitric oxide synthase, altering nerve perfusion (8). In addition, there is deficiency of or a poor response to neurotrophic factors (9). However, there is now increasing evidence to suggest that autoimmunity has a role to play in the development and progression of diabetic neuropathies.
Fifty years ago, Waksman and Adams (10) suggested an autoimmune etiology of peripheral neuropathy when they injected rabbits with neuronal components to produce what they called “allergic neuritis. ” To be able to implicate autoimmunity as a causative factor of neuropathy, there would have to be a clear association between the antibody and the disease; neuropathy would have to be induced by introduction or development of antibodies, and there would have to be reversal of the disease with removal or neutralization of the antibodies. Peripheral nerves are normally protected against the …
