Antibodies to Neuronal Structures

D iabetic 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 immune system by tight capillary endothelial junctions and the perineurium. Nerves are also a rich source of glycoproteins, lipopolysachharides, and other lipoproteins that can potentially form active antigenic material. In the autoimmune onslaught against nerves, there is first damage to the protective sheath and then to the inner components. These can be brought on by viral or bacterial infections (e.g., polio, leprosy, Lyme’s disease), neoplasms, or connective tissue disorders, and often there is strong genetic predisposition, such as HLA DR-3 and -4, in type 1 diabetes. Table 1 illustrates the association of different types of antibodies with various neuropathy syndromes. Neurons and pancreatic -cells are neuroectodermal derivatives and therefore share common antigens, especially in the early stages of cellular evolution. Type 1 diabetes results from an autoimmune destruction of pancreatic -cells. There also may be a direct destruction of neurons by the same autoimmune process in diabetes. The pancreatic islets of Langerhans are surrounded by a Schwann cell sheath. These cells form a tight cellular mantle that envelops the endocrine islet tissue. Components of the peri-islet Schwann cells include GAD (11). There is an early appearance of anti-GAD65– specific T-cells in type 1 diabetes. AntiGAD65 antibody is a strong predictive marker for the onset of type 1 diabetes (12). Presence of this antibody in patients with recent-onset type 1 diabetes is associated with worse glycemic control and worse peripheral nerve function, suggesting a common mechanism for -cell and neuronal damage (13). Patients with high GAD65 antibodies were shown to have positive correlation with motor nerve conduction velocities, F wave latencies, thermal threshold detection, and cardiovascular autonomic function (14). However, many studies have failed to show any significant relation of GAD antibodies to the development of neuropathy. These studies concluded that GAD antibodies had no effects on residual -cell function or diabetic neuropathy (15). There is also no association between GAD antibodies or even islet-associated protein 2/islet cell antibody 512 with autoimmunity to nervous tissue structures or cardiac autonomic functions (16). Serum collected from type 1 diabetic patients is toxic to neuroblastoma cells of the N1E-115 cell line (17). About two-thirds of the toxicity is due to autoimmune serum factors. One of the components of this serum that mediates immune destruction of neuroblastoma cells in cultures was found to be Fasspecific IgG antibodies. These antibodies bind to Fas-ligand on the surface of N1E115 neuroblastoma cells and induce apoptosis. Serum from patients with diabetic neuropathy contains an activator of Fasregulated apoptosis that may contribute to the pathogenesis of diabetic neuropathy (18). There is no doubt that a variety of antibodies are present in the sera of diabetic patients with neuropathy and that the sera exert apoptotic effects on neurons grown in culture, but the missing link is the relation with clinical neuropathy and the potential for reversibility with immune therapy. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●