Neuroimmunotoxicology: humoral assessment of neurotoxicity and autoimmune mechanisms.

Abstract

The interactions between the nervous and immune systems have been recognized in the development of neurodegenerative disease. This can be exploited through detection of the immune response to autoantigens in assessing the neurotoxicity of environmental chemicals. To test this hypothesis, the following questions were addressed. a) Are autoantibodies to nervous system (NS) antigens detected in populations exposed to environmental or occupational chemicals? In sera of male workers exposed to lead or mercury, autoantibodies, primarily IgG, to neuronal cytoskeletal proteins, neurofilaments (NFs), and myelin basic protein (MBP) were prevalent. These findings were confirmed in mice and rats exposed to either metal. b) Do autoantibodies to NS antigens relate to indices of exposure? In humans exposed to either metal, and similarly in exposed rats, titers of IgG against NFs and MBP significantly correlated with blood lead or urinary mercury, the typical indices of exposure. c) Do autoantibodies correlate with sensorimotor deficits? In workers exposed to lead or mercury, a significant correlation was observed between IgG titers and subclinical deficits. Doses of metals used in rat exposures were subclinical, suggesting that autoantibodies may be predictive of neurotoxicity. d) Is the detection indicative of nervous system pathology? In rats exposed to metals, histopathology indicated central nervous system (CNS) and peripheral nervous system (PNS) damage. In addition there was evidence of astrogliosis, which is indicative of neuronal damage in the CNS, and the presence of IgG concentrated along the blood-brain barrier, as indicated by immunostaining for antibodies. e) Are immune responses to NS antigens pathogenic? Immunoglobulin fractions from rat and human sera interfered with neuromuscular function. These studies suggest that the detection of autoantibodies to NS-specific antigens may be used to monitor the development of neurotoxicity to environmental chemicals and that immune mechanisms may be involved in the progression of neurodegeneration.ImagesFigure 5Figure 6Figure 7

Advances in the understanding of the Fc gamma receptors-mediated autoantibodies uptake

“…Patients with demyelinating IgM monoclonal neuropathy bear serum antibodies to myelin-associated glycoprotein and to sulfated glucuronosyl glycolipids, which are capable of penetrating into the myelinated fibers and endoneurial space [12]. Furthermore, it has been suggested that autoantibodies to several nervous system intracellular antigens, elicited by cell damage caused by environmental chemicals, may play a key role in the progression of neurodegenerative diseases [13].…”

Early-Life Lead Exposure Affects the Activity of TNF-α and Expression of SNARE Complex in Hippocampus of Mouse Pups

“…It was reported that the young rats treated with Pb could cause the overexpression of interleukin (IL)-10, IL-12, and increased numbers of monocytes and T lymphocytes in spleen and thymus [9]. The production of autoantibodies against myelin basic protein and glial fibrillary acidic protein after Pb exposure has been reported elsewhere [10]. This raises the possibility that Pb may affect immune processes in brain.…”

Prolongation of Human Neutrophil Survival by Low-Level Mercury via Inhibition of Spontaneous Apoptosis

“…Alteration of human PMN functions by low-level Hg have been reported previously both in vitro (Malamud et al, 1985;Contrino et al, 1988;Obel et al, 1993) and in vivo (Perlingeiro & Queiroz, 1994, 1995, but it is not known whether part of these effects is related to inhibition of PMN spontaneous apoptosis. Genetically prone animal models of Hg-induced autoimmunity are described in rodents (reviewed in Lawrence & McCabe, 1995), and there is some evidence from clinical studies suggesting that exposure to Hg may result in autoimmune responses to various self-antigens in humans (Schrallhammer-Benkler et al, 1992;Bigazzi, 1999;El-Fawal et al, 1999). It is conceivable that attenuation of PMN constitutive apoptosis by Hg may lead to excessive accumulation of senescent PMN, and this may contribute to Hg-induced autoimmunity.…”