The Role of Glycosphinglipids in Neurological Disorders: Mechanisms of Immune Action^a

Abstract

Specific criteria that are required for understanding the significance of glycosphingolipid (GSL) antibodies, as well as mechanisms that may underlie the immunopathogenesis of these disorders, are proposed. These criteria are illustrated by describing the role of a unique family of acidic GSLs, the sulfated glucuronosyl glycolipids (SGGLs), in the pathogenic mechanisms of peripheral neuropathy with IgM paraproteinemia. High anti-SGGL antibody titers are detected in patients suffering from this disorder. It is demonstrated that SGGLs, which possess a common carbohydrate epitope with myelin-associated glycoprotein (MAG), several low-molecular-weight glycoproteins in the PNS, and a number of cell adhesion molecules, are potential target antigens for the neuropathy. Evidence is provided that sensitization of laboratory animals with pure SGGLs elicits experimental peripheral neuropathies that exhibit remarkable similarities with respect to antibody specificity, and electrophysiological and pathological features to the human conditions. By intraneural injection of antibodies into the sciatic nerve of rats, it is demonstrated that pathological changes consisting of demyelination and axonal degeneration are mediated by an antibody- and complement-dependent process. To elucidate the mechanisms of antibody penetration from circulation into the endoneurial space, it is further shown that brain microvascular endothelial cells express SGGLs. Moreover it has been found that inflammatory cytokines are capable of upregulating the expression of SGGLs on the endothelial cell surface, resulting in a greater attachment of leukocytes. This latter observation suggests that SGGLs may also participate in cell-mediated responses in certain inflammatory neurological disorders.

Immunotherapy Targeting Pathological Tau Protein in Alzheimer's Disease and Related Tauopathies

“…Furthermore, numerous studies have shown that antibodies can be found within neurons, which supports the feasibility of our approach; for example [2, 28, 32-35, 37, 47, 48, 54, 74, 82, 85, 102, 105, 127, 130, 131, 136]. The antibodies may be taken up into cells by pinocytosis (e.g., receptor-mediated endocytosis or fluid-phase endocytosis) [75].…”

Lack of Apparent Neurological Abnormalities in Rabbits Sensitized by Gangliosides

“…It is worth mentioning that our GSL preparation was completely free of the contaminating brain proteins (as determined by mass spectrometry following acid hydrolysis) that might stimulate the antibody production directed towards myelin proteins (26,27). High titer antibodies against GSLs, such as GM1, GD1a, GD1b, and LM1 have been a subject of intense interest in human demyelinating diseases in recent years (for review, see 28,29). High titer anti-GSL sera have been implicated in a wide variety of human peripheral autoimmune neuropathy and demyelinating diseases, such as lower motor neuron syndrome (30), multifocal motor neuropathy (31), acute motor axonal neuropathy and gammopathy (32,33), multiple sclerosis (34)(35)(36), GuillainBarre´syndrome (37,38), and the removal of the antibody from the patients' blood by plasmapheresis fosters clinical recovery (39).…”

AIDP and CIDP having specific antibodies to the carbohydrate epitope (–NeuAcα2–8NeuAcα2–3Galβ1–4Glc–) of gangliosides

“…Various anti-ganglioside antibodies have been reported in the sera of patients with Guillain-Barré Syndrome (GBS) or related disorders [11,16,17]. We present clinical features of two patients, one with AIDP and the second with CIDP, who were treated with plasma exchange.…”

“…In addition, the humoral immune response is involved with elevated levels of immunoglobulins (IgG and IgM) and complement deposition in the PNS [7,8]. Although some patients with CIDP have monoclonal gammopathies with high levels of IgM antibodies to PNS antigens, including myelin-associated glycoprotein (MAG) and sulfated glucuronyl paragloboside (SGPG) [9][10][11], the clinical symptoms of CIDP are different from that of other gammopathies [12].…”