Recent studies on the roles of antiglycosphingolipids in the pathogenesis of neurological disorders

Abstract

Evidence is mounting to suggest a causal role of humoral immunity arising from antiglycosphingolipid (GSL) antibodies in a variety of neurological disorders. These disorders include the demyelinating and axonal forms of Guillain-Barre syndrome, multifocal motor neuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, and IgM paraproteinemia. Many claims have been made regarding other neurological disorders, which should be carefully scrutinized for their validity, based on several criteria proposed in this review. These criteria include 1) characterization of the causative antigens and immunoglobulins, 2) correlation of the pathological lesions and clinical manifestation of the antigens, 3) establishment of animal models using pure GSLs as the antigens, 4) immunopathogenic mechanisms of the neurodenerative process, 5) mechanisms for the malfunctioning of blood-nerve barrier and the ensuing leakage of circulating antibodies into peripheral nerve parenchyma, and 6) the roles of anti-GSL antibodies that may cause humorally mediated nerve dysfunction and injury as well as interference with ion channel function at the node of Ranvier, where carbohydrate epitopes are located. Finally, the origin of the anti-GSL antibodies is discussed in light of the recent circumstantial evidence pointing to a molecular mimicry mechanism with infectious agents. With a better understanding of the immunopathogenic mechanisms, it will then be possible to devise rational and effective diagnostic and therapeutic strategies for the treatment of these neurological disorders.

The role of glycosphingolipid metabolism in the developing brain

“…For instance, some GSLs are potent antigens that may underlie certain autoimmune neurodegenerative diseases, such as Guillain-Barré syndrome and related neuropathies (43). Alzheimerʼs disease may also arise as a result of the aggregation of amyloid-b-proteins initiated by GM1 (44).…”

Ganglioside Molecular Mimicry and Its Pathological Roles in Guillain-Barré Syndrome and Related Diseases

“…Much of the research into GBS over the last decade has focused on the forms mediated by antiganglioside antibodies (8,9,88). The sera of approximately 60% of patients with GBS contain a variety of anti-glycosphingolipid (GSL) antibodies.…”

“…Thus, in sera that are antibody negative it is necessary to examine the antibody activity by appropriate ganglioside complexes and suitable methods, such as the use of liposome-incorporated GSLs. Nonetheless, measurements of these GSL antibody titers remain the most effective and reliable means for the diagnosis of GBS and in evaluating the effectiveness of treatments in clinical trials (8,9,87).…”

Design of a covalently bonded glycosphingolipid microarray

“…Although their normal biological functions are not fully understood, it has been appreciated for some time that the distribution of GSLs in neuronal and myelin membranes, and in other tissues and organs, makes them potential targets for involvement in the pathogenesis of autoimmune diseases, as well as potential diagnostic markers for autoimmune neuropathies and other disorders [1][2][3][4]. For example, sulfatide (galactosylceramide-3′-O-sulfate), a major GSL component of the islets of Langerhans expressed both on the surface and secretory granules of the insulin producing β-cells, has been implicated in insulin dependent diabetes mellitus (IDDM) also known as type 1 diabetes [5][6][7][8].…”