i(3)so3-galactosylceramide and Autoimmune-Diseases

Sulfatides (3-O-sulfogalactosylceramides, sulfated galactocerebrosides, SM4) are esters of sulfuric acid with galactosylceramides. These acidic glycosphingolipids, present at the external leaflet of the plasma membrane, are synthesized by a variety of mammalian cells. They are especially abundant in the myelin sheath of oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Studies using cerebroside galactosyltransferase-deficient mice revealed that sulfatides are responsible for proper structure and functioning of myelin. Large amounts of sulfatides are also found in the kidney, gastrointestinal tract, islets of Langerhans, and membranes of erythrocytes, thrombocytes and granulocytes. They are ligands for numerous proteins, but in most cases the biological role of such interactions is poorly understood. A notable exception is their binding by P- and L-selectins. Platelet sulfatides are major ligands for P-selectin, and this interaction is critical for the formation of stable platelet aggregates. Sulfatides also bind to chemokines, and seem to play a role in regulation of cytokine expression in human lymphocytes and monocytes. Aberrant metabolism of sulfatides, could cause several important human diseases. In this article, we describe the changes in sulfatide expression associated with such nervous disorders as metachromatic leukodystrophy (MLD), Parkinson's disease and Alzheimer's disease, and several types of cancer, e.g. colon cancer, kidney cancer, and ovarian cancer. We also discuss the involvement of sulfatides in cancer progression, diabetes and autoimmune and immune disorders such as multiple sclerosis. This acidic glycosphingolipids seem to play an important role in pathogenesis of infectious diseases, serving as receptors for binding various bacteria and viruses.

Topics: Animals; Autoimmune Diseases; Blood Cells; Cell Membrane; Central Nervous System; Cytokines; Galactosylceramides; Gastrointestinal Tract; Humans; Islets of Langerhans; Kidney; Myelin Sheath; Neoplasms; Nervous System Diseases; Peripheral Nervous System; Selectins; Sulfoglycosphingolipids

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Brain; Carbohydrate Sequence; CD57 Antigens; Chronic Disease; G(M1) Ganglioside; Gangliosides; Globosides; Glycolipids; Guillain-Barre Syndrome; Humans; Immunoglobulin M; Molecular Sequence Data; Motor Neuron Disease; Myelin Sheath; Paraproteinemias; Peripheral Nervous System; Polyradiculoneuropathy; Sulfoglycosphingolipids

Approximately 10% of patients with peripheral neuropathy of otherwise unknown etiology have an associated monoclonal gammopathy. Both the neuropathies and the monoclonal gammopathies in these patients are heterogeneous, but several distinct clinical syndromes that may respond to specific therapies can be recognized. It is important to recognize these syndromes because monoclonal gammopathies also occur in 1% of the normal adult population, and in some cases, monoclonal gammopathies are coincidental and unrelated to the neuropathy. In patients with IgM monoclonal gammopathies, IgM M proteins frequently have autoantibody activity and are implicated in the pathogenesis of the neuropathy. IgM M proteins that bind to myelin-associated glycoprotein (MAG) have been shown to cause demyelinating peripheral neuropathy; anti-GM1 antibody activity is associated with predominantly motor neuropathy, and anti-sulfatide or chondroitin sulfate antibodies are associated with sensory neuropathy. The IgM monoclonal gammopathies may be malignant or nonmalignant, and polyclonal antibodies with the same specificities are associated with similar clinical presentations in the absence of monoclonal gammopathy. IgG or IgA monoclonal gammopathies are associated with neuropathy in patients with osteosclerotic myeloma or the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy myeloma, and skin changes). Amyloidosis or cryoglobulinemic neuropathies can occur with either IgM or IgG and IgA monoclonal gammopathies. Therapeutic intervention depends on the specific clinical syndrome but is generally directed at removing the autoantibodies, reducing the number of monoclonal B cells, and interfering with the effector mechanisms.

Topics: Adult; Aged; Amyloidosis; Antibody Specificity; Antineoplastic Agents; Autoantibodies; Autoantigens; Autoimmune Diseases; Chondroitin Sulfates; Gangliosides; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins, Intravenous; Middle Aged; Myelin-Associated Glycoprotein; Paraneoplastic Syndromes; Paraproteinemias; Paraproteins; Peripheral Nervous System Diseases; Plasmapheresis; Sulfoglycosphingolipids

Increasing evidence suggests that in Chagas' disease chronic-phase pathology is autoimmune in nature. There are at least two nonexclusive explanations for the generation of autoimmunity in Chagas disease: a) infection with the parasite perturbs immunoregulation, leading to loss of tolerance for self-antigens; b) immune recognition of T. cruzi antigens is crossreactive with selected mammalian antigens, leading to autoimmunity (molecular mimicry). Through this latter mechanism, T. cruzi antigens that share epitopes with mammalian nervous tissue may drive autoreactive B- or T-cell clones to expand and cause autoimmune lesions in chronic chagasic patients. Several different antigens sharing this characteristic have been studied, as for example the 160-kDa flagellum-associated surface protein (Fl-160), which has a nervous tissue crossreactive epitope composed by twelve amino acids. Additionally, it has been demonstrated that a trypomastigote stage-specific 85kDa surface glycoprotein (Gp85) has terminal galactosyl(alpha 1-3)galactose terminal residues, which are reactive with chronic chagasic sera. Common glycolipid antigens have also been reported, as for example galactocerebroside, sulfogalactocerebroside and sulfoglucuronylcerebroside, all of them specifically present at high concentrations in mammalian nervous system and in T. cruzi trypomastigotes. Chronic chagasic patients produce elevated levels of antibodies against these three glycolipid antigens. They also do against terminal galactosyl(alpha 1-3)galactose residues present on several acid and neutral glycolipids common either to nervous system or parasite. These antibodies are powerful lytic for circulating T. cruzi trypomastigotes. Another common strongly immunogenic residues are galactosyl(alpha 1-2)galactose, galactosyl(alpha 1-6)galactose and galactofuranosyl(beta 1-3)mannose residues present on several glycoinositolphospholipids (GIPL), against which chronic chagasic patients have elevated levels of specific antibodies. In brief, very specific host-parasite relationships existing only in Chagas' disease may explain the particular peripheral nervous tissue damage seen in acute or chronic stages of this disease. This specificity could depend either on invasion of autonomic ganglia by T. cruzi trypomastigotes and modification of nervous cell surface structures by some of the several mechanisms of acquired molecular mimicry.

Topics: Amino Acid Sequence; Animals; Antibodies, Protozoan; Antigens, Protozoan; Autoantibodies; Autoantigens; Autoimmune Diseases; Carbohydrate Sequence; Chagas Disease; Chronic Disease; Cross Reactions; Galactose; Galactosylceramides; Glucose; Glycosylphosphatidylinositols; Molecular Sequence Data; Nerve Tissue Proteins; Protozoan Proteins; Sulfoglycosphingolipids; Trypanosoma cruzi

Recent studies suggest that increased T-cell and autoantibody reactivity to lipids may be present in the autoimmune demyelinating disease multiple sclerosis. To perform large-scale multiplex analysis of antibody responses to lipids in multiple sclerosis, we developed microarrays composed of lipids present in the myelin sheath, including ganglioside, sulfatide, cerebroside, sphingomyelin and total brain lipid fractions. Lipid-array analysis showed lipid-specific antibodies against sulfatide, sphingomyelin and oxidized lipids in cerebrospinal fluid (CSF) derived from individuals with multiple sclerosis. Sulfatide-specific antibodies were also detected in SJL/J mice with acute experimental autoimmune encephalomyelitis (EAE). Immunization of mice with sulfatide plus myelin peptide resulted in a more severe disease course of EAE, and administration of sulfatide-specific antibody exacerbated EAE. Thus, autoimmune responses to sulfatide and other lipids are present in individuals with multiple sclerosis and in EAE, and may contribute to the pathogenesis of autoimmune demyelination.

Topics: Animals; Autoimmune Diseases; Brain; Disease Models, Animal; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Humans; Lipids; Mice; Microarray Analysis; Multiple Sclerosis; Reproducibility of Results; Sensitivity and Specificity; Sulfoglycosphingolipids; T-Lymphocytes

Class I and class II MHC-restricted T cells specific for proteins present in myelin have been shown to be involved in autoimmunity in the central nervous system (CNS). It is not yet known whether CD1d-restricted T cells reactive to myelin-derived lipids are present in the CNS and might be targeted to influence the course of autoimmune demyelination. Using specific glycolipid-CD1d tetramers and cloned T cells we have characterized a T cell population reactive to a myelin-derived glycolipid, sulfatide, presented by CD1d. This population is distinct from the invariant Valpha14+ NK T cells, and a panel of Valpha3/Valpha8+ CD1d-restricted NK T cell hybridomas is unable to recognize sulfatide in the presence of CD1d+ antigen-presenting cells. Interestingly, during experimental autoimmune encephalomyelitis a model for human multiple sclerosis, sulfatide-reactive T cells but not invariant NK T cells are increased severalfold in CNS tissue. Moreover, treatment of mice with sulfatide prevents antigen-induced experimental autoimmune encephalomyelitis in wild-type but not in CD1d-deficient mice. Disease prevention correlates with the ability of sulfatide to suppress both interferon-gamma and interleukin-4 production by pathogenic myelin oligodendrocyte glycoprotein-reactive T cells. Since recognition of sulfatide by CD1d-restricted T cells has now been shown both in mice and humans, study of murine myelin lipid-reactive T cells may form a basis for the development of intervention strategies in human autoimmune demyelinating diseases.

Topics: Animals; Antigen Presentation; Antigens, CD1; Antigens, CD1d; Autoimmune Diseases; Autoimmunity; Demyelinating Autoimmune Diseases, CNS; Encephalomyelitis, Autoimmune, Experimental; Humans; Interferon-gamma; Interleukin-4; Killer Cells, Natural; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Sulfoglycosphingolipids; T-Lymphocyte Subsets

To determine threshold titers and diagnostic accuracy of anti-GM1 and anti-sulfatide antibodies (Ab) for autoimmune polyneuropathies (PN) in overall and for particular subtypes of them.. In this study 84 PN patients, 120 epileptics and 93 healthy controls' sera were tested by enzyme-linked immunosorbent assay for autoAbs and results confirmed by thin-layer chromatography. Frequencies of positive patients at increasing cut-off were compared to determine threshold titers. Accuracy was determined by Receiver Operator Characteristic analysis.. A 1:2,000 titer for IgM anti-GM1 and a 1:4,000 titer for IgM anti-sulfatide Ab resulted to be threshold titers for autoimmune PN in overall. IgM anti-GM1 and anti-sulfatide Ab had low discriminating capacity between autoimmune PN and other PN, but good discriminating capacity between motor neuropathy (for anti-GM1 Ab) or PN in IgM-paraproteinemia or chronic painful sensory axonal PN (for anti-sulfatide Ab) and other PN.. Our results suggest that testing IgM anti-GM1 or anti-sulfatide Ab is useful only for diagnostic confirmation of specific subtypes of autoimmune PN.

Topics: Aged; Antibody Formation; Autoimmune Diseases; Diagnosis, Differential; Female; Gangliosidosis, GM1; Humans; Immunoglobulin M; Male; Middle Aged; Polyneuropathies; Reference Values; Sensitivity and Specificity; Sulfoglycosphingolipids

Lupus anticoagulants are a group of antibodies commonly found in patients with autoimmune diseases such as systemic lupus erythematosus. Lupus anticoagulants inhibit phospholipid dependent coagulation and may bind to negatively charged phospholipids. Recent studies have suggested an association between anti-beta 2-glycoprotein I and a lupus anticoagulant, whose activity is frequently dependent on the presence of beta 2-glycoprotein I. Based on these observations, the effect of anti-beta 2-glycoprotein I on the autoactivation of factor XII in plasma was investigated. Autoactivation initiated by the presence of negatively charged phospholipids, but not by sulfatide, was strongly inhibited by immunoaffinity purified anti-beta 2-glycoprotein I. The dose-response curve of anti-beta 2-glycoprotein I was identical with that of a precipitating antibody, showing no inhibition at low and high antibody dilutions and maximal inhibition at an intermediate dilution. At high antibody concentrations, an increased rate of factor XIIa activation was observed. This increase was of the same magnitude as the decreased rate observed in plasma supplemented with the same amount of beta 2-glycoprotein I as in the plasma itself. This confirms the inhibitory effect of beta 2-GP-I on the contact activation and shows that inhibition is effective on the autoactivation of factor XII in plasma. The inhibitory action of beta 2-glycoprotein I was independent of the inhibition caused by the anti-beta 2-glycoprotein I/beta 2 glycoprotein I complex suggesting a synchronized inhibition of factor XII autoactivation by beta 2-glycoprotein I and anti-beta 2-glycoprotein I. The inhibition caused by the antibody is suggested to be caused by a reduced availability of negatively charged phospholipids due to the binding of the anti-beta 2-GP-I/beta 2-GP-I complex. This complex may be a lupus anticoagulant.

Topics: Animals; Antibodies, Anti-Idiotypic; Autoantibodies; Autoimmune Diseases; beta 2-Glycoprotein I; Chromogenic Compounds; Dose-Response Relationship, Immunologic; Enzyme Activation; Epitopes; Factor XII; Factor XIIa; Glycoproteins; Humans; Lupus Coagulation Inhibitor; Phosphatidylinositol Phosphates; Phospholipids; Protein Binding; Rabbits; Sulfoglycosphingolipids

Topics: Adrenal Cortex Hormones; Antibodies, Antinuclear; Autoantibodies; Autoimmune Diseases; Biomarkers; Diagnosis, Differential; Hepatitis C; Hepatitis, Chronic; Humans; Sulfoglycosphingolipids

We tested sera of patients with various autoimmune rheumatic diseases for the presence of antibodies against sulphatide (an acidic glycosphingolipid), identified as a target antigen for antibodies against the liver cell membrane. Thirty-five percent (7/20) of patients with lupus in the active stage possessed anti-sulphatide antibodies, whereas 10% (2/20) of those in the inactive stage and 20% (4/20) of those in the stationary stage possessed such antibodies. Moreover, 10% (3/29) of patients with other autoimmune rheumatic diseases also possessed anti-sulphatide antibodies. The level of anti-sulphatide antibodies was significantly correlated with the levels of anti-double-stranded (ds) DNA antibodies (r = 0.634, P less than 0.001) and dextran sulphate-binding IgG (r = 0.407, P less than 0.001). The serum levels of antibodies against sulphatide were correlated with a history of seizures or psychosis in patients with autoimmune rheumatic diseases. Gels coupled with polyanionic dextran sulphate, monoanionic sulphanilic acid and DNA were shown effectively to adsorb anti-sulphatide antibodies in the sera of patients with active systemic lupus erythematosus (SLE) and autoimmune chronic active hepatitis (AI-CAH). These results suggest that the observed reactivity with sulphatide is due to the presence of antibodies capable of reacting with various anionic molecules in the sera of patients with autoimmune rheumatic diseases as well as those with AI-CAH.

Topics: Adsorption; Antibodies, Antinuclear; Autoimmune Diseases; Cardiolipins; Chromatography, Gel; Dextran Sulfate; Enzyme-Linked Immunosorbent Assay; Heparitin Sulfate; Hepatitis, Chronic; Humans; Immunoglobulin G; Rheumatic Diseases; Sulfoglycosphingolipids

Sera from patients with autoimmune chronic active hepatitis were found to contain IgG-class antibody to the acidic glycosphingolipid fraction from rabbit hepatocyte plasma membrane by solid-phase enzyme-linked immunosorbent assay. Using serum positive for the antibody as a probe, we isolated the target antigen by Iatrobeads column chromatography. Analysis by thin-layer chromatography and negative ion fast atom-bombardment mass spectrometry revealed that the antigen was sulfatide. The presence of antisulfatide antibody was also confirmed by immunoblotting. The reactivity of the serum with sulfatide was diminished by preincubation of the serum with galactosylceramide-6-sulfate and sulfatide, indicating that the antibody reacted with sulfated galactosylceramide regardless of the position of the sulfate residue. The antibody was found in 92.3%, 42.9%, 15.8%, 14.2%, 0% and 0%, respectively, of patients with autoimmune chronic active hepatitis, primary biliary cirrhosis, cirrhosis, systemic lupus erythematosus, chronic active hepatitis and chronic persistent hepatitis. Thus antisulfatide antibody was characteristic of autoimmune-type chronic liver diseases. Antisulfatide antibody was absorbed by rabbit hepatocyte plasma membrane. Preincubation of sera with sulfatide immobilized on Sepharose decreased their reactivities with not only sulfatide but also rabbit plasma membrane and rat hepatocytes. Therefore sulfatide may be a target antigen of the antibody to hepatocyte surface membrane.

Topics: Antigens, Surface; Autoantibodies; Autoantigens; Autoimmune Diseases; Chromatography, Thin Layer; Enzyme-Linked Immunosorbent Assay; Glycosphingolipids; Hepatitis, Chronic; Humans; Liver; Membrane Lipids; Sulfoglycosphingolipids