Abstract
Antibodies against several self-glycans on glycosphingolipids are frequently detected in different neurological disorders. Their pathogenic role is profusely documented, but the keys for their origin remain elusive. Additionally, antibodies recognizing non-self glycans appear in normal human serum during immune response to bacteria. Using HPTLC-immunostaining we aimed to characterize IgM and IgG subclass antibody responses against glycosphingolipids carrying self glycans (GM1/GM2/GM3/GD1a/GD1b/GD3/GT1b/GQ1b) and non-self glycans (Forssman/GA1/“A” blood group/Nt7) in sera from 27 randomly selected neurological disorder patients presenting IgG reactivity towards any of these antigens. Presence of IgG2 (p = 0.0001) and IgG1 (p = 0.0078) was more frequent for IgG antibodies against non-self glycans, along with less restricted antibody response (two or more simultaneous IgG subclasses). Contrariwise, IgG subclass distribution against self glycans showed clear dominance for IgG3 presence (p = 0.0017) and more restricted IgG-subclass distributions (i.e. a single IgG subclass, p = 0.0133). Interestingly, anti-self glycan IgG antibodies with simultaneous IgM presence had higher proportion of IgG2 (p = 0.0295). IgG subclass frequencies were skewed towards IgG1 (p = 0.0266) for “anti-self glycan A” subgroup (GM2/GM1/GD1b) and to IgG3 (p = 0.0007) for “anti-self glycan B” subgroup (GM3/GD1a/GD3/GT1b/GQ1b). Variations in players and/or antigenic presentation pathways supporting isotype (M-G) and IgG-subclass pattern differences in the humoral immune response against glycosphingolipids carrying non-self versus self-glycans are discussed.
Highlights
Abbreviations PBSt Phosphate buffered saline containing 0.05% Tween 20 BSA-PBSt 1% Bovine serum albumin in PBSt Forssman GalNAcα1-3GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-Cer Nt7 GlcNAcβ1-3Galβ1-3GalNAcα1-4GalNAcβ1-4GlcNAcβ1-3Manβ1
Multiple triggering mechanisms for nervous system dysfunction elicited by anti-ganglioside antibodies have been well documented: formation of a membrane attack complex (MAC) at motor nerve terminals by complement activation on the nerve cell membrane, impairment of axonal membrane properties at the nodes of Ranvier causing disfunction of voltagegated sodium channels (Nav) and conduction block; induction of apoptotic cascade activation in dorsal root ganglion cells; blockade of neurotransmitter release at motor nerve terminals by presynaptic inhibitory effect on voltage-gated Ca channel currents; complement-independent function alteration of certain receptors at lipid rafts acting as signaling platforms; and so forth[9]
Most proteins are internalized by antigen-presenting cells (B-2 cells, macrophages, and dendritic cells), digested into peptide fragments and combined with MHC-class molecules to form MHC-peptide complexes that are displayed on the surface of the antigen-presenting cells to be recognized by T helper (Th)-cell receptors (TCR)
Summary
Abbreviations PBSt Phosphate buffered saline containing 0.05% Tween 20 BSA-PBSt 1% Bovine serum albumin in PBSt Forssman GalNAcα1-3GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-Cer Nt7 GlcNAcβ1-3Galβ1-3GalNAcα1-4GalNAcβ1-4GlcNAcβ1-3Manβ1-. Normal subjects routinely display naturally-occurring antibodies recognizing non-self glycosphingolipids: archetypal examples are the ABO blood group agglutinins, arisen when blood group “0” individuals develop antibodies able to agglutinate blood group “A”/“B” red blood c ells[3]. Recent work on IgM and IgG isotypes has extended this view to explain the origin of other anti-self glycosphingolipid antibodies associated with neurological disorders[17], some questions persist. These types of IgG antibodies are absent in healthy humans[6,17]. Reactivity pattern differences were thoroughly analyzed in the context of potential origin diversity for these antibodies
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