Abstract
The presence of autoantibodies in multiple sclerosis (MuS) is well known, but their target antigens have not been clearly identified. In the present study, IgG autoreactivity to neural antigens of normal human white matter separated by bidimensional electrophoresis was assessed in serum and cerebrospinal fluid of 18 MuS and 20 control patients. Broad IgG autoreactivity was detected by two-dimensional immunoblotting in all cases to neural antigens, most of which were identified by mass spectrometry. The comparative analysis of MuS and non-MuS reactive spots showed that a restricted number of neural protein isoforms were specifically recognized by MuS IgG. Almost all MuS patients had cerebrospinal fluid IgG directed to isoforms of one of the oligodendroglial molecules, transketolase, 2',3'-cyclic-nucleotide 3'-phosphodiesterase type I, collapsin response mediator protein 2, and tubulin beta 4. Interestingly 50% of MuS IgG recognized transketolase, which was mostly localized on oligodendrocytes in human white matter from normal and MuS samples. IgG autoreactivity to cytoskeletal proteins (radixin, sirtuin 2, and actin-interacting protein 1) was prevalent in secondary progressive MuS patients. Among the proteins recognized by serum IgG, almost all MuS patients specifically recognized a restricted number of neuronal/cytoskeletal proteins, whereas 2',3'-cyclic-nucleotide 3'-phosphodiesterase type I was the oligodendroglial antigen most frequently recognized (44%) by MuS seric IgG. Our immunomics approach shed new light on the autoimmune repertoire present in MuS patients revealing novel oligodendroglial and/or neuronal putative autoantigens with potential important pathogenic and diagnostic implications.
Highlights
The presence of autoantibodies in multiple sclerosis (MuS) is well known, but their target antigens have not been clearly identified
When the molecules recognized by MuS cerebrospinal fluid (CSF) IgG were grouped according to their cellular distribution within the central nervous system (CNS), all but one MuS patient displayed IgG autoreactivity to antigens expressed on oligodendrocytes, such as CNPase I [29], tubulin 4 [30], TK (Ref. 31 and paragraph), and CRMP2 [32, 33] (Table IV)
We evaluated the patterns of autoimmune recognition of human white matter antigens by the comparative analysis of autoreactive IgG repertoires present in serum and CSF from MuS and control patients
Summary
The presence of autoantibodies in multiple sclerosis (MuS) is well known, but their target antigens have not been clearly identified. IgG autoreactivity to neural antigens of normal human white matter separated by bidimensional electrophoresis was assessed in serum and cerebrospinal fluid of 18 MuS and 20 control patients. Almost all MuS patients had cerebrospinal fluid IgG directed to isoforms of one of the oligodendroglial molecules, transketolase, 2,3cyclic-nucleotide 3-phosphodiesterase type I, collapsin response mediator protein 2, and tubulin 4. IgG autoreactivity to cytoskeletal proteins (radixin, sirtuin 2, and actin-interacting protein 1) was prevalent in secondary progressive MuS patients. Among the proteins recognized by serum IgG, almost all MuS patients recognized a restricted number of neuronal/cytoskeletal proteins, whereas 2,3cyclic-nucleotide 3-phosphodiesterase type I was the oligodendroglial antigen most frequently recognized (44%) by MuS seric IgG. The molecular targets of the autoimmune response leading to demyelination in MuS have yet to be clearly defined. A MuS, multiple sclerosis. b PP, primary progressive. c SP, secondary progressive. d RR, relapsing-remitting. e All numbers are expressed as mean Ϯ S.D. (range). f At the moment of lumbar puncture. g Expanded disability status scale evaluated at the moment of lumbar puncture
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