T cells from multiple sclerosis patients recognize multiple epitopes on Self-IgG.
The highly diversified variable regions of immunoglobulin (Ig) molecules contain immunogenic determinants denoted idiotopes. We have previously reported that T cells from multiple sclerosis (MS) patients recognize IgG from autologous cerebrospinal fluid (CSF), and mapped a T-cell epitope to an IgG idiotope. To test the ability of CSF IgG molecules to elicit a broad polyclonal T-cell response in MS, we have analysed T-cell responses in the blood and CSF against idiotope peptides spanning complementarity determining region (CDR) 3 and somatic mutations within the variable regions of monoclonal CSF IgG. Consistent with a diversified idiotope-specific T-cell repertoire, CD4(+) T cells from both patients recognized several idiotope peptides presented by HLA-DR molecules. Mutations were critical for T-cell recognition, as T cells specific for a mutated CDR1 peptide did not recognize corresponding germline-encoded peptides. One T-cell clone recognized both an idiotope peptide and the B-cell clone expressing this idiotope, compatible with endogenous processing and presentation of this idiotope by B cells. These results suggest that mutated CSF IgG from MS patients carry several T-cell epitopes, which could mediate intrathecal IgG production and inflammation in MS through idiotope-driven T-B-cell collaboration.
Hestvik
A L K
AL
Institute of Immunology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway.
Vartdal
F
F
Fredriksen
A B
AB
Thompson
K M
KM
Kvale
E O
EO
Skorstad
G
G
Bogen
B
B
Holmoy
T
T
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D022801:Complementarity Determining Regions / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006680:HLA Antigens / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007130:Immunoglobulin Idiotypes / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D022801:Complementarity Determining Regions; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007074:Immunoglobulin G; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region; D007378:Interleukins; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma