Intrathecal CD4(+) and CD8(+) T-cell responses to endogenously synthesized candidate disease-associated human autoantigens in multiple sclerosis patients.
MS pathology is potentially orchestrated by autoreactive T cells, but the antigens recognized remain unknown. A novel APC/T-cell platform was developed to determine intrathecal CD4(+) and CD8(+) T-cell responses to candidate MS-associated autoantigens (cMSAg) in clinically isolated syndrome (CIS, n = 7) and MS (n = 6) patients. Human cMSAg encoding open reading frames (n = 8) were cloned into an Epstein-Barr virus (EBV)-based vector to express cMSAg at high levels in EBV-transformed B-cells (BLCLs). Human cMSAg cloned were myelin-associated and -oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, ATP-dependent potassium channel ATP-dependent inwards rectifying potassium channel 4.1, S100 calcium-binding protein B, contactin-2, and neurofascin. Transduced BLCLs were used as autologous APC in functional T-cell assays to determine cMSAg-specific T-cell frequencies in cerebrospinal fluid derived T-cell lines (CSF-TCLs) by intracellular IFN-γ flow cytometry. Whereas all CSF-TCL responded strongly to mitogenic stimulation, no substantial T-cell reactivity to cMSAg was observed. Contrastingly, measles virus fusion protein-specific CD4(+) and CD8(+) T-cell clones, used as control of the APC/T-cell platform, efficiently recognized transduced BLCL expressing their cognate antigen. The inability to detect substantial T-cell reactivity to eight human endogenously synthesized cMSAg in autologous APC do not support their role as prominent intrathecal T-cell target antigens in CIS and MS patients early after onset of disease.
Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, The Netherlands.|Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Gijsbert P
GP
van Nierop
Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, The Netherlands.
Malou
M
Janssen
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.|Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Hannover, Germany.
Johanna G
JG
Mitterreiter
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
David A M C
DA
van de Vijver
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Rik L
RL
de Swart
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Bart L
BL
Haagmans
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.|Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Hannover, Germany.
Georges M G M
GM
Verjans
Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Rogier Q
RQ
Hintzen
D000328:Adult; D000938:Antigen-Presenting Cells; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002555:Cerebrospinal Fluid / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008459:Measles virus / Q000276:immunology*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D014132:Trachea / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000276:immunology*; D055815:Young Adult
D001324:Autoantigens; D014760:Viral Fusion Proteins; D007371:Interferon-gamma
Autoantigen; Cerebrospinal fluid; Clinically isolated syndrome; Multiple sclerosis; T cell