Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis.
OBJECTIVE
To profile the reactivity of CSF-derived immunoglobulin from patients with multiple sclerosis (MS) against a large panel of antigens, to identify disease-specific reactivities.


METHODS
CSF from subjects with MS with elevated immunoglobulin G and CSF from control subjects presenting with other inflammatory neurologic disease were screened against a protein array consisting of 9,393 proteins. Reactivity to a candidate protein identified using these arrays was confirmed with ELISA and immunocytochemistry.


RESULTS
Autoantibodies against one protein on the array, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), discriminated between patients with MS and controls (p = 0.0052). Using a large validation cohort, we found a higher prevalence of autoantibodies against RBPJ in the CSF of patients with MS (12.5%) compared with the CSF of patients with other neurologic diseases (1.6%; p = 0.02) by ELISA. This difference in reactivity was restricted to the CSF as serum reactivity against RBPJ did not differ between patients and controls. The presence of CSF autoantibodies against RBPJ was further confirmed by immunocytochemistry.


CONCLUSIONS
These data indicate that RBPJ, a ubiquitous protein of the Notch signaling pathway that plays an important role in Epstein-Barr virus infection, is a novel MS autoantigen candidate that is recognized by CSF-derived immunoglobulin G in a subset of patients with MS.
From the Department of Neurology (L.Q., P.L.C., M.A.B., C.C., D.A.H., J.-Y.L., K.C.O.), Human and Translational Immunology Program (D.A.H., K.C.O.), Department of Genetics (C.C.), Department of Pathology (S.H.K., G.Y.), and Department of Immunobiology (D.A.H.), Yale School of Medicine, New Haven, CT; Neuromuscular Diseases Unit (L.Q.), Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Spain; Medical and Population Genetics (C.C.), Broad Institute of MIT and Harvard, Cambridge, MA; Department of Neurology (A.H.C.), Washington University School of Medicine, St. Louis, MO; Interdepartmental Program in Computational Biology and Bioinformatics (S.H.K.), Yale University, New Haven, CT; and Department of Neurology (S.N.W.), Harvard Medical School and Brigham and Women's Hospital, Boston, MA. Simon N. Willis is currently affiliated with the Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Luis
L
Querol
Pamela L
PL
Clark
Mary A
MA
Bailey
Chris
C
Cotsapas
Anne H
AH
Cross
David A
DA
Hafler
Steven H
SH
Kleinstein
Jae-Yun
JY
Lee
Gur
G
Yaari
Simon N
SN
Willis
Kevin C
KC
O'Connor
D001323:Autoantibodies / Q000134:cerebrospinal fluid*; D001324:Autoantigens / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000134:cerebrospinal fluid*; D008297:Male; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000276:immunology*; D040081:Protein Array Analysis / Q000379:methods; D051880:Receptors, Notch / Q000276:immunology; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000276:immunology; D018709:Statistics, Nonparametric
D001323:Autoantibodies; D001324:Autoantigens; D007145:Immunoglobulin kappa-Chains; D051880:Receptors, Notch