Pathogenic myelin-specific antibodies in multiple sclerosis target conformational proteolipid protein 1–anchored membrane domains
Gregory P. Owens, … , Wendy B. Macklin, Jeffrey L. Bennett
Gregory P. Owens, … , Wendy B. Macklin, Jeffrey L. Bennett
Published August 10, 2023
Citation Information: J Clin Invest. 2023;133(19):e162731. https://doi.org/10.1172/JCI162731.
View: Text | PDF
Research Article Autoimmunity Neuroscience Article has an altmetric score of 21

Pathogenic myelin-specific antibodies in multiple sclerosis target conformational proteolipid protein 1–anchored membrane domains

Abstract

B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS). Clone-specific recombinant monoclonal IgG1 Abs (rAbs) derived from MS patient CSF plasmablasts bound to conformational proteolipid protein 1 (PLP1) membrane complexes and, when injected into mouse brain with human complement, recapitulated histologic features of MS pathology: oligodendrocyte cell loss, complement deposition, and CD68+ phagocyte infiltration. Conformational PLP1 membrane epitopes were complex and governed by the local cholesterol and glycolipid microenvironment. Abs against conformational PLP1 membrane complexes targeted multiple surface epitopes, were enriched within the CSF compartment, and were detected in most MS patients, but not in inflammatory and noninflammatory neurologic controls. CSF PLP1 complex Abs provide a pathogenic autoantibody biomarker specific for MS.

Authors

Gregory P. Owens, Timothy J. Fellin, Adeline Matschulat, Vanessa Salas, Kristin L. Schaller, Katherine S. Given, Alanna M. Ritchie, Andre Navarro, Kevin Blauth, Ethan G. Hughes, Wendy B. Macklin, Jeffrey L. Bennett

×

Figure 7

Sulfatide and cholesterol levels modify binding of MS rAbs to PLP1-expressing cells.

Options: View larger image (or click on image) Download as PowerPoint
Sulfatide and cholesterol levels modify binding of MS rAbs to PLP1-expre...
(A) Quantitation and representative images of ON#34 rAb binding to PLP1+ CHOK1 cells coexpressing sulfatide (O4) or galc (O1). Scale bars: 20 μm. The binding intensity ratio of ON#34 rAb (green, G) to PLP1 mAb (red, R) (G/R ratio) is plotted (median ± 95% CI) for single PLP1+ cells (n = 19 PLP1+O4+ and 131 PLP1+O4– cells; n = 52 PLP1+O1– and 65 PLP1+O1+ cells) and significance established using Welch’s t test. White arrowheads on images identify ON#34+O4+PLP1+ cells. (B) Representative images and quantitation of MS#11 rAb binding to PLP1+ CHOK1 cells coexpressing sulfatide or galc. The ratio of MS#11 (green) to PLP (red) is plotted (median ± 95% CI) for PLP1+ cells binned according to O4 (n = 161 PLP1+O4– and 45 PLP1+O4+ cells) or O1 expression (n = 145 PLP1+O1– and 34 PLP1+O1+ cells) and significance established using Welch’s t test. White arrowheads identify MS#11–O4+PLP1+ and gold arrowheads MS#11+O4–PLP1+ cells. (C) The binding ratios of MS#30 (green) or ON#49 (green) to PLP (red) are plotted (median ± 95% CI) for PLP1-expressing CHOK1 cells binned for O4 expression (MS#30: n = 127 PLP1+O4– and 18 PLP1+O4+ cells; ON#49: n = 249 PLP1+O4– and 50 PLP1+O4+ cells). Significance was established using Welch’s t test. (D) Quantification (mean ± SEM) of the percentage of PLP1AA3-expressing cells positive for MS rAb staining (determined by G/R ratio) according to the visual presence or absence of coincident O4 mAb staining. Values represent measurements from 4 to 5 independent experiments per MS rAb. *P < 0.05; **P < 0.01; ***P < 0.001; **** P < 0.0001, Welch’s t test.