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.
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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

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Figure 1

Myelin-specific rAbs initiate complement-dependent oligodendrocyte cell death.

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Myelin-specific rAbs initiate complement-dependent oligodendrocyte cell ...
(A–C) EGFP immunofluorescence in brain sections of C57BL/6 PLP-EGFP mice following ICI of myelin-specific (MS#30, ON#34) or IC (2B4) rAbs with HC. (Left panels) Amorphous regions of EGFP+ oligodendrocyte loss at 72 hours after injection are demarcated by the dotted lines. Asterisks indicate injection site. (Center panels) Higher magnification images of boxed areas reveal a sharp demarcation between areas of complete oligodendrocyte loss and adjacent normal-appearing tissue. (Right panels) CD68+ microglia/macrophages accumulate within the lesion core. Scale bars: 1 mm (left and right); 50 µm (center). (D) Quantitation of the area of EGFP+ oligodendrocyte cell loss (4–6 animals per injection) for IC (2B4, IC#2) rAbs plus HC, myelin-specific (MS#30, ON#34) rAbs plus HC, and myelin-specific ON#34 rAb minus HC (–HC) (Kruskal-Wallis 1-way ANOVA with Dunn’s correction for multiple comparisons, *P < 0.05; ***P < 0.001; ON#34 +/– HC, Mann-Whitney U test, **P < 0.01). (E) High-magnification image of ON#34 rAb without HC (ON#34 – HC) ICI shows a minor loss of EGFP+ oligodendrocyte cell loss at the injection site. Scale bar: 50 µm. (F) Quantitation of CD68+DAPI+ cell density (per subcortical hemisphere) at 72 hours after injection following ICI of rAbs 2B4, MS#30, or ON#34, plus HC (ANOVA with Dunn’s correction for multiple comparisons, **P < 0.01).