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.

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis

“…10 Recombinant monoclonal IgG1 antibodies from MS patients' CSF plasmablasts bound to conformational proteolipid protein 1 membrane complexes, when injected into the mouse brain with human complement recapitulated histologic features of MS pathology including complement deposition. 39 In the cortical and deep gray matter of patients with progressive MS, C1q depositions and activated complement component B and C3b were significantly increased, especially in areas with elevated numbers of complement receptorpositive microglia. 12 These findings are in line with a recent study demonstrating increased immunoreactivity for C1q, C4d, C3b, and Bb in thalamic lesions with an active inflammatory pathology in patients with progressive MS. 40 Complement activation is not restricted to lesional tissue but extends into normal-appearing white matter, the periplaque rims, perivascular inflammatory infiltrates, and astrocytic gliosis.…”

Peripheral memory B cells in multiple sclerosis vs. double negative B cells in neuromyelitis optica spectrum disorder: disease driving B cell subsets during CNS inflammation

“…Other potentially interesting targets for MS antibodies that have been proposed in recent years are chloride-channel protein Anoctamin 2 (ANO2) ( Tengvall et al, 2019 ), which is a transmembrane protein for modulation for neural-excitability; alpha-crystallin B (CRYAB), which is expressed by oligodendrocytes and may have a protective effect by down-regulating the innate immune system ( Thomas et al, 2023 ). Another group recently found antibodies against conformational membrane complexes containing the myelin proteolipid protein 1 (PLP1) ( Owens et al, 2023 ). In addition to these recently described targets, a large number of autoantibodies have been described against various CNS cell types, including neurons, oligodendrocytes and astrocytes, and even immune cells ( Fraussen et al, 2014 ).…”

Mimicking the brain: Epstein-Barr virus and foreign agents as drivers of neuroimmune attack in multiple sclerosis

“…PLP 139-151 is a frequent target of high avidity T cells in MS (45)most likely due to its exclusion from thymic tolerance mechanismsbut several other encephalitogenic PLP peptides have been identified in humans such as PLP 104−117 , PLP 142−153 , PLP 184−199 , and PLP 190−209 , all of which can be presented by the MS risk allele HLA-DRB1*15:01 (47, 109). PLP is also the target of antibody responses, with up to 58% of pwMS in some studies showing antibody responses which are sensitive to protein conformation (114,115).…”