Antibodies in multiple sclerosis oligoclonal bands target debris

Abstract

IgG oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) of more than 90% of multiple sclerosis (MS) patients and are considered the immunological hallmark that supports MS diagnosis. OCB are not unique to MS but are also observed in chronic CNS infections, where they target their causative agents (1-3). However, the target specificities of the IgG within OCB in MS have remained a mystery. Identification of those antigens recognized by OCB antibodies is thought to hold fundamental clues to the pathogenesis of MS. In a recent PNAS publication, Brändle et al. (4) provide evidence that OCB in MS target ubiquitous intracellular antigens released in cellular debris.In 1942, Kabat et al. (5) established the diagnostic value of quantitative determinations of CSF gamma globulins in clinical neurology, and particularly in MS. They observed that changes in CSF IgG were independent of those in serum, suggesting that this Ig production was compartmentalized to the CNS. Advances in CSF analytics and gel electrophoresis led to the identification of OCB in 1959 (6). CSF OCB in MS patients are persistent, which is thought to be a reflection of both ongoing CNS inflammation and immunologic memory. Understanding the specificity of OCB has since captivated the interest of clinical neurologists and scientists alike. It has been assumed that the OCB target antigens are relevant to MS pathogenesis. The most popular theory contends that IgG within OCB target myelin autoantigens and/or viruses that may elicit CNS damage directly or indirectly via molecular mimicry. Some earlier studies that evaluated whole CSF IgG from MS patients identified antibodies to several different viruses, such as measles, varicella zoster, human T-lymphocytic virus 1, and human hepatitis virus 6 (7), whereas other investigations found antibodies targeting major myelin proteins, myelin basic protein (MBP) and myelin oligodencrocyte glycoprotein (MOG) (8, 9) as well as glycolipids, fatty acids, and neurofilament proteins (10). Similarly, more recent investigations that have applied single-cell PCR cloning to individual CSF B cells in MS have detected antibodies to certain viruses or myelin proteins (11-13). However, it has been impossible to match specificity of antibodies identified in CSF to OCB by studying whole CSF IgG or recombinant antibodies constructed from rearranged Ig heavy-and light-chain genes in individual B cells.Dornmair and coworkers used a combination of new biochemical, proteomic, and transcriptomic approaches (4, 14) to examine the specificity of antibodies in MS OCB. Disulfide-linked IgG heavy-(IgH) and IgG light-(IgL) chain complexes were purified from single OCB spots using affinity chromatography and two-dimensional gel electrophoresis. Those antibody (IgH 2 IgL 2 ) complexes were then analyzed by mass spectrometry to generate patient-specific Ig peptidomes. In parallel, IgH and IgL genes, including the unique complementarity-determining region 3, from CSF B cells isolated from the corresponding patient were sequenced ...

Multiple Sclerosis: Immunopathology and Treatment Update

“…In MS plaques plasma cells are noted in large numbers where antigen uptake, processing and presentation takes place as well as synthesis of IgG. Interestingly, over 50 antibodies isolated from cerebrospinal fluid from patients with MS did not react to MBP, PLP or MOG [86] but some groups reporting that they bind to intracellular proteins such as, MKNK1/2, FAM84A, AKAP12A and glial potassium channel KIR4.1, or, against intracellular lipid determinants [87,88]. Moreover, anti-MOG autoantibodies is a hallmark of childhood MS as well as in some patients with neuromyelitis optical spectrum disorder.…”

“…However, this mode of APL induced T cell cross reactivity between the APL and the wild-type/agonist MBP 83−99 peptide and adverse events in some patients resulted [173]. A subsequent multi-center double-blinded phase II clinical trial with NBI-5788 was suspended-Th2 responses were induced (IL-5, IL-13), however, 13/142 patients developed immediate-type hypersensitivity, who also generated anti-NBI-5788 antibodies which cross-reacted with native agonist MBP [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] peptide [172,174]. National Institute of Neurological Disorders and Stroke sponsored trial, CGP77116, was used in a MRI-controlled phase II clinical trial.…”

“…National Institute of Neurological Disorders and Stroke sponsored trial, CGP77116, was used in a MRI-controlled phase II clinical trial. CGP77116, has Ala D-amino acids of MBP [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] peptide at positions 83, 84, 89, 91 (CGP77116) of MBP [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] peptide, in order to enhance stability [174]. However, this peptide was poorly tolerated at the dose tested, and the trial had to be discontinued.…”

“…Three patients showed exacerbations to disease of which two were linked to CGP77116 injection with high IFN-gamma and low IL-4 (Th1-skewing) were secreted by activated CD4 + T cells. These CD4 + T cells also cross reacted with the native agonist MBP [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] peptide [175]. Accordingly, the problems noted with both NBI-5788 and CGP77116 were likely due to inadequate pre-screening of APL effects on the many clonotypes against the targeted epitopes.…”

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients

“…One leading thought is that anti-nuclear autoantibodies can enter the cell and exert cytotoxic effect there [49, 107]. Perhaps a similar effect could be expected from antibodies that bind cytoplasmic proteins in MS, although there are certainly other scenarios that should be considered [104]. As evidenced with orthogonal images, binding of our CIS-PTM plasmablast rhAbs within the cell was largely excluded from the nucleus.…”