Quantitative Cerebrospinal Fluid IgG Measurements as a Marker of Disease Activity in Multiple Sclerosis

Caroscio, James T.; Kochwa, Shaul; Sacks, Henry; Makuku, Sonya; Cohen, Jeffrey A.; Yahr, Melvin D.

doi:10.1001/archneur.1986.00520110029009

Cited by 24 publications

(15 citation statements)

References 13 publications

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“…Furthermore, recent studies have shown that antibodies produced by clonally expanded plasma cells in MS CSF cause demyelination [7], and myelin-specific MS antibodies cause complement-dependent oligodendrocyte loss and demyelination [8]. This evidence supports the notion that intrathecal IgG in MS plays a critical role in disease pathogenesis, consistent with the view that CSF IgG alone remains the best marker of disease activity in individual MS patients [1].…”

Section: Introductionsupporting

confidence: 74%

“…The critical role of intrathecal IgG/oligoclonal bands in MS disease pathogenesis is supported by mounting evidence. For example, actively demyelinating lesions are commonly associated with prominent deposition of immunoglobulins and complement activation products [15][16][17][18], OCBs are shown to be associated with increased levels of disease activity and disability [1,3,6], a greater risk of second attack [19], the conversion from a clinically isolated syndrome (CIS) to early RRMS [4,20], and greater brain atrophy [5,6]. Moreover, the presence of OCB in CSF in the specific clinical context is still the most reliable parameter to confirm the likely diagnosis of MS [21,22], supporting the critical pathological role of intrathecal IgG antibodies in MS. Intrathecal production of antibodies against viruses (measles, rubella, and varicella zoster virus), bacteria and CNS components in MS have up until now shown inconsistent or negative results [23][24][25].…”

Section: Discussionmentioning

confidence: 99%

“…No shared peptide sequences were found between MS patients. 1 Phage peptides used for western blots in. 1,2 Phage peptides used for both western blots and for screening MS and IC CSF (Fig A and B in S1 Fig).…”

Section: Phage Peptides Target Intrathecally Synthesized Oligoclonal mentioning

confidence: 99%

“…Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) and is characterized by inflammatory demyelination and neuronal damage. Cerebrospinal fluid (CSF) oligoclonal bands (OCBs), a characteristic feature of MS, are associated with increased levels of disease activity and disability [1][2][3], the conversion from a clinically isolated syndrome to early relapsing-remitting MS [4], greater brain atrophy [5], and increased cortical lesion load/intrathecal inflammation [6]. Furthermore, recent studies have shown that antibodies produced by clonally expanded plasma cells in MS CSF cause demyelination [7], and myelin-specific MS antibodies cause complement-dependent oligodendrocyte loss and demyelination [8].…”

Section: Introductionmentioning

confidence: 99%

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Oligoclonal IgG antibodies in multiple sclerosis target patient-specific peptides

et al. 2020

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IgG oligoclonal bands (OCBs) are present in the cerebrospinal fluid (CSF) of more than 95% of patients with multiple sclerosis (MS), and are considered to be the immunological hallmark of disease. However, the target specificities of the IgG in MS OCBs have remained undiscovered. Nevertheless, evidence that OCBs are associated with increased levels of disease activity and disability support their probable pathological role in MS. We investigated the antigen specificity of individual MS CSF IgG from 20 OCB-positive patients and identified 40 unique peptides by panning phage-displayed random peptide libraries. Utilizing our unique techniques of phage-mediated real-time Immuno-PCR and phage-probed isoelectric focusing immunoblots, we demonstrated that these peptides were targeted by intrathecal oligoclonal IgG antibodies of IgG1 and IgG3 subclasses. In addition, we showed that these peptides represent epitopes sharing sequence homologies with proteins of viral origin, and proteins involved in cell stress, apoptosis, and inflammatory processes. Although homologous peptides were found within individual patients, no shared peptide sequences were found among any of the 42 MS and 13 inflammatory CSF control specimens. The distinct sets of oligoclonal IgG-reactive peptides identified by individual MS CSF suggest that the elevated intrathecal antibodies may target patient-specific antigens.

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Section: Introductionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Phage Peptides Target Intrathecally Synthesized Oligoclonal mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oligoclonal IgG antibodies in multiple sclerosis target patient-specific peptides

et al. 2020

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“…In contrast, high INL measures correlate with frequencies of intrathecal CD56 bright NK cells and paraclinical inflammatory disease activity as measured by MRI. Increased B-cell frequencies in the CSF were previously reported to be linked with disease worsening in patients with MS. 17 Patterns of intrathecal immunoglobulin production were associated with a worse disease course 19 and brain atrophy. 20 More recently, meningeal inflammation has been considered as a main driver of cortical demyelination, which appears to be associated with disability worsening in MS. 21 Meningeal lymphocyte aggregates, which are evident in progressive MS, consist mainly of B cells and might be directly associated with cortical pathologic findings.…”

Section: Discussionmentioning

confidence: 99%

Association of Retinal Architecture, Intrathecal Immunity, and Clinical Course in Multiple Sclerosis

et al. 2017

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IMPORTANCE Biomarkers to estimate long-term outcomes in patients with multiple sclerosis (MS) and to assign patients to individual treatment regimens are urgently needed.OBJECTIVE To assess whether retinal layer volumes are correlated with immune cell subsets and immunoglobulin indices in the cerebrospinal fluid and whether retinal layer volumes alone or in combination with intrathecal variables are associated with worsening of disease in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS This observational cohort study included 312 patients with relapsing-remitting MS in 2 independent cohorts (72 patients with short disease duration [cohort 1] and 240 patients with longer disease duration [cohort 2]) treated at a single German university hospital from April 15, 2013, through November 11, 2015. MAIN OUTCOMES AND MEASURESThe common ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) volumes were tested for association with the immunoglobulin indices and the frequencies of immune cells in the cerebrospinal fluid (including B cells, T cells, and natural killer cells) (cohort 1). Volumes of GCIPL alone (cohorts 1 and 2) or GCIPL corrected for intrathecal B-cell frequencies (cohort 1) were tested for their association with worsening disability.RESULTS A total of 312 patients (212 women [67.9%] and 100 men [32.1%]; median age, 34.0 years [interquartile range (IQR), 28.0-42.0 years]) were available for analysis. In cohort 1 (50 women [69.4%] and 22 men [30.6%]; median age, 31.0 years [IQR,3 years]), with short disease durations (median, 1.0 months [IQR, 1.0-2.0 months]), low GCIPL volumes were associated with increased intrathecal B-cell frequencies (median, 1.96% [IQR, 1.45%-4.20%]) and intrathecal IgG synthesis (median cerebrospinal fluid/serum IgG index, 0.78 [IQR,). The INL volumes correlated with the frequencies of intrathecal CD56 bright natural killer cells (r = 0.28; P = .007). Individuals with low GCIPL volumes (<1.99 mm 3 ) had a 6.4-fold risk for worsening disability during follow-up compared with patients with higher GCIPL values (95% CI, 1.7-24.2; P = .007). This finding was reproduced in cohort 2 (162 women [67.5%] and 78 men [32.5%]; median age, 34.0 years [IQR, 29.0-42.0 years]) consisting of patients with longer disease durations (median, 36.0 months [IQR, 21.0-60.0 months]) (hazard ratio, 2.4; 95% CI, 1.2-4.8; P = .02). In both cohorts, INL volumes correlated with the prospective increase in T2 lesion load and the number of gadolinium-enhancing lesions.CONCLUSIONS AND RELEVANCE Retinal layers reflect different aspects of disease activity during MS. Loss of GCIPL is associated with intrathecal B-cell immunity and constitutes an independent risk factor for worsening disability, whereas high INL volumes are associated with activity on magnetic resonance imaging in the brain parenchyma. Thus, retinal optical coherence tomography might be a means to support stratification of patients with MS for different therapeutic regimens.

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Cerebrospinal Fluid Immunoglobulins and Multiple Sclerosis

Müller

Hänny²,

Wichmann³

et al. 1989

Arch Neurol

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Quantitative Cerebrospinal Fluid IgG Measurements as a Marker of Disease Activity in Multiple Sclerosis

Cited by 24 publications

References 13 publications

Oligoclonal IgG antibodies in multiple sclerosis target patient-specific peptides

Oligoclonal IgG antibodies in multiple sclerosis target patient-specific peptides

Association of Retinal Architecture, Intrathecal Immunity, and Clinical Course in Multiple Sclerosis

Cerebrospinal Fluid Immunoglobulins and Multiple Sclerosis

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