Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS

Malmeström, Clas; Haghighi, Sara; Rosengren, Lars; Andersen, Oluf; Lycke, Jan

doi:10.1212/01.wnl.0000098880.19793.b6

Cited by 285 publications

(303 citation statements)

References 45 publications

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“…This strongly suggests that either other chemokine receptors are able to guide cell migration to the CLN or that CNS antigens drain as soluble antigens through CSF to the CLN. This hypothesis is supported by increased free neuronal proteins in CSF of MS patients and EAE mice as compared to healthy controls [52,53].…”

Section: Discussionmentioning

confidence: 76%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in J Mol Med (2009) human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.

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Section: Discussionmentioning

confidence: 76%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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“…In this study we clearly demonstrate that self-antigens are presented in the course of MS that have been known for a long time, such as MBP peptides (19,(22)(23)(24)(25)(26). We found peptides derived from glial fibrillary acidic protein (GFAP) and neurofilament that have been shown to be enhanced in cerebrospinal fluid (CSF) of MS patients (27). Furthermore immunization with neurofilament can cause neurological disease and axonal damage in mice (28).…”

Section: Naturally Presented Peptides In Msmentioning

confidence: 74%

Naturally Presented Peptides on Major Histocompatibility Complex I and II Molecules Eluted from Central Nervous System of Multiple Sclerosis Patients

Fissolo

Haag

Graaf

et al. 2009

Molecular & Cellular Proteomics

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Tandem mass spectrometry was used to identify naturally processed peptides bound to major histocompatibility complex (MHC) I and MHC II molecules in central nervous system (CNS) of eight patients with multiple sclerosis (MS). MHC molecules were purified from autopsy CNS material by immunoaffinity chromatography with monoclonal antibody directed against HLA-A, -B, -C, and -DR. Subsequently peptides were separated by reversedphase HPLC and analyzed by mass spectrometry. Database searches revealed 118 amino acid sequences from self-proteins eluted from MHC I molecules and 191 from MHC II molecules, corresponding to 174 identified source proteins. These sequences define previously known and potentially novel autoantigens in MS possibly involved in disease induction and antigen spreading. Taken together, we have initiated the characterization of the CNS-expressed MHC ligandome in CNS diseases and were able to demonstrate the presentation of naturally processed myelin basic protein peptides in the brain of MS patients.

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“…NfL levels are increased in the cerebrospinal fluid (CSF) of MS patients as well as in degenerative and traumatic neurological diseases (eg, dementia, amyotrophic lateral sclerosis, and spinal cord injury) 4, 5, 6, 7, 8, 9. CSF NfL levels are further increased during relapses and are positively associated with magnetic resonance imaging (MRI) lesion load and disability scores in MS 10, 11, 12.…”

mentioning

confidence: 99%

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Disanto

Barro

Benkert

et al. 2017

Annals of Neurology

909

1,069

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ObjectiveNeurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single‐molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS).MethodssNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross‐sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow‐up = 3.1 years, interquartile range [IQR] = 2.0–4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.ResultssNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2–65.3) or both brain and spinal gadolinium‐enhancing lesions (62.5pg/ml, IQR = 42.7–71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9–41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease‐modifying treatment (β = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC‐based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21–3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07–5.42, p = 0.034).InterpretationThese results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857–870

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Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS

Cited by 285 publications

References 45 publications

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Naturally Presented Peptides on Major Histocompatibility Complex I and II Molecules Eluted from Central Nervous System of Multiple Sclerosis Patients

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

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