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Diagnostics of autoimmune neurodegeneration using fluorescent probing.

ABSTRACT: The discovery of antibody-mediated catalysis was a breakthrough that showed antibody function is not limited to specific binding interactions, and that immunoglobulins (Igs) may also chemically transform their target antigens. Recently, so-called "natural catalytic antibodies" have been intimately linked with several pathologies, where they either protect the organism or contribute to the development of autoimmune abnormalities. Previously, we showed that myelin-reactive autoantibodies from patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE) exhibit the ability to recognize and hydrolyse distinct epitopes within myelin basic protein (MBP). Further, the antibody-mediated cleavage of encephalitogenic MBP peptide 81-103, flanked by two fluorescent proteins, can serve as a novel biomarker for MS. Here, we report the next generation of this biomarker, based on the antibody-mediated degradation of a novel chemically synthesized FRET substrate, comprising the fluorophore Cy5 and the quencher QXL680, interconnected by the MBP peptide 81-99: Cy5-MBP81-99-QXL680. This substrate is degraded upon incubation with either purified antibodies from MS patients but not healthy donors or purified antibodies and splenocytes from EAE but not from non-immunized mice. Data presented herein suggest the elaboration of potential specific, rapid, and sensitive diagnostic criteria of active progressive MS.

SUBMITTER: Lomakin Y

PROVIDER: S-EPMC6107501 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Diagnostics of autoimmune neurodegeneration using fluorescent probing.

Lomakin Yakov Y Kudriaeva Anna A Kostin Nikita N Terekhov Stanislav S Kaminskaya Alena A Chernov Alexander A Zakharova Maria M Ivanova Maria M Simaniv Taras T Telegin Georgy G Gabibov Alexander A Belogurov Alexey A

Scientific reports 20180823 1

The discovery of antibody-mediated catalysis was a breakthrough that showed antibody function is not limited to specific binding interactions, and that immunoglobulins (Igs) may also chemically transform their target antigens. Recently, so-called "natural catalytic antibodies" have been intimately linked with several pathologies, where they either protect the organism or contribute to the development of autoimmune abnormalities. Previously, we showed that myelin-reactive autoantibodies from pati ...[more]

PMID: 30139963

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Project description:Progranulin (PGRN), Total-Tau (t-tau), and Neurofilament light chain (NfL) are well known biomarkers of neurodegeneration. The objective of the present study was to investigate whether these parameters represent also biomarkers in autoimmune-mediated Encephalitis (AE) and may give us insights into the pathomechanisms of AE. We retrospectively examined the concentration of PGRN in the cerebrospinal fluid (CSF) and serum of 38 patients suffering from AE in acute phase and/or under treatment. This AE cohort comprises patients with autoantibodies against: NMDAR (n = 18 patients), Caspr2 (n = 8), Lgi-1 (n = 10), GABAB(R) (n = 1), and AMPAR (n = 1). Additionally, the concentrations of NfL (n = 25) and t-tau (n = 13) in CSF were measured when possible. Follow up data including MRI were available in 13 patients. Several age-matched cohorts with neurological diseases besides neuroinflammation or neurodegeneration served as control groups. We observed that PGRN was significantly elevated in the CSF of patients with NMDAR-AE in the acute phase, but normalized at follow up under treatment (p < 0.01). In the CSF of other patients with AE PGRN was in the range of the CSF levels of control groups. T-tau was highly elevated in the CSF of patients with temporal FLAIR-signal in the MRI and in patients developing a hippocampal sclerosis. NfL was exceptionally high initially in Patients with AE with a paraneoplastic or parainfectious cause and also normalized under treatment. The normalizations of all biomarkers were mirrored in an improvement on the modified Rankin scale. The data suggest that the concentration of PGRN in CSF might be a biomarker for acute NMDAR-AE. Pathological high t-tau levels may indicate a risk for hippocampal sclerosis. The biomarker properties of NfL remain unclear since the levels decrease under treatment, but it could not predict severity of disease in this small cohort. According to our results, we recommend to measure in clinical practice PGRN and t-tau in the CSF of patients with AE.

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Diagnostics of autoimmune neurodegeneration using fluorescent probing.

Publications

Diagnostics of autoimmune neurodegeneration using fluorescent probing.

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