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Intrathecal cytokine profile in neuropathy with anti-neurofascin 155 antibody.

ABSTRACT: OBJECTIVE:To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti-NF155 antibodies (NF155- CIDP). METHODS:Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155- CIDP, and 28 with non-inflammatory neurological disease (NIND). RESULTS:CSF CXCL8/IL-8, IL-13, TNF-?, CCL11/eotaxin, CCL2/MCP-1, and IFN-? were significantly higher, while IL-1?, IL-1ra, and G-CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155- CIDP, CXCL8/IL-8 and IL-13 were significantly higher, and IL-1?, IL-1ra, and IL-6 were lower, in NF155+ CIDP. CXCL8/IL-8, IL-13, CCL11/eotaxin, CXCL10/IP-10, CCL3/MIP-1?, CCL4/MIP-1?, and TNF-? levels were positively correlated with markedly elevated CSF protein, while IL-13, CCL11/eotaxin, and IL-17 levels were positively correlated with increased CSF cell counts. IL-13, CXCL8/IL-8, CCL4/MIP-1?, CCL3/MIP-1?, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155- CIDP had significantly increased IFN-? compared with NIND, and exhibited positive correlations of IFN-?, CXCL10/IP-10, and CXCL8/IL-8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155- CIDP were separable, and that IL-4, IL-10, and IL-13 were the three most significant discriminators. INTERPRETATION:Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti-NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.

SUBMITTER: Ogata H

PROVIDER: S-EPMC6856599 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Intrathecal cytokine profile in neuropathy with anti-neurofascin 155 antibody.

Ogata Hidenori H Zhang Xu X Yamasaki Ryo R Fujii Takayuki T Machida Akira A Morimoto Nobutoshi N Kaida Kenichi K Masuda Teruaki T Ando Yukio Y Kuwahara Motoi M Kusunoki Susumu S Nakamura Yuri Y Matsushita Takuya T Isobe Noriko N Kira Jun-Ichi JI

Annals of clinical and translational neurology 20191027 11

<h4>Objective</h4>To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155<sup>+</sup> CIDP) or those lacking anti-NF155 antibodies (NF155<sup>-</sup> CIDP).<h4>Methods</h4>Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155<sup>+</sup> CIDP, 36 with NF155<sup>-</sup> CIDP, and 28 with non-inflammatory neurol ...[more]

PMID: 31657126

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Project description:ObjectiveTo investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsSera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain-Barré syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization.ResultsThe positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did.InterpretationAnti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy.

Project description:BackgroundRecent studies have reported that similar to other IgG4 autoimmune diseases, such as muscle-specific kinase antibody-associated myasthenia gravis, most anti-neurofascin-155 (anti-NF155) nodopathies respond well to rituximab treatment, regardless of the dosage. However, there are still a few patients for which rituximab is ineffective for unknown reasons. Currently, there are no studies on the mechanism of ineffective treatment with rituximab.MethodsA 33-year-old Chinese man presenting with numbness, tremor, and muscle weakness for 4 years was recruited for this study. Anti-NF155 antibodies were identified by cell-based assay and confirmed by immunofluorescence assay on teased fibers. The anti-NF155 immunoglobulin (IgG) subclasses were also detected by immunofluorescence assay. Anti-rituximab antibodies (ARAs) were quantitatively analyzed using enzyme-linked immunosorbent assay (ELISA), and peripheral B cell counts were determined by flow cytometry.ResultsThe patient exhibited anti-NF155 IgG4-antibody positivity. After the first round of rituximab infusion, the patient showed stratified outcomes with improvements in numbness, muscle weakness and ambulation. However, after three rounds of rituximab infusion, the patient's symptoms deteriorated, and the numbness, tremor and muscle weakness returned. No obvious improvement was found after plasma exchange and another round of rituximab treatment. 14 days after the last treatment with rituximab, ARAs were detected. And the titers gradually decreased on day 28 and 60 but remained higher than normal. Peripheral CD19+ B cell counts were less than 1% within the 2-month period following the final rituximab administration.ConclusionsIn this study, ARAs presented in a patient with anti-NF155 nodopathy undergoing rituximab treatment and showed an unfavorable impact on rituximab efficacy. This is the first case to report the occurrence of ARAs in patients with anti-NF155 antibodies. We suggest that ARAs should be tested early during the initial intervention, especially in patients who respond poorly to rituximab treatment. In addition, we believe it is necessary to investigate the association between ARAs and B cell counts, their effect on clinical efficacy, and their potential adverse reactions in a larger cohort of patients with anti-NF155 nodopathy.

Project description:Stability of the myelin-axon unit is achieved, at least in part, by specialized paranodal junctions comprised of the neuronal heterocomplex of contactin and contactin-associated protein and the myelin protein neurofascin 155. In multiple sclerosis, normal distribution of these proteins is altered, resulting in the loss of the insulating myelin and consequently causing axonal dysfunction. Previously, this laboratory reported that mice lacking the myelin-enriched lipid sulphatide are characterized by a progressive deterioration of the paranodal structure. Here, it is shown that this deterioration is preceded by significant loss of neurofascin 155 clustering at the myelin paranode. Interestingly, prolonged electrophoretic separation revealed the existence of two neurofascin 155 bands, neurofascin 155 high and neurofascin 155 low, which are readily observed following N-linked deglycosylation. Neurofascin 155 high is observed at 7 days of age and reaches peak expression at one month of age, while neurofascin 155 low is first observed at 14 days of age and constantly increases until 5 months of age. Studies using conditional neurofascin knockout mice indicated that neurofascin 155 high and neurofascin 155 low are products of the neurofascin gene and are exclusively expressed by oligodendrocytes within the central nervous system. Neurofascin 155 high is a myelin paranodal protein while the distribution of neurofascin 155 low remains to be determined. While neurofascin 155 high levels are significantly reduced in the sulphatide null mice at 15 days, 30 days and 4 months of age, neurofascin 155 low levels remain unaltered. Although maintained at normal levels, neurofascin 155 low is incapable of preserving paranodal structure, thus indicating that neurofascin 155 high is required for paranodal stability. Additionally, comparisons between neurofascin 155 high and neurofascin 155 low in human samples revealed a significant alteration, specifically in multiple sclerosis plaques.

Dataset Information

Intrathecal cytokine profile in neuropathy with anti-neurofascin 155 antibody.

Publications

Intrathecal cytokine profile in neuropathy with anti-neurofascin 155 antibody.

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