Anti-Neurofascin 155 Antibody-Positive Chronic Inflammatory Demyelinating Polyneuropathy/Combined Central and Peripheral Demyelination: Strategies for Diagnosis and Treatment Based on the Disease Mechanism

Abstract

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system (PNS). A small number of CIDP patients harbors autoantibodies against nodal/paranodal proteins, such as neurofascin 155 (NF155), contactin 1, and contactin-associated protein 1. In most cases, the predominant immunoglobulin (IgG) subclass is IgG4. Node/paranode antibody-positive CIDP demonstrates distinct features compared with antibody-negative CIDP, including a poor response to intravenous immunoglobulin. The neuropathology of biopsied sural nerve shows Schwann cell terminal loop detachment from axons without macrophage infiltration or inflammation. This is partly attributable to IgG4, which blocks protein–protein interactions without inducing inflammation. Anti-NF155 antibody-positive (NF155+) CIDP is unique because of the high frequency of subclinical demyelinating lesions in the central nervous system (CNS). This is probably because NF155 coexists in the PNS and CNS. Such cases showing demyelinating lesions in both the CNS and PNS are now termed combined central and peripheral demyelination (CCPD). NF155+ CIDP/CCPD commonly presents hypertrophy of spinal nerve roots and cranial nerves, such as trigeminal and oculomotor nerves, and extremely high levels of cerebrospinal fluid (CSF) protein, which indicates nerve root inflammation. In the CSF, the CXCL8/IL8, IL13, TNFα, CCL11/eotaxin, CCL2/MCP1, and IFNγ levels are significantly higher and the IL1β, IL1ra, and GCSF levels are significantly lower in NF155+ CIDP than in non-inflammatory neurological diseases. Even compared with anti-NF155 antibody-negative (NF155−) CIDP, the CXCL8/IL8 and IL13 levels are significantly higher and the IL1β and IL1ra levels are significantly lower than those in NF155+ CIDP. Canonical discriminant analysis revealed NF155+ and NF155− CIDP to be separable with IL4, IL10, and IL13, the three most significant discriminators, all of which are required for IgG4 class switching. Therefore, upregulation of both Th2 and Th1 cytokines and downregulation of macrophage-related cytokines are characteristic of NF155+ CIDP, which explains spinal root inflammation and the lack of macrophage infiltration in the sural nerves. All Japanese patients with NF155+ CIDP/CCPD have one of two specific human leukocyte antigen (HLA) haplotypes, which results in a significantly higher prevalence of HLA-DRB1*15:01-DQB1*06:02 compared with healthy Japanese controls. This indicates an involvement of specific HLA class II molecules and relevant T cells in addition to IgG4 anti-NF155 antibodies in the mechanism underlying IgG4 NF155+ CIDP/CCPD.

Impact of Neurofascin on Chronic Inflammatory Demyelinating Polyneuropathy via Changing the Node of Ranvier Function: A Review

“…The isoform of NF155 is more vulnerable to attack in immune modulatory dysfunction than other molecules in CIDP ( Delmont et al, 2017 ; Burnor et al, 2018 ; Kira, 2021 ). The IgG subclass was more frequently detected in both the anti-NF186 and anti-NF155 antibody-positive CIDP.…”

“…A study showed that injection of anti-NF antibodies from patients with CIDP to the experimental autoimmune neuritis (EAN) model could enhance and prolong an ongoing neuritis, but injection of anti-NF antibodies to the control group is not pathogenic ( Ng et al, 2012 ). An electrophysiology test of CIDP showed that distal and F-wave latencies are influenced more severely than the motor conduction velocities and compound muscle action potential amplitudes and have a high frequency of spinal root hypertrophy on MRI images, which suggest that nerve terminals, major plexuses, and spinal roots are more frequently involved in patients with anti-NF155 antibody-positive CIDP, where the BNB is anatomically absent or loose ( Ogata et al, 2015 ; Kira, 2021 ). The BNB maintains nerve homeostasis by preventing the free movement of soluble proteins in the circulation into the endoneurium microenvironment under normal physiological conditions.…”

“…Two biopsied sural nerve specimens from patients with anti-NF155 antibody-positive IgG4-predominant CIDP showed occasional paranodal demyelination and subperineural edema, but no inflammatory cell infiltrates, onion bulbs, or vasculitis ( Ogata et al, 2015 ). The pathogenic mechanism of anti-NF155 antibodies blocks the interaction between NF155 and the CNTN1-CASPR1 complex, resulting in saltatory conduction failure but without inducing inflammation ( Kira, 2021 ). An electron microscopy study showed the disappearance of microvilli in the sural nerve biopsy specimen from an anti-NF186 IgG3 antibody patient with CIDP, which were replaced by elongated extensions of Schwann cell cytoplasm, so that the nodal gap was occluded ( Vallat et al, 2018 ).…”

“…Although tremor and ataxia accompanied by cerebellar features commonly occurred in anti-NF155 antibody-positive CIDP, there is no evidence of abnormalities on MRI of the head in anti-NF155 antibody-positive CIDP. Several studies have reported that MRI scans of the cervical and lumbosacral nerves show enlarged nerve roots and proximal nerve segments ( Kira, 2021 ). The clinical features of anti-NF186 antibody-positive CIDP are different from those of anti-NF155 antibody-positive CIDP, which include subacute onset, sensory ataxia, conduction block, and cranial nerve involvement.…”

“…Neurofascin comprises two subtypes such as NF186 and NF155. Due to the diverse functions and structures of each subtype of immunoglobulin (Ig) and the different anatomical features of the paranode and node, the manifestation and therapy of anti-NF155 antibody-positive CIDP are different from those of anti-NF186 antibody-positive CIDP ( Ogata et al, 2015 ; Kira, 2021 ). In this study, we mainly discuss the effects of NF on the assembly and maintenance of the node of Ranvier, the role of anti-NF antibodies in the pathogenesis of CIDP, and the corresponding characteristic manifestation of the mechanism.…”