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.

Keywords: IgG4; chronic inflammatory demyelinating polyneuropathy; combined central and peripheral demyelination; neurofascin 155; node of Ranvier.

Figure 1

Schema of a node of Ranvier indicating proteinaceous antigens targeted by anti-nodal/paranodal antibodies in chronic inflammatory demyelinating polyneuropathy (CIDP). (A) In CIDP, autoantibodies to NF155, NF186, CNTN1, and CASPR1 have been discovered, while antibodies against NF186, gliomedin, and contactin were also reported in a minority of patients with Guillain–Barré syndrome (28). (B) Schematic diagram of the different neurofascin isoforms. In the mature nervous system, neurons express NF186 while oligodendroglia express NF155. NF180 and NF166 are present in immature neurons (17). NF155 and NF186 differ in their extracellular domains: NF155 has FN3, but NF186 lacks this domain and instead harbors a mucin domain between FN4 and FN5. CASPR1, contactin-associated protein 1; CNTN1, contactin 1; FN, fibronectin type III domain; Ig, immunoglobulin; K_v, potassium channel; Na_v, sodium channel; NF, neurofascin; NrCAM, neuronal cell adhesion molecule.

Figure 2

Schematic structure of IgG4. (A) Trans heavy-chain CH1–CH2 domain interaction hinders the CH2 domain within a compact structure (12). As a result, complement proteins cannot access the CH2 domain for fixation. (B) IgG4 is subjected to interchain disulfide bond cleavage by protein disulfide isomerase expressed on immunocytes and endothelial cells, which leads to half-molecule exchange (12). Consequently, in vivo IgG4 exists in a monovalent and bispecific form, which prevents IgG4 from internalizing target surface antigens.

Figure 3

Process of disease progression in NF155⁺ chronic inflammatory demyelinating polyneuropathy (CIDP)/combined central and peripheral demyelination (CCPD). In NF155⁺ CIDP/CCPD, the disease initiates (subclinical) demyelination at the distal nerve terminals of the somatic nerve and then extends to the cranial nerves. Later, hypertrophy of the proximal spinal nerve and roots occurs over the long disease duration, which is followed by hypertrophy of the cranial nerves, such as trigeminal and oculomotor nerves. Somatic and cranial nerve involvements develop in parallel except for the optic nerve, while peripheral nervous system (PNS) and central nervous system (CNS) involvements do not occur in parallel.

Figure 4

Hypothetical mechanism of NF155⁺ chronic inflammatory demyelinating polyneuropathy (CIDP)/combined central and peripheral demyelination (CCPD). NF155 peptides are presented by a DRB1*15:01/DRB1*15:02 and/or DQA1*01:02-DQB1*06:02/DQA1*01:03-DQB1*06:01 complex to naive T cells, initiating Tfh2/Th1 cell differentiation. Tfh2 cells produce IL4/IL13/IL10, which induce IgG4 class switching. IgG4 anti-NF155 antibodies invade the nerve terminal and nerve roots where the blood nerve barrier is absent or leaky. Invaded anti-NF155 antibodies disrupt the interaction between NF155 and the CNTN-1/CASPR1 complex at the paranode, which leads to Schwann cell terminal loop detachment from axons. Activated Th2 and Th1 cells cause inflammation at the spinal roots, resulting in nerve root hypertrophy, occasionally producing periventricular ovoid lesions in the central nervous system (CNS). Overproduction of IL13 downregulates IL1β production, which depresses macrophage activation and recruitment. Cranial nerves, such as trigeminal, facial, oculomotor, and optic nerves, are also affected by anti-NF155 antibodies and possibly by activated Th2/Th1 cells.