Anti-nodal/paranodal antibodies in human demyelinating disorders

Anti-nodal/paranodal antibodies have been reported in human demyelinating disorders. Anti-nodal protein antibodies, namely, anti-neurofascin (NF) 186 antibodies and antibodies against paranodal proteins, such as NF155, contactin 1 (CNTN1), and contactin-associated protein 1 (CASPR1), are found in subsets of chronic inflammatory demyelinating polyneuropathy (CIDP). In particular, CIDP patients with IgG4 anti-NF155 antibodies and those with IgG4 anti-CNTN1 antibodies commonly show sensory ataxia, severe demyelination on nerve conduction studies, very high cerebrospinal (CSF) protein levels and poor response to intravenous immunoglobulin. However, younger age at onset, higher frequency of tremor, and nerve root hypertrophy are characteristic of anti-NF155 antibody–positive CIDP, whereas anti-CNTN1 antibody–positive CIDP is characterized by higher age at onset, early axonal damage, subacute aggressive course, and concurrence of membranous nephropathy. Interestingly, anti-NF155 antibody–positive CIDP occasionally accompanies central nervous system lesions suggestive of demyelination. Such cases are termed combined central and peripheral demyelination. Both CIDP with anti-NF155 antibodies and CIDP with anti-CNTN1 antibodies usually demonstrate detachment of terminal loops from the axolemma at the node of Ranvier in biopsied sural nerves. IgG4 in vivo is monovalent and bispecific and lacks complement-binding capability; therefore, IgG4 autoantibodies can only interfere with protein–protein interactions. This property of IgG4 explains the sural nerve pathology but the reasons behind nerve root hypertrophy and CSF protein increase are not known. Recently, we found significant elevation of both Th1 and Th2 cytokines in CSF from anti-NF155 antibody–positive CIDP patients, indicating T-cell involvement in this condition.