Difference in the Source of Anti-AQP4-IgG and Anti-MOG-IgG Antibodies in CSF in Patients With Neuromyelitis Optica Spectrum Disorder

Abstract

Objective: To elucidate the differences in the source and in the level of intrathecal synthesis between anti-aquaporin-4 antibodies (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).

Methods: Thirty-eight patients with MOG-IgG-associated disease and 36 with AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD) were studied for the antibody titers in the sera and CSF simultaneously collected in the acute attacks. The quotients between CSF and serum levels of albumin, total immunoglobulin G, and each disease-specific antibody were calculated. Intrathecal production level in each disease-specific antibody was evaluated by calculating the antibody index from these quotients.

Results: Eleven of the 38 patients with MOG-IgG were positive for the antibody only in the CSF, while no patient with AQP4-IgG showed CSF-restricted AQP4-IgG. Blood-brain barrier compromise as shown by raised albumin quotients was seen in 75.0% of MOG-IgG-positive cases and 43.8% of AQP4-IgG-positive cases. Moreover, MOG-IgG quotients were >10 times higher than AQP4-IgG quotients (effect size r = 0.659, p < 0.0001). Elevated antibody index (>4.0) was confirmed in 12 of 21 with MOG-IgG, whereas it was seen only in 1 of 16 with AQP4-IgG (φ = 0.528, p < 0.0001). The CSF MOG-IgG titers (ρ = 0.519, p = 0.001) and antibody indexes for MOG-IgG (ρ = 0.472, p = 0.036) correlated with the CSF cell counts but not with clinical disability.

Conclusions: Intrathecal production of MOG-IgG may occur more frequently than that of AQP4-IgG. This finding implies the different properties of B-cell trafficking and antibody production between MOG-IgG-associated disease and AQP4-IgG-positive NMOSD.

Figure 1. Simultaneous Titers of Specific Antibodies (MOG-IgG, AQP4-IgG) in the Serum and CSF

Anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG) showed higher quotients (i.e., ratio of CSF/serum levels) than anti–aquaporin-4 antibodies (AQP4-IgG) regardless of the serum titer levels. This shows that a larger proportion of specific antibody in the CSF originates intrathecally in MOG-IgG compared to AQP4-IgG.

Figure 2. Scatterplots for Each Patient on the Reibergram According to Disease Type

(A) Scatterplots with albumin quotient () and immunoglobulin G quotient () on the Reibergram. Plots in patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG) or anti–aquaporin-4 antibodies (AQP4-IgG) distribute below and along the upper line of the distribution of patients without intrathecal IgG synthesis on the Reibergram () line, whereas many of them were with raised . (B) Scatterplots with and quotient for each specific antibody (i.e., , ) () on the Reibergram. Plots in patients with MOG-IgG distribute above the line and not along the line. MS = multiple sclerosis.

Figure 3. Distributions of IgG Index, Q_IgG−spec, and AI by Disease Type

Grouped scatterplots by disease groups for (A) immunoglobulin G (IgG) index, (B) quotient for each specific antibody (i.e., , ) (), and (C) antibody index (AI) are shown. IgG index reflects the intrathecal total IgG production, whereas and AI represent the intrathecal production of each specific antibody. AQP4-IgG = anti–aquaporin-4 antibodies; MS = multiple sclerosis; MOG-IgG = anti-myelin oligodendrocyte glycoprotein antibody.

Figure 4. Distributions of AI Among Untreated Seropositive Patients

Scatterplots of antibody index (AI) after the exclusion of patients with relapse prevention therapy or with CSF-restricted anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG) are shown. Both the distribution of AI value and the prevalence of AI value ≥1.5 or >4 were still significantly higher in the MOG-IgG seropositive patients than in the anti–aquaporin-4 antibodies (AQP4-IgG) seropositive patients. Diagonal solid lines represent the AI values of 1.5 and 4.0. IgG = immunoglobulin G; = quotient for each specific antibody (i.e., , ); = upper line of the distribution of patients without intrathecal IgG synthesis on the Reibergram.