Since the discovery of antibodies against aquaporin-4 (AQP4-IgG) in patients with Neuromyelitis Optica Spectrum Disorders (NMOSD), an increasing number of AQP4-IgG+ NMOSD patients were described having limited forms such as longitudinally extensive myelitis or recurrent and/or bilateral optic neuritis, area postrema attacks with persistent (> 48 hours) hiccups, nausea and vomiting and those patients with associated diencephalic, brainstem and cerebral lesions “typical” for NMOSD. According to the international consensus diagnostic criteria for NMOSD published on 2015, the diagnosis of NMOSD for AQP4-IgG positive cases is possible if there is a suggestive attack with involvement 1 of 6 core locations (optic nerve, spinal cord, area postrema of the dorsal medulla, brainstem, diencephalon or cerebrum). In seronegative patients, two or more core locations must be affected, with at least one of the attacks in the optic nerve, spinal cord or the area postrema, and additional magnetic resonance imaging (MRI) criteria should be fulfilled. The 2015 NMOSD diagnostic criteria recommends cell-based assays (CBA) to detected AQP4-IgG. However, the availability of diagnostic tests such as AQP4-IgG by CBA is still limited in low income countries, as well as long-term treatments recently approved for NMOSD. More recently, antibodies against the myelin oligodendrocyte glycoprotein (MOG-IgG) have been incorporated in the clinical practice in many developed countries as an important tool to differentiate patients with MOG-IgG associated Optic Neuritis, Encephalitis, and/or Myelitis (MONEM) from seronegative NMOSD and other demyelinating CNS disorders. Nevertheless, the availability of MOG-IgG CBAs is even more restricted than AQP4-IgG, as it is limited to research laboratories in many countries. The management of these patients require an international effort to support patients from countries without access to antibody testing for AQP4-IgG and MOG-IgG, as well as provide drugs to reduce the risk of further attacks and disability.
Neuromyelitis optica spectrum disorders (NMOSD) are a group of rare, but severe autoimmune diseases characterized by antibody-driven inflammation of mainly the ocular nerves and spinal cord. Although naive B cells are considered key players, it remains unknown whether their composition and outgrowth differ between serological NMOSD subgroups.
We examined how ex vivo proportions and germinal center-like development of naive B cells are related to AQP4- and MOG-IgG serostatus, steroid treatment and relapse occurrence in NMOSD.
The presence of blood transitional, naive mature and both switched and unswitched memory B cells was determined in 10 AQP4- and 8 MOG-IgG-positive NMOSD patients without any form of previous immune suppressive treatment. Results were compared to 9 steroid-treated AQP4- or MOG-IgG-positive patients, 20 age- and gender-matched healthy controls (HCs) and 10 treatment-naive RRMS patients. Furthermore, naive B cells were cultured under T-bet-inducing, germinal center-like conditions for 11 days to address plasmablast formation in vitro.
Under complete treatment-naive circumstances, naive mature/transitional B-cell ratios were significantly reduced in AQP4-IgG-positive NMOSD vs MOG-IgG-positive NMOSD, MS and HC groups. This was caused by increased proportions of transitional B cells, which were the highest in 2 AQP4-IgG-positive cases with relapsing disease (35% and 44% of the total B-cell pool). In steroid-treated patients, transitional B-cell proportions were strongly diminished and correlated negatively with time since start of treatment. For naive B cells from 7 relapsing NMOSD patients, TLR9 ligand CpG synergized with IFN-γ to enhance plasmablast formation in IL-21/CD40L-containing cultures. This was not seen for 11 non-relapsing patients or 9 HCs. IFN-γ- and CpG-induced naive B cells showed increased secretion of total IgG in the AQP4-IgG-positive group, and especially for patients with relapsing disease. In vitro-induced AQP4-IgG secretion was found for 3 relapsing but not for 6 non-relapsing patients, which was enhanced by IFN-γ and CpG (2 out of 3 relapsing patients). MOG-IgG was not detected in any of the naive B-cell culture supernatants of 4 relapsing and 4 non-relapsing MOG-IgG-positive patients.
These findings reveal that naive B-cell homeostasis is different and affected by steroid treatment amongst NMOSD subgroups, and offers a first rationale for exploring TLR9-dependent in vitro platforms to predict NMOSD activity.