Upregulated Complement Receptors Correlate With Fc Gamma Receptor 3A-Positive Natural Killer Cells (NK) and Natural Killer-T Cells (NKT) in Neuromyelitis Optica Spectrum Disorder

Abstract

Objective To clarify if NK and NKT cells are activated via complement in NMOSD. Background Inhibition of terminal complement in NMOSD using eculizumab has been shown to be helpful in preventing relapses but exactly how the drug is working is not clear. Similarly, genetic variants in the Fc Gamma receptor 3A are correlated with outcomes in NMOSD but the immune cells expressing those FcGR3A receptors are unknown. We compared FcGR3A expression on immune cells modulated by complement activity in NK cells and NKT cells in NMOSD to disease controls and healthy people. Design/Methods Peripheral blood cell (PBMC) samples from 45 patients with NMOSD with AQP4-IgG, 18 disease controls, and 19 normal controls were analyzed for FcGR3A expression and complement receptors in vitro. Results At baseline, the number of NKT cells were increased in NMOSD (p < 0.001), but the proportion that were FcGR3A positive was lower compared to healthy and disease controls (p = 0.0012). NK cell count was normal at baseline but also but the proportion that were FcGR3A positive was also relatively lower (p < 0.001). In both NK cells and NKT cells from NMOSD, C5 complement receptor expression was much higher compared to healthy and disease controls (p < 0.001 for both). We also evaluated activation markers CD69 and CD83, which were also much higher in NK and NKT cells from NMOSD patients. Conclusions Our results support a model of immunopathogenesis model in which complement pathway activation in NK/NKT cells upregulate FcGR3A expression that bind to antibody/antigen complexes. In the context of NMOSD, these complement-sensitive cells may be responsible for escalating autoimmune activity.