Autoantibodies Against the Complement Regulator Factor H in the Serum of Patients With Neuromyelitis Optica Spectrum Disorder
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Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the
central nervous system (CNS), characterized by pathogenic, complement-activating autoantibodies
against the main water channel in the CNS, aquaporin 4 (AQP4). NMOSD is frequently associated
with additional autoantibodies and antibody-mediated diseases. Because the alternative pathway
amplifies complement activation, our aim was to evaluate the presence of autoantibodies against
the alternative pathway C3 convertase, its components C3b and factor B, and the complement
regulator factor H (FH) in NMOSD. Four out of 45 AQP4-seropositive NMOSD patients (~9%) had FH
autoantibodies in serum and none had antibodies to C3b, factor B and C3bBb. The FH autoantibody
titers were low in three and high in one of the patients, and the avidity indexes were low.
FH-IgG complexes were detected in the purified IgG fractions by Western blot. The autoantibodies
bound to FH domains 19-20, and also recognized the homologous FH-related protein 1 (FHR-1),
similar to FH autoantibodies associated with atypical hemolytic uremic syndrome (aHUS). However,
in contrast to the majority of autoantibody-positive aHUS patients, these four NMOSD patients
did not lack FHR-1. Analysis of autoantibody binding to FH19-20 mutants and linear synthetic
peptides of the C-terminal FH and FHR-1 domains, as well as reduced FH, revealed differences in
the exact binding sites of the autoantibodies. Importantly, all four autoantibodies inhibited
C3b binding to FH. In conclusion, our results demonstrate that FH autoantibodies are not
uncommon in NMOSD and suggest that generation of antibodies against complement regulating
factors among other autoantibodies may contribute to the complement-mediated damage in NMOSD.
Keywords: aquaporin (AQP) 4; autoantibody; autoimmunity; central nervous system; complement;
factor H; inflammation; neuromyelitis optica spectrum disorder.
Reference
Uzonyi, B., Szabó, Z., Trojnár, E., Hyvärinen, S., Uray, K., Nielsen, H. H., ... & Józsi, M. (2021). Autoantibodies against the complement regulator factor H in the serum of patients with neuromyelitis optica spectrum disorder. Frontiers in immunology, 12.
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