Abstract
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.
Highlights
Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory disease of the central nervous system (CNS) with a prevalence of 0.7-10/100,000 worldwide [1] and is characterized by pathogenic complement-activating autoantibodies against aquaporin 4 (AQP4), the main water channel of the CNS [2, 3]
We tested the presence of autoantibodies to C1q; a few but none of the factor H (FH) autoantibody positive NMOSD serum samples were positive for C1q autoantibodies (Supplementary Figure 2), confirming previous report [19]
FH autoantibodies appear pathogenic in atypical hemolytic uremic syndrome (aHUS) and dense deposit disease, as functional consequence of the presence of the autoantibodies was described in terms of interfering with the interaction of FH with C3b and host cells and with the cofactor activity of FH, respectively [33, 34]
Summary
Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory disease of the central nervous system (CNS) with a prevalence of 0.7-10/100,000 worldwide [1] and is characterized by pathogenic complement-activating autoantibodies against aquaporin 4 (AQP4), the main water channel of the CNS [2, 3]. The complement system can be activated via three main pathways, the classical, the lectin and the alternative pathways. It provides a first-line defense against infections, participates in the clearance of immune complexes and cellular waste, and influences adaptive immune responses [8,9,10]. In addition to genetic alterations, autoantibodies to complement proteins can cause or contribute to diseases via binding to their target, which in turn may impair the function of the respective proteins and result in pathological complement activation [12,13,14]
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