Complement regulator CD59 prevents peripheral organ injury in rats made seropositive for neuromyelitis optica immunoglobulin G

Xiaoming Yao,Alan S Verkman

doi:10.1186/s40478-017-0462-4

Xiaoming Yao, Alan S Verkman

Open Access

https://doi.org/10.1186/s40478-017-0462-4

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Abstract

Pathogenesis in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (herein called NMO) involves complement-dependent cytotoxicity initiated by AQP4-IgG binding to astrocyte AQP4. We recently reported that rats lacking complement inhibitor protein CD59 were highly susceptible to development of NMO pathology in brain and spinal cord following direct AQP4-IgG administration (Yao and Verkman, Acta Neuropath Commun 2017, 5:15). Here, we report evidence that CD59 is responsible for protection of peripheral, AQP4-expressing tissues in seropositive NMO. Rats made seropositive by intraperitoneal injection of AQP4-IgG developed marked weakness by 24 h and died soon thereafter. Serum creatine phosphokinase at 24 h was >900-fold greater in seropositive CD59−/− rats than in seropositive CD59+/+ (or control) rats. AQP4-expressing cells in skeletal muscle and kidney, but not in stomach, of seropositive CD59−/− rats showed injury with deposition of AQP4-IgG and activated complement C5b-9, and inflammation. Organ injury in seropositive CD59−/− rats was prevented by a complement inhibitor. Significant pathological changes in seropositive CD59−/− rats were not seen in optic nerve, spinal cord or brain, including circumventricular tissue. These results implicate a major protective role of CD59 outside of the central nervous system in seropositive NMO, and hence offer an explanation as to why peripheral, AQP4-expressing cells are largely unaffected in NMO.

Highlights

Complement-mediated cytotoxicity plays a central role in the pathogenesis of seropositive neuromyelitis optica spectrum disorders, in which immunoglobulin G autoantibodies against water channel aquaporin-4 (AQP4), called AQP4-IgG, bind to astrocytes in brain, spinal cord and optic nerve [9, 10]
Some peripheral organs outside of the central nervous system, including skeletal muscle, kidney and stomach [8, 19], these organs are rarely affected in NMO, with only a few reports of NMO-associated myositis associated with elevated creatine phosphokinase and skeletal muscle pathology [7, 13, 27]
We report here marked injury to skeletal muscle following systemic AQP4-IgG administration to CD59−/− rats, offering an explanation for the sparing of peripheral organs in seropositive NMO

Summary

Introduction

Complement-mediated cytotoxicity plays a central role in the pathogenesis of seropositive neuromyelitis optica spectrum disorders ( called NMO), in which immunoglobulin G autoantibodies against water channel aquaporin-4 (AQP4), called AQP4-IgG, bind to astrocytes in brain, spinal cord and optic nerve [9, 10]. Though AQP4 is expressed in some peripheral organs outside of the central nervous system, including skeletal muscle, kidney and stomach [8, 19], these organs are rarely affected in NMO, with only a few reports of NMO-associated myositis associated with elevated creatine phosphokinase and skeletal muscle pathology [7, 13, 27]. It has been unclear why peripheral AQP4-expressing cells, which are exposed to high levels of circulating AQP4-IgG in seropositive NMO, are largely spared. Rodents administered AQP4-IgG systemically do not spontaneously develop pathological changes in the central nervous system or in peripheral organs, though pathology in

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