COVID-19における抗リン脂質抗体の重要性

重症なCOVID-19患者では血栓形成が促進しており、重症化と関連していることが知られています。またこのような患者で抗リン脂質抗体（aPL抗体, anti-phospholipid antibodies）が出現する頻度が高く、抗リン脂質抗体症候群と共通した病態が存在するのではないかとされていました。この論文で著者らは入院COVID-19患者において８種類の抗リン脂質抗体（aPL抗体, anti-phospholipid antibodies）の存在を検討し、52%の患者で少なくとも１つのaPL抗体が存在することを明らかにしました。aPL抗体の中ではaPS/PT IgGが24%と最も多く、aCL IgM 23%, aPS/PT IgM 18%の順でした。高いaPL抗体を有する患者では好中球の過活性化が生じており、感染制御や血栓形成に重要とされているneutrophil extracellular traps（NETs）形成が促進していました。また臨床的には血小板増加、重症肺炎、低eGFRと相関していました。高いaPL抗体を有する患者から得られたIgGはin vitroで好中球を活性化し、NETs形成を促進しました。またIgGをマウスに投与すると血栓形成を促進しました。これらの結果はCOVID-19患者では何らかの機序でaPL抗体産生が亢進しており、これが血栓産生および重症化と関連している可能性を示唆しています。

Zuo et al., Sci Transl Med. 2020 Nov 18;12(570):eabd3876. doi: 10.1126/scitranslmed.abd3876. Epub 2020 Nov 2.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19

Patients with severe COVID-19 are at high risk for occlusion of blood vessels of all sizes. This prothrombotic phenotype is reminiscent of patients with lupus and antiphospholipid syndrome, who have long-lived circulating antiphospholipid autoantibodies. In new work, Zuo et al. measured eight types of antiphospholipid antibodies in serum from patients hospitalized with COVID-19 and found at least one antibody in half of patients. Antibody levels were associated with neutrophil and coagulation pathway activation. Purified antibodies from some patients activated neutrophils in vitro and potentiated thrombosis when injected into mice. Together, these findings suggest that autoantibodies are a potential therapeutic target in severe COVID-19. Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19. Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti–β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19