Rick Kapur

Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-related fatalities and, to date, is without available therapies. Here, we investigated the role of the complement system in TRALI. Murine anti–major histocompatibility complex class I antibodies were used in TRALI mouse models, in combination with analyses of plasma samples from patients with TRALI. We found that in vitro complement activation was related to in vivo antibody-mediated TRALI induction, which was correlated with increased macrophage trafficking from the lungs to the blood in a fragment crystallizable region (Fc)-dependent manner and that this was dependent on C5. Human immunoglobulin G 1 variants of the murine TRALI-inducing antibody 34-1-2S, either unable to activate complement and/or bind to Fcγ receptors (FcγRs), revealed an essential role for the complement system, but not for FcγRs, in the onset of 34-1-2S–mediated TRALI in mice. In addition, we found high levels of complement activation in the plasma of patients with TRALI (n = 53), which correlated with elevated neutrophil extracellular trap (NET) markers. In vitro we found that NETs could be formed in a murine, 2-hit model, mimicking TRALI with lipopolysaccharide and C5a stimulation. Collectively, this reveals a critical role of Fc-mediated complement activation in TRALI, with a direct relation to macrophage trafficking from the lungs to the blood and an association with NET formation, suggesting that targeting the complement system may be an attractive therapeutic approach for combating TRALI.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by an isolated thrombocytopenia. The pathophysiology is complex but involves platelet‐autoantibodies and/or cytotoxic T cells, with the spleen playing an important regulatory role. Accessory spleen (AcS) may possibly contribute to ITP relapse following splenectomy; however, the microenvironment of AcS has not been directly compared to the main spleen. Pizzi et al. conducted a histological study of adult ITP patients where they compared eight matched AcS to main spleens, and they observed a similar immunological composition in both groups. This supports the possibility of AcS‐mediated ITP relapse post splenectomy. Commentary on: Pizzi et al. Accessory spleens recapitulate the immune microenvironment of the main spleen in immune thrombocytopenia. Br J Haematol 2023;202:147–152.