Transfusion of target antigens to preimmunized recipients: a new mechanism in transfusion-related acute lung injury

Abstract

Transfusion-related lung injury (TRALI) is a serious side effect of blood transfusion. Exclusion of antibody carriers from the donor pool has significantly decreased the number of cases, but TRALI remains the leading cause of transfusion-related morbidity and mortality in industrialized countries. Here, we show that proteins released from donor cells during processing of blood components are capable of inducing a new type of reverse TRALI when transfused to preimmunized recipients. First, we show that soluble neutrophil surface protein CD177 in complex with proteinase 3 (sCD177/PR3) is not only present in human plasma but also in packed red blood cell (PRBC) supernatant. Filtration or storage enhances the concentration of sCD177/PR3 in PRBCs. Second, we show that sCD177/PR3 specifically binds to PECAM-1 on stimulated (but not on unstimulated) endothelial cells (ECs). Third, we provide evidence that the sCD177/PR3/PECAM-1 complex is functional. In the presence of monoclonal or human antibodies against CD177 or PR3, ECs produce reactive oxygen species and become apoptotic. Albumin flux through an EC monolayer increases significantly whenever antibodies and the cognate antigens are present. Finally, we describe a clinical case in which anti-CD177 present in a transfusion recipient precipitated TRALI after the transfusion of CD177-positive, but not CD177-negative, PRBCs. In conclusion, we introduce a new TRALI mechanism based on the specific binding of transfused, soluble antigens to activated ECs in preimmunized recipients. We suggest that further studies and clinical work-up of TRALI should also include antibody investigation of the recipient.

The CD177 c.1291A Allele Leads to a Loss of Membrane Expression and Mimics a CD177-Null Phenotype

“…This suggests that the protein encoded by CD177 c.1291A still binds to PR3. It has been demonstrated that both proteins interact in their soluble form in vitro and it was speculated that CD177 may function as a protective agent that down-regulates the enzymatic activity of PR3 [ 7 , 13 ]. Although the conclusion of co-localisation of PR3 with CD177 c.1291A was based on a comparison of co-localisation of wildtype CD177 with PR3 (as a known fact), given the limitations of the fluorescence microscopy technique for inferring comparable co-localisation of CD177 c.1291 A with wild-type CD177, alternative techniques such as surface plasmon resonance analysis of PR3 as a ligand for immobilised CD177 c.1291A or wildtype are required to support this conclusion.…”

“…We have previously shown that transfused CD177/PR3 complexes present in blood components may become adsorbed to PECAM-1 on activated endothelial cells. Here, they can trigger endothelial barrier dysfunction and transfusion-related acute lung injury TRALI in anti-HNA-2 antibody carriers [ 13 ]. We are currently unable to state whether variant CD177/PR3 is also able to interact with PECAM-1, but data obtained in the study presented here have not brought evidence that would argue against it.…”

The transfusion-associated dyspnea prospective observation and laboratory assessment study: a protocol for investigating and disambiguating cardiopulmonary and high-grade febrile transfusion reactions in adults

“…[29][30][31][32][33][34] However, seronegative cases exist, "transfused ARDS" counts increase despite mitigation, and reverse TRALI is described. [35][36][37][38][39][40][41][42][43] TRALI may also have a "too-sick" or "not-sick-enough" underrecognition bias, with consideration dismissed despite heightened vulnerability in the already-critically ill on the one hand, and constraints upon serologic examinations on the other, be this due to less serious or convincing cases, costs, and/or hidden tensions on retaining high-value/performance donors. seronegative ones.…”

Neutrophil-Specific Antigens: Immunobiology, Genetics and Roles in Clinical Disorders

“…PECAM-1 on pre-activated endothelial cells absorbs soluble CD177/PR3 complex from plasma. Binding of CD177 isoantibodies to the absorbed CD177/PR3 complex on endothelial cells, induced endothelial barrier dysfunction implicated in the mechanism of anti-CD177 mediated reverse TRALI [74]. In severe cases of COVID-19 infections, progressive respiratory failure results from immunothrombosis that is driven by activated neutrophils and platelets.…”