IL-1β–dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction

Abstract

Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1β–mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.

B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling

“…However, the presence of alloantigens may predispose to C4d deposition in grafts (8). While we showed that these early graft-infiltrating B cells are not instrumental in secreting LRAs (43), whether they produce alloantibodies responsible for complement deposition and antibody-mediated rejection is unclear and warrants further investigation.…”

Hexamerization: explaining the original sin of IgG-mediated complement activation in acute lung injury

“…Although antibody-mediated lung damage is a major contributing factor in transfusion-related acute lung injury (TRALI) ( 9 ), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome) ( 10 ), as well as primary graft dysfunction (PGD) occurring after lung transplantation ( 11 ), the mechanism by which antigen-antibody complexes activate the complement system to induce lung damage remains unclear. A theory that has increasingly gained traction involves the formation of IgG hexamers from IgG1 and IgG3 antibodies on antigenic surfaces by Fc-domain interactions that result in complement activation and increased deposition on these target surfaces ( 2 , 12 ).…”

Intestinal microbiota links to allograft stability after lung transplantation: a prospective cohort study

“…In addition, the Bacteroides uniformis was negatively associated with IL-1β and IL-12, which indicated that the gut microbiome is involved in allograft diseases possibly via modulating host immune responses in lung transplant. 24,25 Alternation of fecal metagenome correlates with serum metabolites Next, we asked which environmental factors explain the levels of the altered gut microbiome. Serum metabolites are known to play a key role in mediating the metabolic and immune interactions between the microbiome and its host, thus providing a fundamental view into the complex dynamics of environmental exposures.…”