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New research out in @JClinicalInvest! Critical roles for endothelial antigen and complement in a model of antibody-mediated lung injury + imaging of #ARDS lung pathology initiation #InMice @UCSF @immunox. Free access: https://jci.me/138136/pdf Summary below: 1/
Anti-HLA/MHC antibodies cause injury in transfusion reactions (TRALI) and transplant rejection. These ‘anti-leukocyte’ antibodies actually bind many cell types – movie shows pattern of anti-MHC I binding in mouse lungs after i.v. injection. 2/
The 1st gene knocked out in mice was B2m. No B2m -> v. little surface MHC class I. New mouse strains allowed us to selectively remove/restore MHC I on different cell types 
Creators: B2mfl/fl: @CraigMorrell5 & @ZackHiltXC49 @UR_Med, B2minv/inv: Zimring lab @uvamedicine. 3/
Creators: B2mfl/fl: @CraigMorrell5 & @ZackHiltXC49 @UR_Med, B2minv/inv: Zimring lab @uvamedicine. 3/
Removal of MHC I from endothelial cells protected against anti-MHC I-induced lung vascular permeability, restoring MHC I exclusively on endothelium restored susceptibility. So antibody binding endothelium -> lung injury! 4/
Depleting complement with cobra venom factor 
prevented anti-MHC I-induced lung vascular permeability, and also lung platelet retention & release of neutrophil extracellular traps. Movies show these processes captured in lungs. 5/
prevented anti-MHC I-induced lung vascular permeability, and also lung platelet retention & release of neutrophil extracellular traps. Movies show these processes captured in lungs. 5/
Is this relevant to human disease? Human pulmonary endothelium has high HLA class I expression, & plasma of people who developed TRALI tended to have elevated complement C4d post-transfusion... 6/
...antibodies can activate complement on endothelium of transplanted lungs, & increase risk of chronic allograft dysfunction/death (data: @UCSF lung transplant program incl. Danny Calabrese, @jrgreenland, see also: research from @ReedLabUCLA). 7/
…and (of course) #COVID19 – COVID-19 involves ARDS, endothelial inflammation, complement activation, pulmonary thrombosis, NET release & sometimes autoantibodies. Perhaps COVID-19 thrombotic microangiopathy and other complications have similar origins. 8/
Check out exciting recent #COVID19-relevant papers from:
@hskulkarni – role of complement
@EricVivier1 – C5aR1 blockade
@jasonsknight – release of NETs
@BREATH_Hannover – thrombosis & endothelialitis
& @andymoz78 – C5a-induced impairment in killing bacteria 9/
@hskulkarni – role of complement
@EricVivier1 – C5aR1 blockade
@jasonsknight – release of NETs
@BREATH_Hannover – thrombosis & endothelialitis
& @andymoz78 – C5a-induced impairment in killing bacteria 9/
