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      MICB Genomic Variant Is Associated with NKG2D-mediated Acute Lung Injury and Death.

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          Abstract

          Rationale: Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. Objectives: To investigate the association of a common missense variant, MICBG406A, with ALI. Methods: We assessed MICBG406A genotypes within two multicenter observational study cohorts at risk for ALI: primary graft dysfunction (N = 619) and acute respiratory distress syndrome (N = 1,376). Variant protein functional effects were determined in cultured and ex vivo human samples. Measurements and Main Results: Recipients of MICBG406A-homozygous allografts had an 11.1% absolute risk reduction (95% confidence interval [CI], 3.2-19.4%) for severe primary graft dysfunction after lung transplantation and reduced risk for allograft failure (hazard ratio, 0.36; 95% CI, 0.13-0.98). In participants with sepsis, we observed 39% reduced odds of moderately or severely impaired oxygenation among MICBG406A-homozygous individuals (95% CI, 0.43-0.86). BAL NK cells were less frequent and less mature in participants with MICBG406A. Expression of missense variant protein MICBD136N in cultured cells resulted in reduced surface MICB and reduced NKG2D ligation relative to wild-type MICB. Coculture of variant MICBD136N cells with NK cells resulted in less NKG2D activation and less susceptibility to NK cell killing relative to the wild-type cells. Conclusions: These data support a role for MICB signaling through the NKG2D receptor in mediating ALI, suggesting a novel therapeutic approach.

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          Author and article information

          Journal
          Am J Respir Crit Care Med
          American journal of respiratory and critical care medicine
          American Thoracic Society
          1535-4970
          1073-449X
          Jan 01 2024
          : 209
          : 1
          Affiliations
          [1 ] Department Microbiology and Immunology.
          [2 ] Parker Institute for Cancer Immunotherapy.
          [3 ] Department Medicine and.
          [4 ] Department Medicine.
          [5 ] Cardiovascular Research Institute, and.
          [6 ] Department of Surgery, University of California San Francisco, San Francisco, California.
          [7 ] Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
          [8 ] Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania; and.
          [9 ] San Francisco Veterans Affairs Medical Center, San Francisco, California.
          Article
          10.1164/rccm.202303-0472OC
          10870895
          37878820
          1e788262-cfda-4a86-90e4-cb7b49a5ea8d
          History

          acute respiratory distress syndrome,acute lung injury,primary graft dysfunction,NK cells

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