Year: 2023
Type: article
Study design: Observational Study
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.
Authors: Oscar A. Aguilar, Anita E. Qualls, Maria D. R. Gonzalez-Hinojosa, Sarah Obeidalla, V. Eric Kerchberger, Tasha Tsao, Jonathan P. Singer, Mark R. Looney, Wilfred Raymond, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Ciara M. Shaver, Lorraine B. Ware, Jason Christie, Joshua M. Diamond, Lewis L. Lanier, John R. Greenland, Daniel R. Calabrese
Institutions: University of California, San Francisco, Parker Institute for Cancer Immunotherapy, Vanderbilt University Medical Center, Cardiovascular Institute Hospital, University of California San Francisco Medical Center, Vanderbilt University, University of Pennsylvania, San Francisco VA Medical Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, Cancer Research Institute, Cystic Fibrosis Foundation, American Thoracic Society, Office of Research and Development, Biomedical Laboratory Research and Development, VA Office of Research and Development, Parker Institute for Cancer Immunotherapy, National Institutes of Health, Genentech, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1338247870, G1668201262, Frailty and patient centered outcomes in candidates for lung transplantation, NK Memory, Mechanisms of airspace inflammation caused by cell-free hemoglobin during ARDS, G3145721550, G331810742, BD FACSAria Fusion Cell Sorter, G5360101567, G5708188481, Haptoglobin 2 variant and endothelial glycocalyx shedding in sepsis-induced ARDS, Genetics of primary graft dysfunction, G6677021859, Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction, Innate Immune Mechanisms of Primary Graft Dysfunction after Lung Transplantation, G7098737504, G7179566437, Clinical Risk Factors for Primary Graft Dysfunction, G8105834585, G8512603748, G8680220733, Diabetes Research Center, Mechanisms and pathogenicity of SARS-CoV-2-induced neutrophil extracellular traps, Tissue-specific functional genomics in the acute respiratory distress syndrome, Long Term Follow up of the Lung Transplant Outcomes Group Cohort, Immunobiology of the normal and injured lung, Peri-operative factors that drive cell-free hemoglobin-mediated primary graft dysfunction, Mechanisms of organ dysfunction and recovery in the Acetaminophen and Ascorbate Trial in Sepsis
OpenAlex ID: W4387949696