Dectin-1 genetic deficiency predicts chronic lung allograft dysfunction and death
Daniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, John R. Greenland
Daniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, John R. Greenland
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Clinical Research and Public Health Immunology Transplantation

Dectin-1 genetic deficiency predicts chronic lung allograft dysfunction and death

Abstract

BACKGROUND Innate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients.METHODS We assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multicenter Lung Transplant Outcomes Group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed.RESULTS Y238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in bronchoalveolar lavage (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared with wild-type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0–1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0–2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1–3.8) and in the LTOG cohort (HR 1.3, CI 1.1–1.6), compared with wild-type CLEC7A subjects.CONCLUSION Increased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition.FUNDING The UCSF Nina Ireland Program for Lung Health Innovative Grant program, the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.

Authors

Daniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, John R. Greenland

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Figure 3

Decreased dectin-1 expression on monocytes from Y238X AC individuals.

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Decreased dectin-1 expression on monocytes from Y238X AC individuals. Fo...
Following 4 hours of stimulation with control media or zymosan, monocytes were assessed by immunophenotyping those from CLEC7A variants (AC, n = 8) and wild-type CLEC7A (AA, n = 8). (A) Monocytes were defined by forward scatter, side scatter, size, viability, and staining for CD14 and HLA-DR. (B) Surface dectin-1 receptors were measured on monocytes by MFI. Box-and-whisker plots show dectin-1 and HLA-DR monocyte surface expression, with boxes defining the 25th and 75th percentile of data, bisecting line depicting the median value, and whiskers capturing minimum and maximum values. (C) In control media, surface dectin-1 receptor MFI was increased on wild-type monocytes (AA) relative to Y238X variants (AC, P = 0.006). Following zymosan stimulation, this difference was maintained between AA and AC genotypes (P = 0.05). There was no difference in dectin-1 receptor MFI on wild-type or variant-genotype monocytes in control media or following stimulation. (D) HLA-DR MFI was also measured. There was significantly decreased HLA-DR MFI on CLEC7A-variant monocytes (AC) compared with wild-type monocytes (AA, P = 0.03) in control media. The HLA-DR MFI decreased on AA-genotype monocytes (P = 0.01) but not on AC-genotype monocytes following stimulation. Compared to wild-type CLEC7A genotypes, there was no difference in HLA-DR MFI on Y238X variant-genotype monocytes following zymosan stimulation. Differences were assessed using 2-tailed Student’s t test and the experiment was conducted twice.