Complex Linkage Disequilibrium Effects in HLA-DPB1 Expression and Molecular Mismatch Analyses of Transplantation Outcomes.

BACKGROUND: HLA molecular mismatch (MM) is a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation. HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk. METHODS: One hundred three HLA-DP-mismatched solid organ transplantation pairs were retrospectively analyzed. MM was computed using amino acids (aa), eplets, and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or rs9277534-G (high-expression) linked. To determine the associations between risk factors and dnDSA, logistic regression, linkage disequilibrium (LD), and population-based analyses were performed. RESULTS: A high-risk AA:GX (recipient:donor) expression combination (X = A or G) demonstrated strong association with HLA-DP dnDSA (P = 0.001). MM was also associated with HLA-DP dnDSA when evaluated by itself (eplet P = 0.007, aa P = 0.003, Grantham P = 0.005, Epstein P = 0.004). When attempting to determine the relative individual effects of the risk factors in multivariable analysis, only AA:GX expression status retained a strong association (relative risk = 18.6, P = 0.007 with eplet; relative risk = 15.8, P = 0.02 with aa), while MM was no longer significant (eplet P = 0.56, aa P = 0.51). Importantly, these risk factors are correlated, due to LD between the expression-tagging single-nucleotide polymorphism and polymorphisms along HLA-DPB1. CONCLUSIONS: The MM and expression risk factors each appear to be strong predictors of HLA-DP dnDSA and to possess clinical utility; however, these two risk factors are closely correlated. These metrics may represent distinct ways of characterizing a common overlapping dnDSA risk profile, but they are not independent. Further, we demonstrate the importance and detailed implications of LD effects in dnDSA risk assessment and possibly transplantation overall.

LuxR- and luxI-type quorum-sensing circuits are prevalent in members of the Populus deltoides microbiome.

We are interested in the root microbiome of the fast-growing Eastern cottonwood tree, Populus deltoides. There is a large bank of bacterial isolates from P. deltoides, and there are 44 draft genomes of bacterial endophyte and rhizosphere isolates. As a first step in efforts to understand the roles of bacterial communication and plant-bacterial signaling in P. deltoides, we focused on the prevalence of acyl-homoserine lactone (AHL) quorum-sensing-signal production and reception in members of the P. deltoides microbiome. We screened 129 bacterial isolates for AHL production using a broad-spectrum bioassay that responds to many but not all AHLs, and we queried the available genome sequences of microbiome isolates for homologs of AHL synthase and receptor genes. AHL signal production was detected in 40% of 129 strains tested. Positive isolates included members of the Alpha-, Beta-, and Gammaproteobacteria. Members of the luxI family of AHL synthases were identified in 18 of 39 proteobacterial genomes, including genomes of some isolates that tested negative in the bioassay. Members of the luxR family of transcription factors, which includes AHL-responsive factors, were more abundant than luxI homologs. There were 72 in the 39 proteobacterial genomes. Some of the luxR homologs appear to be members of a subfamily of LuxRs that respond to as-yet-unknown plant signals rather than bacterial AHLs. Apparently, there is a substantial capacity for AHL cell-to-cell communication in proteobacteria of the P. deltoides microbiota, and there are also Proteobacteria with LuxR homologs of the type hypothesized to respond to plant signals or cues.