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Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n05,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket. This may help explain the differential pattern Electronic supplementary material The online version of this article

The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5,KIR2DS3S5 and KIR2DS3S5,KIR2DL1, and telomeric KIR3DL1,KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.

Donor-directed human leukocyte antigen (HLA)-specific allo-antibodies (DSAs) cause graft failure in animal models of hematopoietic stem cell transplantation (HCT). Archived pretransplantation sera from graft failure patients (n ‫؍‬ 37) and a matched case-control cohort (n ‫؍‬ 78) were tested to evaluate the role of DSAs in unrelated donor HCT. Controls were matched for disease, disease status, graft type, patient age, and transplantation year.

Aim: TEDDY is an international program seeking to identify possible environmental triggers of T1D in genetically susceptible newborns, using HLA genotyping of cord blood or blood spots. Individuals with high and moderate risk genotypes for DRB1, DQA1, and DQB1 are considered "Eligible" for follow-up testing and monitored closely longitudinally for possible environmental exposures and the development of autoantibodies against islet cell autoantigens (GAD-65, Insulin, and IA-2) and subsequent diabetes.

BACKGROUND: Allogeneic hematopoietic stem cell transplants from unrelated donors are routinely used in the treatment of patients with hematologic malignancies. These cellular products are often collected off-site and require transport from the collection site to transplantation centers. However, the effects of transport conditions and media on stem cell graft composition during short-term storage have not been well described. STUDY DESIGN AND METHODS: Five bone marrow (BM), four filgrastim-mobilized peripheral blood stem cell (PBSC), and four nonmobilized peripheral blood mononuclear cell (PBMNC) products were collected from healthy volunteer donors and stored at 4 or 20°C for up to 72 hours in 10% PlasmaLyte A plus anticoagulants such as 10% acid citrate dextran-A (ACD-A) and/or 10 IU/mL heparin. Products were evaluated at 0, 24, 48, and 72 hours for cellular content, viability, and metabolic activities. RESULTS: BM products maintained equivalent cell viability when stored at either 4 or 20°C over 72 hours, but cell viability was better maintained for PBSC products stored at 4°C. The mean viable CD34+ cell recovery for PBSC and BM products stored over 72 hours at 4°C was higher than 75%. Significantly lower CD34+ cell and colony-forming unit recoveries were seen in PBSC products but not BM products stored at room temperature. Faster lactic acid accumulation was observed in PBMNC and PBSC products stored without ACD-A. CONCLUSIONS: Seventy-two-hour storage of BM, PBSC, and PBMNC products at refrigerated temperature maintains optimal cell viability and recovery. Anticoagulation with ACD-A is preferred over heparin to reduce lactic acid accumulation in the product media. ABBREVIATIONS: 7-AAD = 7-aminoactinomycin D; BM = bone marrow; CFU-GEMM = colony-forming units-granulocyteserythroid-macrophage-megakaryocyte; PA = PlasmaLyte A plus ACD-A; PH = PlasmaLyte A plus heparin; PHA = PlasmaLyte A plus heparin plus ACD-A; PBSC(s) = peripheral blood stem cell(s); TNC = total nucleated cell count.

a new DRB1 allele and 5 novel DQB1 alleles. Comparison of legacy and NGS data revealed 38 (0.78%) discordant DRB1 allele assignments, including 9 legacy data transcription errors, 8 legacy discordant alleles, and 21 of false homozygosity in the NGS results. At DQB1 the 283 (5.8%) discordant alleles included 4 legacy transcription errors, 24 legacy miscalls with exon 2 disparity and 208 legacy disparities involving exon 3 (not tested in legacy). NGS results exhibited 7 allele miscalls, 16 ''script'' errors involving exon 3 polymorphism, and 4 ''rule set'' errors in failure to detect DQB1*05:04.

and Purkinje cell pathology that are very similar to those seen in SCA1 patients. Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles in Purkinje cells seem to originate as large invaginations of the outer cell membrane. The cytoplasmic vacuoles contained proteins from the somatodendritic membrane, including mGluR1, GluR⌬1/⌬2, GluR2/3, and protein kinase C (PKC) ␥. Further examination of PKC␥ revealed that its sequestration into cytoplasmic vacuoles was accompanied by concurrent loss of PKC␥ localization at the Purkinje cell dendritic membrane and decreased detection of PKC␥ by Western blot analysis. In addition, the vacuoles were immunoreactive for components of the ubiquitin/proteasome degradative pathway. These findings present a link between vacuole formation and loss of dendrites in Purkinje cells of SCA1 mice and indicate that altered somatodendritic membrane trafficking and loss of proteins including PKC␥, are a part of the neuronal dysfunction in SCA1 transgenic mice.