| 1. |
- Abi-Rached, Laurent, et al.
(författare)
-
The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans
- 2011
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 334:6052, s. 89-94
-
Tidskriftsartikel (refereegranskat)abstract
- Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.
|
|
| 2. |
- Petersdorf, Effie W., et al.
(författare)
-
Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation : a retrospective cohort study
- 2020
-
Ingår i: The Lancet Haematology. - : ELSEVIER SCI LTD. - 2352-3026. ; 7:1, s. E50-E60
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT.Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, japan, North America, and the UK between jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50.3%) HLA-matched and 1457 (4.3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors.Findings: Between jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1.89, 95% CI 1. 53-2.33; p<0.0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1.73, 1.02-2.94; p=0 .042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1.98, 1.39-2.81; p=0.0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1836 939 [91.6%]) of the 2004742 US registry donors have the TT or MT genotype.Interpretation: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials.
|
|
