Department of Clinical and Experimental Oncology, Hematology and Hemotherapy Discipline, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
Faculty of Medicine of Marília, FAMEMA, São Paulo, Brazil.
Transfusion. 2021 May;61(5):1617-1630. doi: 10.1111/trf.16313. Epub 2021 Mar 5.
Antigens from the Rh and Kell systems are recognized as the most immunogenic in clinical practice. This study evaluated the possible molecular mechanisms involved in the interaction of antigenic peptides with the DRB1 molecules, which help to explain the high frequency of anti-K and association of D + C antibodies in transfusion and incompatible pregnancy.
We included 201 patients with antibodies against antigens from the Rh and Kell systems and compare them with 174,015 controls. HLA-DRB1 genotyping and in silico analysis were performed. The NetMHCIIpan software was used to identify RhD-, RhCE-, and KEL-derived anchor peptides that bind to DRB1 molecules.
HLA-DRB115 is associated with an increased risk of D, C, E, and K alloimmunization, while the HLA-DRB101 and 12 alleles are overrepresented in patients with anti-C and anti-D, respectively. In silico analysis showed that three polymorphic points (60I, 68S, and 103S) common to C and D antigens can be presented by several DRB1 molecules, including DRB115:01. The DRB1*09:01 molecule, although not showing statistical significance, was able to interact strongly with almost all five anchor peptides from the sequence containing the polymorphic determinants of E antigen, except 217-WMFWPSVNS-225.
The DRB1*15 molecule has specific physicochemical characteristics in residues 11P and 13R in the P4 pocket that can favor the response to various antigenic peptides. Anti-K alloimmunization is unrestricted for interaction with specific DRB1 molecules, which suggests that almost all individuals in our population have DRB1 molecules capable of binding to KEL-derived anchor peptides and produce anti-K when stimulated.
Rh 和 Kell 系统的抗原在临床实践中被认为是最具免疫原性的。本研究评估了与抗原肽与 DRB1 分子相互作用相关的可能分子机制，这有助于解释抗-K 抗体的高频率和在输血和不相容妊娠中的 D+C 抗体的关联。
我们纳入了 201 名针对 Rh 和 Kell 系统抗原的抗体患者，并与 174015 名对照进行比较。进行了 HLA-DRB1 基因分型和计算机分析。使用 NetMHCIIpan 软件鉴定与 DRB1 分子结合的 RhD、RhCE 和 KEL 衍生锚肽。
HLA-DRB115 与 D、C、E 和 K 同种免疫的风险增加相关，而 HLA-DRB101 和 12 等位基因在分别具有抗-C 和抗-D 的患者中过度表达。计算机分析表明，C 和 D 抗原的三个多态性点（60I、68S 和 103S）可由几种 DRB1 分子呈现，包括 DRB115:01。尽管 DRB1*09:01 分子没有显示统计学意义，但它能够与包含 E 抗原多态决定簇的序列中的几乎所有五个锚肽强烈相互作用，除了 217-WMFWPSVNS-225。
DRB1*15 分子在 P4 口袋的 11P 和 13R 残基上具有特定的物理化学特性，这可以促进对各种抗原肽的反应。抗-K 同种免疫不受与特定 DRB1 分子相互作用的限制，这表明我们人群中的几乎所有个体都具有能够结合 KEL 衍生锚肽的 DRB1 分子，并在受到刺激时产生抗-K。
