Department of Biomedical Sciences, College of Health Sciences and Technology, Rochester Institute of Technology, Rochester, NY, USA.
Department of Medical Microbiology and Parasitology, Ladoke Akintola University of Technology, Osogbo, Nigeria.
Hum Immunol. 2019 Nov;80(11):930-936. doi: 10.1016/j.humimm.2019.08.005. Epub 2019 Aug 29.
Variable immune response to external stimuli remains a major concern in sickle cell disease (SCD), with such responses predicted to be contributors to disease pathogenesis. Elucidating the diversity of host genes contributing to immune response would assist to clarify differing outcomes among and between disease groups. We hypothesize that there is a significant interethnic diversity in the CD14 (rs2569190), CD28 (rs35593994), CTLA-4 (rs5742909) and ICOS (rs4404254) gene polymorphisms among and between SCD groups. We genotyped single nucleotide polymorphisms of the 4 loci among African and African American SCD and control groups and between SCD groups. In all, 375 individuals from Mali (145 SCD and 230 controls) and 700 DNA samples from the United States (321 SCD and 379 controls) were subjected to a PCR-RFLP assay. We found no intraethnic difference in genotypic and allelic frequencies of the 4 loci among Africans and African Americans, potentially significant in disease association studies, including a similar observation for interethnic frequencies of CD28, CTLA-4 and ICOS genes, but not CD14. The CD14 (rs2569190) gene promoter demonstrated a significant difference (p < 0.02) between African and African American SCD groups, with the mutant variant (-159 T/T) more frequent (p < 0.0002) in African American SCD (38.9% versus 26.2%). The higher frequency of CD14 mutants among African Americans without an accompanying defect in CD28, CTLA-4 and ICOS diversity possibly indicates a defective innate response, driven by CD14, is untethered to downstream T cell differentiation or effector function. Additionally, we show that CD28 (rs35593994) mutant variants have no impact on T cell differentiation, as the ICOS gene provides an alternative pathway to override this impairment. We conclude that in spite of the defect in CD14, T cell selection and differentiation is unimpeded and a robust adaptive immune response initiated.
对外部刺激的可变免疫反应仍然是镰状细胞病（SCD）的主要关注点，这种反应预计是疾病发病机制的促成因素。阐明宿主基因对免疫反应的多样性将有助于阐明疾病组之间和组内的不同结果。我们假设，在 SCD 组之间和组内，CD14（rs2569190）、CD28（rs35593994）、CTLA-4（rs5742909）和 ICOS（rs4404254）基因多态性存在显著的种族间多样性。我们对马里的非洲裔和非裔美国 SCD 和对照组以及 SCD 组之间的 4 个基因座的单核苷酸多态性进行了基因分型。共有来自马里的 375 名个体（145 名 SCD 和 230 名对照组）和来自美国的 700 个 DNA 样本（321 名 SCD 和 379 名对照组）接受了 PCR-RFLP 检测。我们发现，在非洲裔和非裔美国人中，4 个基因座的基因型和等位基因频率在种族内没有差异，这在疾病关联研究中可能具有重要意义，包括对 CD28、CTLA-4 和 ICOS 基因的种族间频率的类似观察，但 CD14 除外。CD14（rs2569190）基因启动子在非洲和非裔美国 SCD 组之间表现出显著差异（p<0.02），突变型（-159T/T）在非裔美国 SCD 中更为常见（p<0.0002）（38.9%对 26.2%）。在没有 CD28、CTLA-4 和 ICOS 多样性缺陷的情况下，非洲裔美国人中 CD14 突变体的更高频率可能表明，由 CD14 驱动的先天反应不受控制，无法与下游 T 细胞分化或效应功能相关联。此外，我们还表明，CD28（rs35593994）突变型变体对 T 细胞分化没有影响，因为 ICOS 基因提供了一种替代途径来克服这种缺陷。我们得出结论，尽管存在 CD14 缺陷，但 T 细胞选择和分化不受阻碍，并启动了强大的适应性免疫反应。
