Vallée Nicolas, Dugrenot Emmanuel, Desruelle Anne-Virginie, Richard Simone, Coupé Stéphane, Ramdani Céline, Guieu Régis, Risso Jean-Jacques, Gaillard Sandrine, Guerrero François
Institut de Recherche Biomédicale des Armées, Equipe de Recherche Subaquatique Opérationnelle, Toulon, France.
Université de Brest Occidentale, ORPHY, IBSAM, Brest, France.
Front Physiol. 2023 Aug 17;14:1253856. doi: 10.3389/fphys.2023.1253856. eCollection 2023.
Decompression sickness (DCS) with neurological disorders includes an inappropriate inflammatory response which degenerates slowly, even after the disappearance of the bubbles. There is high inter-individual variability in terms of the occurrence of DCS that could have been mastered by the selection and then the breeding of DCS-resistant rats. We hypothesized the selection of single-nucleotide polymorphisms (SNPs) linked to autoimmunity operated upon a generation of a DCS-resistant strain of rats. We used the candidate gene approach and targeted SNPs linked to the signaling cascade that directly regulates inflammation of innate immunity transiting by the Toll-like receptors. Twenty candidate SNPs were investigated in 36 standard rats and 33 DCS-resistant rats. For the first time, we identify a diplotype (i.e., with matched haplotypes)-when coinherited-that strengthens protection against DCS, which is not strictly homozygous and suggests that a certain tolerance may be considered. We deduced an ideal haplotype of six variants from it (MyD88_50-T, _49-A, _97-C coupled to NFKB_85-T, _69-T, _45-T) linked to the resistant phenotype. Four among the six identified variants are located in pre- and/or post-transcriptional areas regulating MyD88 or NFKB1 expression. Because of missense mutations, the other two variants induce a structural change in the NFKB1 protein complex including one damage alteration according to the Missense3D algorithm. In addition to the MyD88/NFKB1 haplotype providing rats with a strong resistance to DCS, this also highlights the importance that the immune response, here linked to the genetic heritage, can have in the development of DCS and offer a new perspective for therapeutic strategies.
伴有神经功能障碍的减压病（DCS）包括一种不适当的炎症反应，这种反应会缓慢退化，即使在气泡消失后也是如此。DCS的发生存在高度个体差异，通过选择然后培育抗DCS大鼠有可能掌握这种差异。我们假设选择与自身免疫相关的单核苷酸多态性（SNP）可培育出抗DCS大鼠品系。我们采用候选基因方法，针对与通过Toll样受体直接调节先天免疫炎症的信号级联相关的SNP。在36只标准大鼠和33只抗DCS大鼠中研究了20个候选SNP。我们首次鉴定出一种双倍型（即具有匹配的单倍型），当共同遗传时，它能增强对DCS的保护作用，这种双倍型并非严格纯合，这表明可能存在某种耐受性。我们从中推导出一种与抗性表型相关的由六个变体组成的理想单倍型（MyD88_50 - T、_49 - A、_97 - C与NFKB_85 - T、_69 - T、_45 - T）。六个已鉴定变体中的四个位于调节MyD88或NFKB1表达的转录前和/或转录后区域。由于错义突变，另外两个变体导致NFKB1蛋白复合物发生结构变化，根据错义3D算法其中一个是损伤性改变。除了MyD88/NFKB1单倍型赋予大鼠对DCS的强大抗性外，这也突出了免疫反应（在此与遗传遗产相关）在DCS发展中可能具有的重要性，并为治疗策略提供了新的视角。
