Japanese Collaborative Research Group on Autoimmune Coagulation Factor Deficiencies (JCRG supported by the Japanese Ministry of Health, Labor and Welfare), Yamagata, Japan.
Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan.
PLoS One. 2021 Sep 10;16(9):e0257322. doi: 10.1371/journal.pone.0257322. eCollection 2021.
Autoimmune coagulation factor XIII deficiency is a bleeding disorder caused by the formation of autoantibodies against the coagulation factor XIII (FXIII); however, the molecular mechanism underlying this process is unknown. Therefore, in the present study, we aimed to elucidate this mechanism by performing whole-exome sequencing analysis of 20 cases of autoimmune FXIII deficiency. We identified approximately 21,788-23,916 variants in each case. In addition to their ability to activate T cells, present antigens, and immune tolerance, the candidate alleles were further narrowed down according to their allelic frequencies and the magnitude of damage caused by the substitution of amino acids. After selecting 44 candidate alleles, we investigated whether they were associated with the FXIII inhibitory titers and/or the anti-FXIII autoantibodies. We found that two polymorphisms whose variant allele frequencies were significantly lower in the patients tended to decrease FXIII inhibitory titers as the number of variant alleles increased. We also found that five polymorphisms whose variant allele frequencies were significantly higher in the patients tended to increase the levels of the anti-FXIII autoantibodies as the number of variant alleles increased. All of these polymorphisms were found in the human leukocyte antigen (HLA) class I and II molecules and their associated genes. In particular, the HLA class II molecule and its associated genes were found to be involved in the presentation of foreign antigens as well as the negative regulation of the proliferation of T-cells and the release of cytokines. Polymorphisms in the HLA class II molecules and the cytotoxic T lymphocyte antigen 4 have been reported to be associated with the development of autoantibodies in acquired hemophilia A. Therefore, we hypothesized that these polymorphisms may be associated with the development of autoantibodies in autoimmune FXIII deficiency.
自身免疫性凝血因子 XIII 缺乏症是一种由针对凝血因子 XIII (FXIII) 的自身抗体形成引起的出血性疾病；然而，这一过程的分子机制尚不清楚。因此，在本研究中，我们通过对 20 例自身免疫性 FXIII 缺乏症患者进行全外显子组测序分析，旨在阐明这一机制。我们在每个病例中鉴定出大约 21788-23916 个变体。除了它们能够激活 T 细胞、现有抗原和免疫耐受外，候选等位基因还根据它们的等位基因频率和氨基酸取代引起的损伤程度进一步缩小范围。在选择了 44 个候选等位基因后，我们研究了它们是否与 FXIII 抑制滴度和/或抗 FXIII 自身抗体有关。我们发现，两个在患者中变异等位基因频率显著较低的多态性倾向于随着变异等位基因数量的增加而降低 FXIII 抑制滴度。我们还发现，五个在患者中变异等位基因频率显著较高的多态性倾向于随着变异等位基因数量的增加而增加抗 FXIII 自身抗体的水平。所有这些多态性都存在于人类白细胞抗原（HLA）I 类和 II 类分子及其相关基因中。特别是，HLA II 类分子及其相关基因被发现参与了外来抗原的呈递以及 T 细胞的增殖和细胞因子释放的负调节。HLA II 类分子和细胞毒性 T 淋巴细胞抗原 4 的多态性已被报道与获得性血友病 A 中自身抗体的发展有关。因此，我们假设这些多态性可能与自身免疫性 FXIII 缺乏症中自身抗体的发展有关。
