Important roles of the human leukocyte antigen class I and II molecules and their associated genes in the autoimmune coagulation factor XIII deficiency via whole-exome sequencing analysis.
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| Abstract |
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.
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| Authors | Tsukasa Osaki, Masayoshi Souri, Akitada Ichinose |
| Journal | PloS one (PLoS One) Vol. 16 Issue 9 Pg. e0257322 ( 2021) ISSN: 1932-6203 [Electronic] United States |
| PMID | 34506591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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