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.
Highlights
Coagulation factor XIII (FXIII) is a plasma pro-transglutaminase consisting of two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B)
The distribution of autoimmune FXIII deficiency was not significantly different in different areas of Japan; two cases were identified in the Gunma prefecture (S1 and S2 Tables)
Among polymorphisms with significantly higher frequencies in autoimmune FXIII deficiency cases, we found that five polymorphisms, human leukocyte antigen (HLA)-B, MICA, BTNL2, HLA-DQB1, and HLA-DPB1, tended to increase levels of anti-FXIII-A autoantibodies measured using immunochromatographic test (ICT) as the number of variant alleles increased (Fig 2B, Tables 5 and S9)
Summary
Coagulation factor XIII (FXIII) is a plasma pro-transglutaminase consisting of two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). It plays an important role in maintaining hemostasis by cross-linking and stabilizing fibrin clots and increasing the resistance to mechanical stress and fibrinolysis [1,2]. About half of the autoimmune FXIII deficiency cases are idiopathic in nature, while the other half are associated with underlying diseases [4]; all of them occur as a result of the spontaneous production of autoantibodies against endogenous FXIII. Autoimmune FXIII deficiency is characterized by a sudden onset of bleeding, which is often life-threatening, in patients with no history of bleeding, without either prolonged prothrombin time or prolonged activated partial thromboplastin time
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