It is clear that the HLA antigen system more than any other genetic marker is associated with disease susceptibility.5 That system contains many closely linked loci that control several immunologic functions, in which determination of cell-surface molecules, immune response differences, and possibly other functions of cell-cell regulation are included.19 The abundant polymorphism of HLA antigen systems, which is genetically inherited by children from their parents, also led us to seek association between preeclampsia and HLA antigen systems because a genetic background in preeclampsia has been reported.20,21
Earlier studies that used serologic methods found significant differences in the distribution of HLA-A, -B, -C, and -DR antigens between preeclamptic women and control subjects.6,7
A molecular biologic procedure was developed recently for determining types of HLA antigens more precisely, especially HLA class II antigens. The association between antigen systems and preeclamptic patients also was investigated. Wilton et al8,9 reported an absence of association between the maternal HLA-DRB genes and preeclampsia or eclampsia. We recently reported the association between HLA-DRB1 genotype and preeclampsia, using PCR-RFLP.10
Autoimmune factors such as antiphospholipid antibodies or lupus anticoagulants are believed to be generative factors in recurrent miscarriages22,23 and preeclampsia.11–13 Investigations using genotyping methods found that women who had recurrent miscarriages and were positive for antiphospholipid antibodies had significantly more frequent HLA class II alleles.14,15
We found that patients with severe preeclampsia, who were positive for antiphospholipid antibodies had an HLA-DRB1 genotype association, whereas patients who were negative for antiphospholipid antibodies had no association.10 Thus, it is possible that women with preeclampsia who are positive for antiphospholipid antibodies have different immunogenetic backgrounds than women who are negative for antiphospholipid antibodies. Consequently, we excluded women who were positive for antiphospholipid antibodies from the current study.
The frequency of DQB1*04 in our subjects was significantly higher compared with that of the control group, indicating that the HLA-DQB1*04 allele might be involved in preeclampsia. A recent investigation showed the critical influence of specific HLA-DQ polymorphisms in establishing the nature of bound antigens, thereby influencing the potential immune repertoire.24
Various authors have reported a possible effect of predominance of Th1 over Th2 in the T cell repertoire, in the genesis of diversity in reproductive failures.25,26 Tumor necrosis factor-α, one of the Th1-type cytokines, is now believed to influence the pathogenesis of preeclampsia.4,27 Kilpatrick3 reported that HLA and tumor necrosis factor genes are closely related in women with it.
Aberrations in immune mechanisms, such as predominance of Th1 against Th2 repertoire, followed by increased production of tumor necrosis factor α, could be important in the genesis of preeclampsia in women with HLA-DQB1*04. Examination of amino acid residues from the DQB1 alleles has shown that glutamic acid at position 70 and aspartic acid at position 71 are specific to the DQB1*04 allele,28 the frequency of which was higher in our preeclamptic subjects. Those amino acid residues are on an alpha helix sheet at the bottom of the antigen binding groove, and a specially processed epitope on a foreign or self-triggered antigen might have specific, unusual affinity for the DQB1 molecule with DQB1*04 specificities, leading to generation of aberrant immune reactions in preeclamptic women.
The number of subjects analyzed in this study was insufficient, and it is necessary to increase the sample size in further investigations. Details of the association of the HLA-DQB1*04 allele and preeclampsia remain unknown, and further investigations into frequency of HLA antigen alleles in connection with immune response genes are warranted to associate antigen systems and preeclamptic women.
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