A combination of the HLA-DRB1*03 phenotype and low plasma mannose-binding lectin predisposes to autoantibody formation in women with recurrent pregnancy loss

Abstract

IntroductionIt is documented that a series of autoantibodies can be detected with increased frequency in women with recurrent pregnancy loss (RPL) and they may impact the pregnancy prognosis negatively. It is unknown whether the autoantibodies per se or the basic immune disturbances underlying autoantibody production, are the reason for this association. Our group has previously found that some genetically determined immunological biomarkers are associated with RPL and the same biomarkers are also in various degrees known to predispose to autoantibody production. The aim of this study was to clarify whether the RPL-associated immunogenetic biomarkers are associated with positivity for three major classes of autoantibodies associated with RPL.MethodsIn 663 patients with RPL in whom we had results for HLA-DRB1 typing and plasma mannose-binding lectin (p-MBL) measurement, it was investigated whether there is a correlation between positivity for the autoantibodies: anticardiolipin antibodies, β2 glycoprotein I antibodies, and lupus anticoagulant (jointly called antiphospholipid antibodies), thyroid-peroxidase antibodies, and antinuclear antibodies and each of the HLA-DRB1 alleles HLA-DRB1*03 or HLA-DRB1*07 either alone or in combination with low p-MBL defined as ≤500 µg/l.ResultsAlthough slightly higher frequencies of positivity of two or more autoantibodies were seen in patients with either p-MBL ≤500 µg/l or being positive for HLA-DRB1*03, none were significantly associated. However, in patients with the combination of low p-MBL and HLA-DRB1*03, presence of at least one autoantibody was significantly more frequent than in patients with no such combination (OR= 2.4; 95% CI 1.2-5.0, p = 0.01). In an analysis of which autoantibodies were most strongly associated with the low p-MBL/HLA-DRB1*03 combination, antinuclear antibodies were significantly more frequent in these patients (OR 2.0; 95% CI 1.0-3.9, p=0.05) whereas the other autoantibodies were also positively but more weakly associated with this combination.DiscussionIn conclusion, to clarify the pathogenetic background, underlying immunogenetic factors should be examined in autoantibody positive RPL patients (as well as other patients with autoimmune diseases) but the genetic background may be complex.

Maternal HLA class II alleles and haplotypes associated with altered risk of recurrent pregnancy loss: A case‐control study

“…The positive ( DRB1*04:01:01 and DRB1*08:01:01 ) and negative ( DRB1*07:01:01, DPB1*04:01:01; DPB1*14:01:01 ) class II alleles association with RPL suggest an at‐risk, or protective aspect to these alleles, respectively. This was in evident disagreement with studies on Brazilian, 47 Danish, 37,48 Japanese, 49 Kazakh, 40 and South Indian 25 women, which demonstrated the association of other DRB1 alleles with an increased risk of RPL, namely, DRB1*03:01:01 , and DRB1*07/*07 40,48 . This was further exemplified by the association of DRB1*03:01 with increased risk of RPL with a high risk of RPL in the (Central Asian) Kazakh subjects, 40 but not (Middle Eastern] Lebanese 5 or South European 33 populations.…”

“…These findings were in line with findings on Lebanese 5 and Japanese 31 women with RPL but in disagreement with the findings of a French study which reported no link between DPB1 alleles and RPL. 54 These apparently inconsistent and conflicting find- of the production of target-specific antibodies, 37,51,57 and imbalance of proinflammatory-anti-inflammatory cytokine expression and activity.…”

“…Mounting evidence connected HLA class II genes with the pathogenesis of pregnancy complications, including polycystic ovary syndrome, 21 preeclampsia, 28,29,36 and RPL. 5,30,33,37 Recent data report that HLA class II antigens are essential to the presentation of antigenic fragments and autoimmunity, and RPL is linked with an imbalance of proinflammatory and anti-inflammatory immune mechanisms. 1,38,39 This case-control report is the first to assess the association of spe- to the risk of RPL in distinct populations.…”

“…The identification of shared, and unique, HLA class II alleles and haplotypes linked with altered risk of RPPL in Tunisian women further supports the role of HLA class II alleles, and consequently altered immunological mechanisms, in the pathogenesis of RPL. The exact mechanism by which specific HLA alleles and haplotypes alter disease risk, including RPL, is largely unknown, and several hypotheses were postulated, ranging from altered immunoreactive‐immunosuppressive cellular activity, 33,56 stimulation of the production of target‐specific antibodies, 37,51,57 and imbalance of proinflammatory‐anti‐inflammatory cytokine expression and activity.…”

Recurrent Pregnancy Loss: immunological risk factors and immunomodulatory treatments

“…In contrast, no difference between groups was found for the prevalence of the HLA-DRB1*07 phenotype, which suggests that these are not immunogenetic susceptibly markers for RPL. Thus, no immunogenetic susceptibility to RPL and only a weak immunogenetic susceptibility to autoimmunity in RPL patients could be found, and this may indicate that nongenetic factors play a more dominant role in RPL pathogenesis [4].…”