Thyroid autoimmunity and recurrent miscarriage

Citation Ticconi C, Giuliani E, Veglia M, Pietropolli A, Piccione E, Di Simone N. Thyroid autoimmunity and recurrent miscarriage. Am J Reprod Immunol 2011; 66: 452–459 Problem To investigate the role of antithyroid autoantibodies (ATA) in recurrent miscarriage (RM). Methods In this case‐control study, a total of 160 women with RM and 100 healthy women were investigated for the presence of serum ATA directed against thyreoglobulin (TG‐Ab), thyroid peroxidase (TPO‐Ab) and TSH receptor (TSHr‐Ab), which were determined by either chemiluminescence or radioimmunoassay. Results Antithyroid autoantibodies were detected in 46 (28.75%) women with RM and in 13 (13%) women of the control group (P < 0.05). The frequencies for TG‐Ab and TPO‐Ab were higher in RM than in control women. Among the women of RM group, 91.3% of ATA+ women were positive also for other autoantibodies. The majority of study women were euthyroid. Conclusions Antithyroid autoantibodies, particularly TG‐Ab, are associated with RM and could be an expression of a more general maternal immune system abnormality leading to RM. ATA could have a role in RM irrespective of thyroid hormone status.     

Embryo loss pattern is predominant in miscarriages with normal chromosome karyotype among women with repeated miscarriage

OBJECTIVE: The aim of this study was to assess pregnancy loss patterns in women with repeated miscarriage (RM), according to fetal chromosome karyotypes and aetiologies of RM. METHODS: In this cohort study, 168 fetal chromosome karyotypes of miscarriages were investigated. The pregnancy loss patterns were compared between 75 miscarriages from RM women who had a history of two or more consecutive miscarriages and 93 miscarriages from control women whose previous pregnancies ended in live births without a history of RM. By serial ultrasonography, embryo loss (EL) was defined as miscarriage before fetal heat movement was identified and fetal loss (FL) as miscarriage after fetal heat movement was identified. The EL rate was calculated as EL/(EL+FL). RESULTS: The EL rate (66.7%) in miscarriages with normal karyotypes among RM women (n=42) was higher (P<0.05) than that (45.7%) in controls (n=46), while the EL rate (30.3%) in miscarriages with abnormal karyotypes among RM women (n=33) did not differ from that (25.5%) in the controls (n=47). The EL rate (71.4%) in miscarriages with normal karyotypes among unexplained RM women (n=21) was much higher (P<0.05) than that in the controls. CONCLUSIONS: By evaluating fetal karyotypes, we demonstrated for the first time that EL was predominant in miscarriages with normal karyotype among RM women.     

The Presence of Antithyroid Antibodies in Euthyroid Patients With Unexplained Infertility and Tubal Obstruction

PROBLEM: The presence of antithyroid antibodies in euthyroid patients with unexplained infertility and tubal obstruction. METHOD: The presence of antithyroid autoantibodies (microsomal and thyroglobulin) was measured in 40 patients with unexplained infertility, and 40 patients with tubal obstruction infertility, and compared to 40 healthy nulligravidae. RESULTS: Eight patients (20%) in the unexplained infertility study group, seven (17.5%) in the tubal obstruction group and two (5%) in the healthy nulligravida group, were positive for antithyroid autoantibodies: five (12.5%) were positive for antimicrosomal antibodies, two (5%) were positive for antithyroglobulin antibodies, and one patient (2.5%) was positive for both. The tubal obstruction group comprised seven (17.5%) patients positive for antithyroid autoantibodies: four (10%) for antimicrosomal antibodies, two (5%) for antithyroglobulin antibodies, and one patient (2.5%) was positive for both. In the healthy nulligravidae group only two patients (5%) were positive for antithyroid antibodies: one for antimicrosomal and one for antithyroglobulin. No significant differences were found in the presence of antithyroid antibodies between patients with unexplained infertility and those with tubal obstruction infertility. Both groups differed significantly from the healthy controls with regard to the presence of antithyroid antibodies (P < 0.05). CONCLUSION: Subclinical presence of antithyroid autoantibodies is characteristic of both unexplained and mechanical infertility, as opposed to healthy controls. Further investigation of larger groups is needed to determine the prevalence of antithyroid antibodies in the unique population of infertile women.     

Autoantibodies and prediction of reproductive failure

PROBLEM: To determine which autoantibodies are associated with reproductive failure. METHOD OF STUDY: Sera from 269 patients with autoimmune disease and/or reproductive failure were analyzed for anti-phospholipid (aPL), anti-annexin-V, anti-lactoferrin, anti-thyroglobulin, anti-thyroid peroxidase, anti-prothrombin, anti-nuclear, and anti-saccharomycetes cerevisiae antibodies (ASCA), by enzyme-linked immunosorbent assay. Patients were classified as: recurrent pregnancy loss (RPL), infertility, and autoimmune diseases. The results were compared with those of 120 healthy volunteers. RESULTS: In autoimmune diseases, the prevalence of anti-prothrombin, anti-annexin, anti-phospholipid and anti-nuclear antibodies was significantly higher than in the control group, OR 11.0 [CI, 3.5-35.2], 33 [CI, 7.2-174.2], 13 [CI, 1.4-309.7], and 16.1 [CI 2.4-122], respectively. In infertility, the antibodies with significantly higher levels than controls were: aPL OR, 5.11 [CI 1.2-25.4], and anti-prothrombin antibodies, OR, 5.15 [CI, 2.1-12.7]. In RPL, ASCA, anti-prothrombin and aPL were more prevalent than in controls, OR 3.9 [CI, 1.5-10.6], 5.4 [CI, 2.4-12.5] and 4.8[CI, 1.2-22.2] for each antibody, respectively. Anti-prothrombin antibodies and aPL were more significantly associated with late pregnancy losses than early losses. CONCLUSION: ASCA antibodies have not previously been described in RPL. Nor are anti-prothrombin antibodies usually assessed in infertility or RPL. If these results are confirmed in further studies, these antibodies might be assessed routinely in reproductive failure.     

Pregnancy: Antiphospholipid antibodies and human reproductive failure

Routine screening for circulating antiphospholipid antibodies(aPL), namely the lupus anticoagulant (LA) and anticardiolipinantibodies (aCL), was carried out in a total of 1273 women aged<45 years. Of them, 822 were experimental subjects and 451were controls. The former comprised the following three studygroups: 498 infertile patients (group 1), 284 spontaneous recurrentaborters (group 2), and 40 patients with repeated failure ofembryo transfer (group 3). Controls included five groups ofwomen: 125 normal healthy women who had never been pregnant(group 4), 125 normal healthy parous women with no previousabortion (group 5), 52 women in labour after normal pregnanciesat term (group 6), 49 infertile patients achieving a livebirthwith their first in-vitro fertilization (IVF) and embryo transfer(group 7), and 100 female patients with systemic lupus erythematosus(positive controls, group 8). aPL positivity in the eight groupsstudied was as follows: 2.4, 9.2, 10, 0.8, 0, 0, 0 and 42% respectivelyfor groups 1 to 8. There were no differences within groups 1and 3 regarding incidence of aPL when patients were groupedaccording to infertility aetiological factors and indicationsfor IVF respectively. Twenty-six out of 284 recurrent aborters(9.2%) tested positive for aPL, and the LA and/or aCL were identifiedas the aetiological factor in 12% of patients (24/199) withsupposedly unexplained recurrent abortion. Incidence of positivesera for aPL in group 1 was similar to that observed in controlgroups 4, 5 and 6. On the contrary, incidence of aPL positivityin groups 2 and 3 was significantly higher than in control groups4, 5 and 6 and among infertile women (group 1). The differencebetween groups 3 and 7 almost reached statistical significance.Interestingly, there was no difference between groups 2 and3, but groups 2 and 7 resulted probably different regardingincidence of aPL positive sera. As expected, the highest incidenceof patients testing positive for aPL was found in group 8. Seveninfertile patients having circulating aPL and becoming pregnantspontaneously or after specific infertility treatment, successfullycarried to term in spite of the fact that they did not receiveimmunotherapy. Among recurrent aborters, the live-born babyrate was significantly higher after treatment with low-doseaspirin than prior therapy. It is concluded that the presenceof circulating aPL may be associated with recurrent abortionbut not with infertility. In addition, our results favour apossible role of aPL hi failure of implantation after IVF andembryo transfer.     

14th International Congress on Antiphospholipid Antibodies Task Force Report on Obstetric Antiphospholipid Syndrome

Pregnancy morbidity is one of the clinical manifestations used for classification criteria of antiphospholipid syndrome (APS). During the 14th International Congress on Antiphospholipid Antibodies (aPL), a Task Force with internationally-known experts was created to carry out a critical appraisal of the literature available regarding the association of aPL with obstetric manifestations present in actual classification criteria (recurrent early miscarriage, fetal death, preeclampsia and placental insufficiency) and the quality of the evidence that treatment(s) provide benefit in terms of avoiding recurrent adverse obstetric outcomes. The association of infertility with aPL and the effectiveness of the treatment of patients with infertility and positive aPL was also investigated. This report presents current knowledge and limitations of published studies regarding pregnancy morbidity, infertility and aPL, identifying areas that need better investigative efforts and proposing how critical flaws could be avoided in future studies, as suggested by participants of the Task Force. Except for fetal death, there are limitations in the quality of the data supporting the association of aPL with obstetric complications included in the current APS classification criteria. Recommended treatments for all pregnancy morbidity associated to APS also lack well-designed studies to confirm its efficacy. APL does not seem to be associated with infertility and treatment does not improve the outcomes in infertile patients with aPL. In another section of the Task Force, Dr. Jane Salmon reviewed complement-mediated inflammation in reproductive failure in APS, considering new therapeutic targets to obstetric APS (Ob APS).     

Impact of the sex of first child on the prognosis in secondary recurrent miscarriage

BACKGROUND: The carriage of a male fetus often initiates maternal immunological reactions against male-specific minor histocompatibility (HY) antigens, which, in theory, could result in subsequent recurrent miscarriage (RM). METHODS: Information about subsequent pregnancy outcome was procured among 182 women with RM after a birth (secondary RM) referred since 1986 using questionnaires, telephone interviews and registers. RESULTS: Significantly more of the women had had a male first-born as compared with a female first-born (110 versus 72; P < 0.02). By January 2002, 58% of those who had a male first-born had given birth to a second live infant compared with 76% of those who previously had had a female first-born (P = 0.01). Women in the former group had a significantly lower chance of having a second child than those in the latter (adjusted hazard ratio 0.59; 95% confidence interval 0.41-0.86). The number of miscarriages after admission and the risk of secondary infertility were significantly greater in women with a male first-born than among those with a female first-born (P < 0.001 and P = 0.02; respectively). CONCLUSIONS: A male first-born seems to be associated with a less favourable reproductive potential among women with secondary RM. Maternal immunization against HY antigens may be responsible for these findings.     

Obstetric antiphospholipid syndrome: A recent classification for an old defined disorder

Obstetric antiphospholipid syndrome (APS) is now being recognized as a distinct entity from vascular APS. Pregnancy morbidity includes > 3 consecutive and spontaneous early miscarriages before 10 weeks of gestation; at least one unexplained fetal death after the 10th week of gestation of a morphologically normal fetus; a premature birth before the 34th week of gestation of a normal neonate due to eclampsia or severe pre-eclampsia or placental insufficiency. It is not well understood how antiphospholipid antibodies (aPLs), beyond their diagnostic and prognostic role, contribute to pregnancy manifestations. Indeed aPL-mediated thrombotic events cannot explain the obstetric manifestations and additional pathogenic mechanisms, such as a placental aPL mediated complement activation and a direct effect of aPLs on placental development, have been reported. Still debated is the possible association between aPLs and infertility and the effect of maternal autoantibodies on non-vascular manifestations in the babies. Combination of low dose aspirin and unfractionated or low molecular weight heparin is the effective treatment in most of the cases. However, pregnancy complications, in spite of this therapy, can occur in up to 20% of the patients. Novel alternative therapies able to abrogate the aPL pathogenic action either by interfering with aPL binding at the placental level or by inhibiting the aPL-mediated detrimental effect are under active investigation.     

HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis

ProblemThe aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM).Method of studyA systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated.ResultsWe included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05–1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15–2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20–1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45–0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31–0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11–1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10–1.25) were both associated with the occurrence of RM.ConclusionAlthough the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully.     

Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes.

The autoimmune attack in type 1 diabetes is not only targeted to beta cells. We assessed the prevalence of thyroid peroxidase (aTPO), parietal cell (PCA), antiadrenal (AAA) and endomysial antibodies (EmA-IgA), and of overt autoimmune disease in type 1 diabetes, in relation to gender, age, duration of disease, age at onset, beta-cell antibody status (ICA, GADA, IA2A) and HLA-DQ type. Sera from 399 type 1 diabetic patients (M/F: 188/211; mean age: 26 +/- 16 years; duration: 9 +/- 8 years) were tested for ICA, PCA, AAA and EmA-IgA by indirect immunofluorescence, and for IA2A (tyrosine phosphatase antibodies), GADA (glutamic acid decarboxylase-65 antibodies) and aTPO by radiobinding assays. The prevalence rates were: GADA 70%; IA2A, 44%; ICA, 39%; aTPO, 22%; PCA, 18%; EmA-IgA, 2%; and AAA, 1%. aTPO status was determined by female gender (beta = - 1.15, P = 0.002), age (beta = 0.02, P = 0.01) and GADA + (beta = 1.06, P = 0.02), but not by HLA-DQ type or IA2A status. Dysthyroidism (P < 0.0001) was more frequent in aTPO + subjects. PCA status was determined by age (beta = 0.03, P = 0.002). We also observed an association between PCA + and GADA + (OR = 1.9, P = 0.049), aTPO + (OR = 1.9, P = 0.04) and HLA DQA1*0501-DQB1*0301 status (OR = 2.4, P = 0.045). Iron deficiency anaemia (OR = 3.0, P = 0.003) and pernicious anaemia (OR = 40, P < 0.0001) were more frequent in PCA + subjects. EmA-IgA + was linked to HLA DQA1*0501-DQB1*0201 + (OR = 7.5, P = 0.039), and coeliac disease was found in three patients. No patient had Addison's disease. In conclusion, GADA but not IA2A indicate the presence of thyrogastric autoimmunity in type 1 diabetes. aTPO have a female preponderance, PCA are weakly associated with HLA DQA1*0501-DQB1*0301 and EmA-IgA + with HLA DQA1*0501-DQB1*0201.     

Antinuclear autoantibodies, complement level, hypergammaglobulinemia and spontaneous intrauterine hematoma in pregnant women

PROBLEM: To examine the associative relationship among autoantibodies, C4 levels and intrauterine hematomas (IUH) in more detail than in the studies published earlier. METHOD OF STUDY: We performed a retrospective study of 54 women with poor obstetric outcomes. Sera were screened for antinuclear antibodies (ANA), anti-DNA antibodies, antiphospholipid antibodies (aPL), and antithyroid antibodies. C4-complement and gammaglobulin levels were also monitored. We compared the main variables in IUH complicated pregnancy group with the risk pregnancy group without IUH. We also compared these variables in the IUH cases before and during IUH. RESULTS: Eight IUH were detected. The average number of spontaneous losses for these eight women was 3.3 +/- 2.1 (range: 1-8). aPL was present in 100% of cases. ANAs and hypergammaglobulinemia were present in 50% of cases and low C4 in 87.5% of cases. After comparing these variables apart from C4 before and during IUH, we found no statistical differences. However, C4 was low in four patients before IUH and in seven patients during IUH (OR: 7.0; 95% CI: 0.57-86.33). When we compared autoantibodies apart from lupus anticoagulant (LAC) between the two groups, no differences were observed. However, seven of the eight (87.5%) patients with IUH were LAC positive whereas only 24 of the 46 patients (52.1%) were positive in the non-IUH group (OR: 6.42; 95% CI: 0.73-56.41). Rapid plasma reagin was present in 8/46 in the non-IUH group (16.7%) and 5/8 in the IUH group (62.5%) P < 0.015). CONCLUSIONS: In women with poor obstetric histories, autoantibodies, especially antiphospholid antibodies, may play a role in the IUH development especially if low C4 and/or hypergammaglobulinemia are present.     

Prevalence of autoantibodies in patients with recurrent miscarriages

PROBLEM: It is well known that the prevalence of several autoantibodies is higher in patients with recurrent miscarriages than in normal women. However, links between individual autoantibodies are unclear. The present study focuses on the possible association between beta 2-glycoprotein I (beta 2-GPI)-dependent anticardiolipin antibody (aCL), lupus anticoagulant (LA), and antinuclear antibody (ANA) in patients with recurrent miscarriages. METHOD OF STUDY: Three hundred and one patients, with a history of two or more unexplained miscarriages, were studied. The titers of beta 2-GPI-dependent aCL and LA were then compared between single-antibody-positive and three-antibody-positive groups. RESULTS: The prevalences of beta 2-GPI-dependent aCL, LA, and ANA were 3.3, 10.0, and 25.2%, respectively. Four of the 301 patients had all three antibodies. The LA titers in patients with positive values for three antibodies was significantly higher than in cases with only LA. CONCLUSION: beta 2-GPI-dependent aCL, LA, and ANA define three distinct, but partly related populations in patients with recurrent miscarriage. We should test at least two kinds of autoantibodies in recurrent aborters, because it has been found that, e.g., beta 2-GPI-dependent aCL and LA are predictors for miscarriages.     

Anti-Phospholipid Antibodies And Infertility

Antiphospholipid syndrome (APS) or the presence of antiphospholipid antibodies (aPL), usually presents as pregnancy loss. However, aPL have also been reported to affect implantation, placentation, and early embryonic development. The binding of aPl to β2GP1 may lead to breakdown of the phospholipid adhesion molecules between different elements of trophoblast. As aPL affect placental growth and function, aPl may prevent implantation presenting as infertility. Lupus anticoagulant and anticardiolipin antibody have been implicated in the prothrombotic effects of APS. Antibodies to other phospholipids such as anti-phosphatidylserine, phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl Inositol etc. may be more relevant in infertility. Their role remains to be clarified. There is theoretical evidence from animal models and clinical infertility practice that aPL has a role in infertility. However, a large-scale meta-analysis has failed to confirm the association. To determine whether infertility or even pregnancy loss is associated with aPL, it is necessary to know that the embryo is chromosomally normal. Pregestational diagnosis has shown that up to 60% of embryos may be chromosomally aneuploid in failed in vitro fertilization (IVF); hence, may confound our understanding concerning the association between aPL and infertility, failed IVF or even pregnancy loss.     

Circulating cell-derived microparticles in women with pregnancy loss

Citation
Alijotas‐Reig J, Palacio‐Garcia C, Farran‐Codina I, Zarzoso C, Cabero‐Roura L, Vilardell‐Tarres M. Circulating cell‐derived microparticles in women with pregnancy loss. Am J Reprod Immunol 2011; 66: 199–208 Problem To analyze cell‐derived microparticles (cMP) in pregnancy loss (PL), both recurrent miscarriages (RM) and unexplained fetal loss (UFL). Method of study Non‐matched case–control study was performed at Vall d’Hebron Hospital. Cell‐derived microparticles of 53 PL cases, 30 with RM, 16 with UFL, and 7 (RM + UFL), were compared to 38 healthy pregnant women. Twenty healthy non‐pregnant women act as controls. Cell‐derived microparticles were analyzed through flow cytometry. Results are given as total annexin (A5+), endothelial‐(CD144+/CD31+ CD41?), platelet‐(CD41+), leukocyte‐(CD45+) and CD41? c‐MP/μL of plasma. Antiphospholipid antibodies (aPLA) were analyzed according to established methods. Results Comparing PL versus healthy pregnant, we observed a significant endothelial cMP decrease in PL. When comparing RM subgroup with controls, we observed significant decreases in endothelial cMP. When comparing the PL positive for aPLA versus PL‐aPLA‐negative, no cMP numbering differences were seen. Conclusion Pregnancy loss seems to be related to endothelial cell activation and/or consumption. A relationship between aPLA and cMP could not be demonstrated.     

An association of IgG anti-laminin-1 autoantibodies with endometriosis in infertile patients

BACKGROUND: Laminin-1, a multifunctional glycoprotein of the basement membrane, is thought to be important in embryogenesis, embryonic implantation, and placentation. We recently showed that serum IgG anti-laminin-1 autoantibodies (auto-Abs) are associated with recurrent first-trimester miscarriages. The present study assessed the clinical significance of anti-laminin-1 Abs with infertility, accompanied with or without endometriosis. METHODS: Sixty-eight infertile patients who underwent laparoscopy or laparotomy and 39 healthy non-pregnant women were tested for IgG anti-laminin-1 Abs. The association between the Abs and endometriosis was analysed. The presence of laminin-1 mRNA was detected in endometriotic lesions. RESULTS: Twenty infertile patients were positive for anti-laminin-1 Abs. The Ab levels in those patients were significantly higher than those in healthy non-pregnant women (P = 0.0005). The presence of the Abs was significantly associated with endometriosis in those patients (P = 0.0096). The Abs recognized a particular domain, i.e., the laminin-alpha1 chain G domain. mRNA encoding laminin-alpha1, -beta1, and -gamma1 chains was expressed in 90% of endometriotic lesions. CONCLUSIONS: IgG anti-laminin-1 Abs were significantly associated with endometriosis in infertile patients. The Abs might be clinically important in the development of autoimmune-mediated reproductive failures and the assessment of the Abs may provide a novel non-invasive diagnosis of endometriosis.     

High NK cell activity in recurrent miscarriage: what are we really measuring?

BACKGROUND: Several studies have shown that women with unexplained recurrent miscarriage (RM) have increased numbers and activity of peripheral blood NK cells and that elevated levels of these cells predict subsequent miscarriages in women with RM. Because catecholamines rapidly mobilize NK cells into the circulation, such increases may not reflect a steady state of overactive immunity but may result from a transient increase in the number of NK cells because of the stress associated with blood withdrawal. METHODS: Blood was drawn from 22 controls and 38 RM patients immediately after vein cannulation, and again 20 min later. The percentage of NK cells within lymphocytes, their concentration per microlitre of blood and their activity were assessed. RESULTS: All three indices of NK cells did not change in the controls across the two samples. However, women with RM had elevated levels in all three NK indices in the first blood sample, but these levels declined to values similar to those seen in the controls. This decline was mainly observed in primary aborters whose NK activity was highest in the first blood withdrawal. Accordingly, there was a high correlation between the magnitude of the decline and the initial NK cell indices in women with RM. The change in activity highly correlated with the change in the concentration of NK cells. CONCLUSION: The increased NK number and activity previously observed in RM patients may result from a transient stress response at the time of blood withdrawal. Patients with primary RM may be characterized by exaggerated acute stress responses in other circumstances.     

Serum CD40/CD40L system in Graves' disease and Hashimoto's thyroiditis related to soluble Fas, FasL and humoral markers of autoimmune response

Activated CD4 T cells' express CD40 ligand (CD154) interacting with CD40 on the B cells surface, protecting them from Fas-mediated apoptosis and in this study, influence humoral response. The aim of the study was to assess soluble CD40 and CD154 in Graves' disease (GD) and Hashimoto's thyroiditis (HT) in relation to Fas and FasL and to the markers of humoral response: aTPO, aTG and aTSHR. The study was carried out in 5 groups of subjects: 1/14 patients with GD in euthyreosis on methimazol (euGD), 2/20 patients with hyperthyroid GD (hrGD), 3/15 patients with HT in euthyreosis on levothyroxine (euHT), 4/16 patients with hypothyroid Ht (hoHT), 5/12 healthy volunteers, age and sex-matched to groups 1-4. The serum levels of CD40, CD154, Fas and FasL, aTPO and aTG were determined by ELISA and aTSHR was determined by the RIA method. CD40 serum concentration was significantly higher in hoHT individuals: 55.8 (24.0-83.2) pg/ml (p<0.01) and euHT patients: 51.2 (20.0-80.1) (p<0.05) as compared to the controls. Also sCD40L values were significantly increased in euHT individuals: 5.1 (1.0-11.8) (p<0.05) and hoHT patients: 3.9 (0.7-11.2) ng/ml (p<0.05) as compared to the controls. There was a positive correlation between sCD40 and sCD154 in the patients studied (r=0.36, p<0.001). In HT patients we found positive correlations between sCD40 and aTPO (r=0.45, p<0.001) and sFas (r=0.36, p<0.05) as well as a negative correlation between sCD40 and FasL (r=-0.24, p<0.05). In GD patients there was a positive correlation between sCD40 and aTSHR (r=0.28, p<0.05). In summary, our results suggest that CD40/CD154 interaction plays an important role in the regulation of autoimmune humoral response, both in Hashimoto's thyroiditis and Graves' disease. Fas-mediated apoptosis seems to be involved in this process especially in Hashimoto thyroiditis. Soluble CD40 may serve as a marker of the active stage of autoimmune thyroid disease.     

The association of anti-phospholipid antibodies with parity in placental malaria

Anti-phospholipid antibodies (aPL) are autoantibodies associated with both infections and the pathogenesis of certain pregnancy complications. In the latter, but not the former, aPL are dependent on a co-factor, beta(2) glycoprotein I (beta2GPI), which can also be used as an antigen for detection of such aPL in pregnancy. A cross-sectional study was carried out on serum samples from Kumasi, Ghana, to determine the occurrence and beta2GPI-dependence of aPL in placental malaria. Anti-cardiolipin, anti-phosphatidylserine and anti-beta2GPI enzyme-linked immunosorbent assays (ELISAs) were performed on sera from 103 HIV-non-infected gravid women. Placental malaria, both active and past infection, was diagnosed in 33/103 (32%) based on placental histology. In multiparae, beta2GPI-independent IgM antibodies to cardiolipin (P = 0.018) and phosphatidylserine (P = 0.009) were observed, which were most pronounced in past placental malaria infection. In primiparae, no association emerged between aPL and placental malaria. Trends for improved clinical parameters were identified in infected women with levels of anti-cardiolipin beyond the 99th multiple of the median for a healthy, non-malarious population. This study in placental malaria reports parity associations of beta2GPI-independent aPL profiles, and does not support a role for beta2GPI-dependent aPL. It is of significance in the context of the known parity differences in pregnancy malaria immunity.     

Unexplained recurrent miscarriage: how can we explain it?

Unexplained recurrent miscarriage (RM) can be a challenging and frustrating condition for both patients and clinicians. For the former, there is no diagnosis available for consolation, while for the latter there is little evidence-based treatment to offer. However, the majority of these patients have an excellent prognosis without the need for any treatment. Epidemiological associations suggest that the reason for this is that the majority of women with unexplained RM are in fact healthy individuals, with no underlying pathology, who have suffered three miscarriages purely by chance. Nevertheless, a certain proportion of women with unexplained RM will continue to miscarry, and preliminary studies suggest the presence of pathology in some women of this group. As a result, two types of unexplained RM can be described: Type I unexplained RM, which occurs by chance in women who have no underlying pathology and has a good prognosis; and Type II unexplained RM, which occurs due to an underlying pathology that is currently not yet identified by routine clinical investigations and has a poorer prognosis. Distinguishing between Types I and II unexplained RM can be achieved by considering several factors: the age of the woman, the definition used for RM (i.e. whether biochemical pregnancy losses are considered as miscarriages), the number of previous miscarriages suffered and the karyotype of the products of conception, where available. A better understanding of the two types of unexplained RM could lead to more targeted referrals, investigations and treatments, which would improve cost-effectiveness and overall clinical care.