Faculty Bibliography

OBJECTIVE: To analyze the structure, specificity, and in vivo pathogenetic potential of 2 human anticardiolipin (aCL) monoclonal antibodies (MAb). METHODS: Human aCL IgG MAb were generated from hybridized Epstein-Barr virus-induced B cell lines from a healthy subject (MAb 519) and from a patient with primary antiphospholipid syndrome (MAb 516). Studies of antigen-binding specificity and analysis of Ig V-gene mutations were carried out. The MAb were independently injected into mated female BALB/c mice, and their effect on pregnancy outcome was compared with that of MAb 57, a highly mutated and antigen-selected human IgG1lambda rabies virus antibody. RESULTS: Both MAb 519 and MAb 516 utilized minimally mutated V(H)DJ(H) and VkappaJkappa gene segments and bound cardiolipin and other anionic phospholipids in the absence of beta2-glycoprotein I (beta2-GPI). The mice injected with aCL MAb displayed a significantly higher rate of fetal resorption and a significant reduction in fetal and placental weight as compared with those injected with MAb 57. These findings were accompanied by a finding of placental human IgG deposition and necrosis in the aCL MAb-treated animals. CONCLUSION: The results of this study indicate that human aCL IgG that are beta2-GPI independent can induce pathology

Internal gestation of a genetically foreign conceptus challenges the maternal host to circumvent immunological processes that recognize and eliminate nonself molecules. Accordingly, human viviparity involves a wide range of immunological modifications. This review examines the relationship between pregnancy and several autoimmune diseases prevalent in women. Pregnancy is associated with improvement in the clinical signs and symptoms of rheumatoid arthritis in more than 70% of patients. Maternal-fetal disparity in alleles of HLA-DRbeta1, DQalpha, and DQbeta has been reported to be associated with pregnancies characterized by remission or improvement. These observations suggest that presentation of fetal DQalpha peptides might correct autoimmunity in patients with RA either by induction of maternal-regulatory T cells, or by affecting the maternal T cell receptor repertoire. In contrast, the course of systemic lupus erythematosus is more variable. Whether flare rates increase during or after pregnancy is unsettled, since individual patient series vary in the characteristics of patients accepted for study and in definitions of flare. Despite a high overall flare rate in some series approaching 60%, recorded flares were usually not severe. Only limited data are available regarding the incidence or outcome for either the mother with scleroderma or her fetus. The extent of diffuse skin disease and systemic involvement, particularly pulmonary, cardiac and renal, may be more important than the duration of the disease; limited disease carries a better prognosis for the mother and fetus. Highly specific autoantibody profiles in the mother (independent of whether she has a clinical disease) are associated with fetal demise and neonatal lupus syndromes, the most serious manifestation of which is isolated congenital heart block. The former is associated with antiphospholipid antibodies and the latter with antibodies directed against SSA/Ro and SSB/La polypeptides

Given the female preponderance of systemic lupus erythematosus (SLE) in humans, the adverse effects of female gender and sex hormones in murine lupus, and numerous reports (retrospective, often anecdotal and uncontrolled) describing a temporal association between estrogen exposure and development or exacerbation of SLE, it is easy to accept that estrogens and SLE simply do not mix. While there are valid concerns regarding the use of exogenous estrogens in women with SLE, there are also potential health benefits to be considered. Several salutary effects of postmenopausal estrogens assume particular importance in SLE where the risks of osteoporosis, exaggerated by menopause (natural or cyclophosphamide-induced) and glucocorticoids, are substantial. Moreover, hormone replacement therapy (HRT) is associated with a 40% reduction in the risk of coronary artery disease, higher levels of high-density lipoprotein-cholesterol, and decreased levels of low-density lipoprotein-cholesterol and plasminogen-activator inhibitor type 1, benefits that should be especially applicable to post-menopausal women with SLE. More recent studies, albeit retrospective and absent the use of validated measures of disease activity, suggest that HRT may be well tolerated. In counseling patients regarding lupus and pregnancy, there are now clinical predictors of pregnancy outcome, and patients in remission tend to have good outcomes. The same principles may be true regarding advice on the use of HRT; patients with inactive or stable/moderate disease and at low risk for thrombosis may benefit without a change in lupus activity. Large prospective double-blind placebo controlled studies inclusive of all ethnic groups such as the Safety of Estrogens in Lupus Erythematosus-National Assessment (SELENA) trial should provide the basis for definitive recommendations

We present a case of congenital complete heart block associated with maternal autoantibodies in which a normal labor and delivery could safely be allowed to proceed despite the absence of the usual tool of electronic fetal heart rate monitoring for fetal distress, by the technique of rupturing membranes and using a fetal scalp electrode electrocardiographic tracing to assess the fetal atrial rate