Prevalence of Agonistic Autoantibodies Against the Angiotensin II Type 1 Receptor and Soluble fms-Like Tyrosine Kinase 1 in a Gestational Age–Matched Case Study

Abstract

Abstract-We showed earlier that activating autoantibodies against the angiotensin II type 1 (AT 1 ) receptor (AT1-AA) circulate in preeclamptic women. They may be involved in the pathogenesis of preeclampsia. Protein alignment suggests that the binding site for AT1-AAs is highly homologous to the capsid protein VP2 of parvovirus B19. We performed a prospective, nested, case-control study of 30 gestational age-matched women with preeclampsia and 30 normotensive pregnant women. We measured AT1-AA, soluble fms-like tyrosine kinase 1 (sFlt-1), and serum immunoglobulin G against parvovirus B19 proteins. AT1-AAs were present in 70% of preeclamptic patients and absent in 80% of controls. Prediction by AT1-AA was improved in late-onset preeclampsia. The discrimination for sFlt-1 was 96%. We did not find an interaction between sFlt-1 and AT1-AA. A human monoclonal immunoglobulin G antibody against parvovirus B19 VP2-protein showed a positive reaction in the AT1-AA bioassay, which could be blocked by an AT 1 receptor blocker, as well as by the epitope amino acid sequence. Immunoglobulin G against parvovirus B19 proteins was similarly distributed between preeclamptic patients and controls and had no significant importance. We detected significantly more AT1-AA in women with an immune response corresponding with parvovirus B19 infection corresponding with a distant viral infection associated with virus elimination. We concluded that AT1-AAs were common in patients with preeclampsia in a prospective case-control study, although sFlt-1 was a superior biomarker. AT1-AA may represent a better marker for late disease, whereas sFlt1 is a better marker for early onset disease. Key Words: preeclampsia Ⅲ activating autoantibodies Ⅲ angiogenesis Ⅲ parvovirus B19 Ⅲ molecular mimicry P reeclampsia is defined as new-onset hypertension after 20 weeks' gestation accompanied by new-onset proteinuria; the condition causes acute morbidity and mortality. 1,2 The incidence is 2% to 5% worldwide and is associated with subsequent cardiovascular diseases in both mother and child. 3 The pathogenesis is unknown but is likely to be multifactorial. 4 We described circulating autoantibodies directed at the second extracellular loop of the angiotensin (Ang) II type 1 (AT 1 ) receptor (AT1-AA) in women with preeclampsia. 5 AT1-AAs induce reactive oxygen species, inhibit trophoblast migration, and occur in rat models. 6 -8 AT1-AAs induced preeclampsia-like symptoms in C57BL/6J mice by passive transfer. 9 However, AT1-AAs are not specific for preeclampsia and also occur in patients with humoral kidney transplant rejection. 10 An epitope on the second extracellular loop of the human AT 1 receptor (AFHYESQ) represents the binding site for AT1-AAs; the same sequence inhibits the AT1-AAmediated effects completely in vivo and in vitro. The epitope is highly homologous to the capsid protein VP2 from parvovirus B19 (AFHYETQ).Parvovirus B19 is a single-stranded DNA virus and can cause erythema infectiosum, a generally (but not always) mild childhood exanthem. 11,...

Effectiveness and Safety of a Therapeutic Vaccine Against Angiotensin II Receptor Type 1 in Hypertensive Animals

“…5,6,11 Although the antibodies against this ECL2 sequence discovered thus far show agonistic effects, [12][13][14][15][16] we cannot rule out the possible existence of blocking antibodies to that region. Many researchers have attempted to identify a G protein coupling receptor antibody that can act as an agonist or an antagonist.…”

CD19 + CD5 + Cells as Indicators of Preeclampsia

“…Since Wallukat et al 7 described the presence of AT 1 -AA in PE patients, many features of the disease has been explained by the ability of this autoantibodies to bind to and to activate the angiotensin receptor on a variety of cells. [29][30][31][32][33] However, despite much information concerning the presence of autoantibodies in PE patients, no attention has so far been focused on the cells producing them. We focused our attention on the B-1a B cells.…”

REVIEW ARTICLE: Immunology of Pre‐Eclampsia

“…65 In a case-control study, we found that such antibodies were relatively common in normal pregnancy controls and not present in a substantial minority of cases. 66 Cross-reactivity with parvovirus B19 VP2 protein was demonstrated although serological evidence of previous parvovirus infection was not more common in pre-eclampsia cases. Th17 activity predisposes to autoimmunity.…”