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Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT₁ receptor

Gerd Wallukat, Volker Homuth, Thorsten Fischer, Carsten Lindschau, Björn Horstkamp, Axel Jüpner, Evi Baur, Eberhard Nissen, Klaus Vetter, Dajana Neichel, Joachim W. Dudenhausen, Hermann Haller, Friedrich C. Luft

Published in Volume 103, Issue 7

J Clin Invest. 1999; 103(7):945 doi:10.1172/JCI4106

Abstract | Full text | PDF

I mmune mechanisms and the renin–angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT₁ receptor–mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Immunoglobulin from all preeclamptic patients stimulated the AT₁ receptor, whereas immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. Affinity-column purification and anti–human IgG and IgM antibody exposure implicated an IgG antibody directed at the AT₁ receptor. Peptides corresponding to sites on the AT₁ receptor's second extracellular loop abolished the stimulatory effect. Western blotting with purified patient IgG and a commercially obtained AT₁ receptor antibody produced bands of identical molecular weight. Furthermore, confocal microscopy of vascular smooth muscle cells showed colocalization of purified patient IgG and AT₁ receptor antibody. The protein kinase C (PKC) inhibitor calphostin C prevented the stimulatory effect. Our results suggest that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT₁ receptor loop. The effect appears to be PKC-mediated. These novel autoantibodies may participate in the angiotensin II–induced vascular lesions in these patients.

AT1 autoantibodies due to HLA-DR molecular mimicry?

Charles J. Hoff, Ph.D. | choff@usamail.usouthal.edu

College of Medicine, University of South Alabama, Mobile, AL 36608

Wallukat et al. (1) have reported that preeclamptic women have IgG autoantibodies to the angiotensin AT1 vascular receptor whereas nonpregnant and normotensive pregnant women do not. Their findings implicate the second extracellular loop of the AT1 molecule as the reactive site. Labarrere and Faulk (2) have found that fetal HLA-DR antigens are expressed in the endovascular cytotrophoblasts in the uteroplacental arteries of preeclamptic women, but not in normotensive women. They speculate that when paternally-derived fetal HLA-DR antigens are allogeneic, this expression may cause a maternal immune response contributing to the development of preeclampsia. Because autoimmune responses are rare events in young adults, a possible explanation for the occurrence of anti-AT1 autoantibody in preeclampsia is the production of cross-reactive anti-fetal HLA-DR antibody resulting from HLA-DR allogenicity combined with homology between the constant regions of fetal HLA-DR alloantigens and the AT1 receptor.
Using the ENTREZ browser (3), I obtained the peptide sequences of human AT1 (gi code: 4501997) and the HLADRalpha (gi: 122206) and HLA- DRbeta chains (gi: 2529486). I next compared the peptide sequences of these two proteins using the local sequence alignment program, LALIGN (4), to determine whether any homology existed. The HLA-DRalpha chain showed the most homology with AT1. Only those pairs of segments containing three or more amino acids in sequence for the HLA-DRalpha chain and AT1 are reported here.
Comparing AT1 with HLA-DRalpha, I found four pairs of segments showing homology. There were two sets of segment-pairs of 18 amino acids with 33.3% homology, one segment-pair of 37 amino acids with 27% homology, and one segment-pair of 10 amino acids with 50% homology. The latter AT1 homology was within the reactive site of the second extracellular loop which the authors noted in their paper (1).
These findings suggest that it is possible anti-fetal HLA-DR antibodies may be produced in preeclampsia which are cross-reactive and target the AT1 receptor. If this is the case, they may contribute to the vasculopathy underlying preeclampsia.
1. Wallukat, G. et al. 1999. Patients with preeclampsia develop agonistic autoantibodies against angiotensin AT1 receptor. J. Clin. Invest. 103:945-952.
2. Labarrere, C.A. and Faulk, W.P. 1995. Intercellular adhesion molecule-1 (ICAM-1) and HLA-DR antigens are expressed on endovascular cytotrophoblast in abnormal pregnancies. Am. J. Reprod. Immunol. 33:47- 53.
3. National Center for Biotechnology Information. ENTREZ Browser. http://www.ncbi.nlm.nih.gov/Entrez/. April 1999.
4. Huang, X. and Miller W. 1991 LALIGN. Adv. Appl. Math. 12:373-381.