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. 2023 Apr;89(4):e13693.
doi: 10.1111/aji.13693. Epub 2023 Feb 27.

Inhibiting B cell activating factor attenuates preeclamptic symptoms in placental ischemic rats

Owen Herrock  1 , Evangeline Deer  1 , Lorena M Amaral  1 , Nathan Campbell  1 , Darby Whitney  1 , Nicole Ingram  1 , Denise C Cornelius  2 , Ty Turner  1 , Ja'Nasa Hardy-Hardin  1 , George W Booz  1 , Tarek Ibrahim  1 , Babbette LaMarca  1   3
Affiliations

Inhibiting B cell activating factor attenuates preeclamptic symptoms in placental ischemic rats

Owen Herrock et al. Am J Reprod Immunol. 2023 Apr.

Abstract

Problem: Preeclampsia (PE), new-onset hypertension during pregnancy, is associated with a pro-inflammatory state with activated T cells, cytolytic natural killer (NK) cells, dysregulated complement proteins, and B cells secreting agonistic autoantibodies to the angiotensin II type-1 receptor (AT1-AA). The reduced uterine perfusion pressure (RUPP) model of placental ischemia recapitulates these features of PE. Blocking CD40L-CD40 communication between T and B cells or B cell depletion with Rituximab prevents hypertension and AT1-AA production in RUPP rats. This suggests that T cell-dependent B cell activation contributes to the hypertension and AT1-AA associated with PE. B2 cells maturing into antibody producing plasma cells are the product of T cell-dependent B cell-interactions and B cell Activating Factor (BAFF) is an integral cytokine in the development of B2 cells specifically. Thus, we hypothesize that BAFF blockade will selectively deplete B2 cells, therefore reducing blood pressure, AT1-AA, activated NK Cells, and complement in the RUPP rat model of PE.

Method of study: Gestational Day (GD) 14 pregnant rats underwent the RUPP procedure, and a subset were treated with 1 mg/kg Anti-BAFF antibodies via jugular catheters. On GD19, blood pressure was measured, B cells and NK cells were measured by flow cytometry, AT1-AA was measured by cardiomyocyte bioassay, and complement activation was measured by ELISA.

Results: Anti-BAFF therapy attenuated hypertension, AT1-AA, NK cell activation, and APRIL levels in RUPP rats without negatively impacting fetal outcomes.

Conclusions: This study demonstrates that B2 cells contribute to hypertension, AT1-AA, and NK cell activation in response to placental ischemia during pregnancy.

Keywords: animal model; autoantibodies; baff; hypertension; inflammation; preeclampsia; pregnancy.

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Conflict of interest statement

Disclosures

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
RUPP rats (n=12) had increased Mean Arterial Pressure (MAP) compared to NP (n=9, p<0.01. NP+Anti-BAFF (n=8) compared to NP, but RUPP+Anti-BAFF (n=11, p<0.01) had normalized MAP compared to RUPP. NP+Anti-BAFF had decreased circulating B cells (n=6) compared to untreated NP rats (n=6, <0.01) and RUPP+Anti-BAFF (n=5) had decreased circulating B cells compared to untreated RUPP rats (n=9, p<0.05). There was no difference in circulating B1 cells in NP (n=6) compared to RUPP (n=9). There was a trending decrease in circulating B1 cells between NP compared to NP+Anti-BAFF (n=6) and between RUPP compared to RUPP+Anti-BAFF (n=5). There was no change in circulating B2 cells between NP (n=6) compared to RUPP (n=9). There was a significant decrease in circulating B2 cells in NP+Anti-BAFF (n=6, p<0.05) compared to NP. There was a trending decrease in circulating B2 cells in RUPP+Anti-BAFF (n=5) compared to RUPP.
Figure 2.
Figure 2.
NP+Anti-BAFF (n=8) had no change in pup weight compared to NP (n=8). RUPP rats had smaller pups (n=12, p<0.05) compared to NP. RUPP+Anti-BAFF (n=9, p<0.01) had smaller pups compared to NP+Anti-BAFF, but there was no change between RUPP and RUPP+Anti-BAFF. There was no change in placenta weight between NP (n=8) and NP+Anti-BAFF (n=8). RUPPs (n=11) had smaller placentas compared to NP, but RUPP+Anti-BAFF (n=9) did not have smaller pups than NP+Anti-BAFF. There was no change in offspring viability between NP (n=8) and NP+Anti-BAFF (n=8). RUPP rats (n=11) had decreased fetal viability compared to NP and RUPP+Anti-BAFF (n=9) had decreased fetal viability compared to NP+Anti-BAFF. There was no change in fetal viability between RUPP and RUPP+Anti-BAFF.
Figure 3.
Figure 3.
There was no change in circulating AT1-AA between NP (n=6) and NP+Anti-BAFF (n=5). As previously described, RUPPs had significantly increased AT1-AA (n=6, p<0.001) compared to NP. RUPP+Anti-BAFF (n=6, p<0.01) had significantly decreased AT1-AA compared to RUPP.
Figure 4.
Figure 4.
There was no change in circulating cytolytic NK cells between NP (n=6) and NP+Anti-BAFF (n=5), but RUPP rats (n=7, p<0.05) had increased circulating cytolytic NK cells compared to NP. RUPP+Anti-BAFF (n=8, p<0.01) had decreased circulating cytolytic NK cells compared to RUPP. There was no change in placental cytolytic NK cells between NP (n=6) and NP+Anti-BAFF (n=4), but RUPP rats (n=7, p<0.05) had increased placental cytolytic NK cells compared to NP. RUPP+Anti-BAFF (n=5, p<0.05) compared to RUPP.
Figure 5.
Figure 5.
There was no change in circulating complement C3 between NP (n=5), NP+Anti-BAFF (n=5), RUPP (n=4), or RUPP+Anti-BAFF (n=6). There was no change in circulating C3a between NP (n=5) compared to NP+Anti-BAFF (n=5), but RUPP (n=5, p<0.05) had increased C3a compared to NP. RUPP+Anti-BAFF (n=6, p<0.01) had increased C3a compared to NP+Anti-BAFF, but there was no difference between RUPP and RUPP+Anti-BAFF.
Figure 6.
Figure 6.
Circulating BAFF trended to decrease between NP (n=7) and NP+Anti-BAFF (n=7) but it did not reach significance. There was no change in BAFF between NP and RUPP (n=7), there was also no change in BAFF between RUPP and RUPP+Anti-BAFF (n=6). There was no change in circulating APRIL between NP (n=8) and NP+Anti-BAFF (n=7), but RUPPs (n=7, p<0.05) had increased APRIL compared to NP. Increased APRIL in the RUPP was attenuated in RUPP+Anti-BAFF (n=8, p<0.01).
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