Background/Purpose: The most serious manifestation of fetal exposure to maternal anti-Ro antibodies is the development of heart block. This work addresses the hypothesis that fetal disease occurs in the absence of check point inhibition of inflammation initiated by anti-Ro. This study describes a novel murine model in which deficient PD1 signaling exacerbates mild conduction defects induced by anti-Ro and results in histologic evidence of fibrosis and multinucleated giant cells paralleling observations in human autopsies. Accordingly, these data suggest that checkpoint inhibition may play a role in the pathogenesis of CHB.

Methods: To inhibit PD1 signaling, pregnant wild type CD1 mice treated with anti-CD274 (anti-PD1) Abs, or pregnant PD1 knock out (KO) mice were selected. For both models, mice were injected at E12 and E15 with IgG fractions from either a healthy donor or a mother with anti-52Ro, 60Ro and La (anti-Ro) and 3 children with CHB. As controls, other pregnant CD1 mice received CHB IgG or anti-CD274 Abs alone.

Results: To assure access of autoantibodies to the fetal circulation, blood from embryos (N = 14) dissected from the uterus of a CHB IgG treated pregnant CD1 mouse contained antibody reactivities to all Ro/La components, which were not detected in embryos of mothers injected with control IgG. Exposure of mice to CHB IgG resulted in a prolonged PR interval (5.28 + 0.3, p=0.004 vs control), a result not obtained with anti-PDL1 alone (3.39 + 0.3, p=0.69 vs control). Exposure of CD1 mice to CHB IgG + anti-PDL1 resulted in an even more pronounced conduction defect as reflected by lengthening of the PR interval (PR/√RR, 81 total pups) versus Control IgG (11.3 + 0.2 and 3.4+ 0.1, respectively, p<0.0001). Histology of anti-Ro injected mice showed diffuse positive staining using anti-CD274 Abs (for detection of PDL1 ligand) but not isotype control. Injection of the PD1KO mouse with CHB IgG resulted in the most advanced conduction abnormality as reflected by the PR interval (36 total pups) versus Control IgG (16.24 + 1.56 and 4.55+ 0.11, respectively, p<0.0001). In one of the pups in this group, the block resembled retrograde V-A conduction and the heart removed for histologic evaluation. Consistent with autopsies of human fetuses dying with CHB, there was focal injury with myocyte calcifications, multinucleated giant cells and fibrosis, findings never demonstrated in any previous CHB murine model.

Conclusion: Diminished PD1 signaling exacerbates mild conduction defects induced by anti-Ro/La, which supports the hypothesis that checkpoint inhibitors may play a role in the pathogenesis of CHB.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exploiting-inhibition-of-pd1-signaling-in-a-murine-model-of-anti-ssaro-associated-congenital-heart-block/