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- Ambrosi, A, et al.
(författare)
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Anti-Ro52 monoclonal antibodies specific for amino acid 200-239, but not other Ro52 epitopes, induce congenital heart block in a rat model
- 2012
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 71:3, s. 448-454
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Tidskriftsartikel (refereegranskat)abstract
- Congenital heart block (CHB) may develop in fetuses of women with anti-Ro/La autoantibodies following placental transfer of maternal autoantibodies and disruption of the fetal atrioventricular (AV) conduction system. Animal models of CHB currently rely on immunisation or transfer of anti-Ro/La antibodies purified from mothers of children with CHB, which does not allow precise identification of the disease-inducing antibody specificity.ObjectiveTo determine the ability of different anti-Ro52 monoclonal antibodies to induce cardiac electrophysiological abnormalities in vivo and affect the calcium homoeostasis of cardiomyocytes in vitro.MethodsMonoclonal antibodies recognising different domains of Ro52 were generated and injected into pregnant rats, and ECG was recorded on newborn pups. Cultures of rat neonatal cardiomyocytes were established to assess the effect of the different anti-Ro52 monoclonal antibodies on calcium homoeostasis.ResultsFirst-degree AV block and bradycardia developed after maternal transfer of antibodies specific for amino acids 200–239 of Ro52 (p200), while pups exposed to antibodies targeting N- or C-terminal epitopes of Ro52 did not show any electrocardiogram abnormalities. Addition of an anti-p200 antibody to cultured cardiomyocytes induced calcium dyshomoeostasis in a time- and dose-dependent manner, while addition of other Ro52 antibodies had no effect.ConclusionThese data for the first time show unambiguously that antibodies specific for amino acids 200–239 of Ro52 can induce cardiac conduction defects in the absence of other autoantibodies, and may therefore be the main initiators of cardiac pathology in the pool of anti-Ro52 antibodies in mothers of children with CHB.
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- Brauner, S, et al.
(författare)
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Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content
- 2018
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Ingår i: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 114:1, s. 158-167
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Tidskriftsartikel (refereegranskat)abstract
- AimsPatients with hyperlipidemia are at risk of atherosclerosis, but not all develop cardiovascular disease, highlighting the importance of other risk factors such as inflammation. Both the innate and adaptive arms of the immune system have been suggested in the initiation and propagation of plaque formation. Tri-partite motif (TRIM) 21 is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in chronic inflammatory disease. Here, we investigate a potential role for TRIM21 in coronary artery disease.Methods and resultsTrim21-deficient or wild-type bone marrow was transplanted into Ldlr-/- mice fed a hypercholesterolemic diet. The Trim21-/-->Ldlr-/- mice developed larger atherosclerotic plaques, with significantly higher collagen content compared to mice transplanted with wild-type cells. High collagen content of the atheroma is stabilizing, and has recently been linked to IL-17. Interestingly, Trim21-/-->Ldlr-/- mice had elevated CD4 and IL-17 mRNA expression in plaques, and increased numbers of activated CD4+ T cells in the periphery. An increased differentiation of naïve T cells lacking Trim21 into Th17 cells was confirmed in vitro, with transcriptomic analysis revealing upregulation of genes of a non-pathogenic Th17 phenotype. Also, decreased expression of matrix metalloproteinases (MMPs) was noted in aortic plaques. Analysis of human carotid plaques confirmed that TRIM21 expression negatively correlates with the expression of key Th17 genes and collagen, but positively to MMPs also in patients, linking our findings to a clinical setting.ConclusionIn this study, we demonstrate that TRIM21 influences atherosclerosis via regulation of Th17 responses, with TRIM21 deficiency promoting IL-17 expression and a more fibrous, stable, phenotype of the plaques.
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- Meisgen, S, et al.
(författare)
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Auxilin is a novel susceptibility gene for congenital heart block which directly impacts fetal heart function
- 2022
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 81:8, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function.MethodsA genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography.ResultsWe identified DNAJC6 as a novel fetal susceptibility gene, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by DNAJC6, have abnormal connectivity and Ca2+ homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals.ConclusionsOur study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.
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