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Hoxha, Ariela (2013) New insight into the pathogenesis and treatment of
autoimmune congenital heart block.
[Tesi di dottorato]

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Abstract (inglese)

Background. Congenital atrioventricular block (CHB) is the most frequent manifestation of neonatal lupus which is attributed to anti-Ro/SSA and/or anti-La/SSB-mediated inflammation and subsequent fibrosis of the atrioventricular node. Despite the observation of a direct role for maternal antibodies in inducing CHB both in vitro and in vivo studies, the mechanisms involved remain unclear. Currently no therapy is found to be effective in the treatment of 2nd and 3rd degree CHB induced by maternal antibodies; also because the rarity of the disease does not allow for controlled clinical trials.
Objectives. To explore the role of anti-Ro52 antibodies in the pathogenesis of CHB by identifying of the epitope specificity of anti-p200 antibodies. To study in an animal model the effect on heart conduction system of the different doses of injected human IgG antibodies from a CHB patient. To evaluate the clinical efficacy and safety of a combined therapy protocol utilizing plasmapheresis, intravenous immunoglobulin (IVIG) and betamethasone and the effect of this treatment on anti-Ro52, anti-p200 and anti-La antibody levels.
Materials and Methods. Laboratory methods: ELISA assay, circular dichroism spectroscopy and antibody purification. Procedure: antibody transfer by intra-peritoneally injection of purified IgG. Instrumental methods: fetal ecocardiography and electrocardiogram recordings. Treatment strategy: Six consecutive women diagnosed CHB underwent a combination therapy protocol composed of weekly plasmapheresis, fortnightly 1 g/Kg IVIG and daily Betamethasone (4 mg/day) throughout pregnancy. IVIG (1 g/Kg) treatment in the neonates was begun at birth and administered every fifteen days until passive maternal antibodies became undetectable. Statistical analysis: Wilcoxon, Mann-Whitney U, two way ANOVA and Spearman’s tests; p<0.05 was considered as significant.
Results and Conclusion. Part I: The epitope specificity of anti-p200 antibodies was the position 233. We suggest that this antibody specificity might be a tool to identify high risk pregnancies for CHB. The results might contribute to identify antibody specificity closely associated with development of CHB and to provide the possibility to explore the role of this antibody in the pathogenesis of CHB.
Part II: We developed an animal model for CHB by a simple technique of passive transfer of human IgG from a patient with a child with CHB. High levels (4 mg) of anti-SSA/Ro and anti-SSB/La antibodies induce bradycardia, atrioventricular time prolongation and a decreased cardiac performance. Whereas, low levels (2 mg) of these antibodies determine a decrease in cardiac performance.
Part III: The obtained results from these case series are: a) the efficacy in treating 2nd degree CHB, and b) the safety of plasmapheresis and IVIG therapies. The low number of treated cases, the relatively short follow-up (mean 22.7 months ± 10.4 SD, range 12-42 months) and the high cost of the procedure can all be considered limits.
Part IV: Plasmapheresis reduces the levels of anti-Ro52, anti-p200 and anti-La antibodies. However, a decrease of antibody amounts in patients with the highest anti-Ro52 antibody levels has not been demonstrated

Abstract (italiano)

Premesse. Il blocco atrioventricolare congenito (CHB) è la manifestazione più frequente del lupus neonatale. Esso è causato dal passaggio transplacentare degli anticorpi anti-Ro/SSA e/o anti-La/SSB con successiva infiammazione e fibrosi del nodo atrioventricolare. Nonostante la dimostrazione di un ruolo diretto degli anticorpi materni nell'indurre CHB sia in vitro che in vivo, i meccanismi coinvolti rimangono poco chiari. Inoltre finora nessuna terapia è risultata efficace nel trattamento del CHB sia di secondo che terzo grado, anche perché la rarità della malattia non consente studi clinici controllati.
Obiettivi. Studiare il ruolo degli anticorpi anti-Ro52 nella patogenesi del CHB attraverso la definizione della specificità epitopica degli anticorpi anti-p200. Sviluppare un modello animale per studiare l'effetto sul sistema di conduzione cardiaco degli anticorpi IgG purificati da una paziente con CHB fetale. Infine valutare l'efficacia clinica e la sicurezza di un protocollo di terapia combinato comprendente l’impiego di plasmaferesi, immunoglobuline per via endovenosa (IVIG) e betametasone, nonchè l'effetto di questo trattamento su i livelli degli anticorpi anti-Ro52, anti-p200 e anti-La.
Materiali e Metodi. Metodi di laboratorio: ELISA, spettroscopia con dicroismo circolare e purificazione di IgG umane. Procedura sperimentale: trasferimento per via intra-peritoneale degli anticorpi mediante l’iniezione di IgG purificate da una madre con CHB. Metodi strumentali: ecocardiografia fetale ed elettrocardiografia dopo la nascita. Strategia di trattamento: Sei donne diagnosticate con CHB sono state trattate durante la gravidanza con un protocollo di terapia di associazione composta da plasmaferesi settimanale, IVIG 1g/kg a cadenza quindicinale e Betametasone giornaliero (4 mg). Inoltre, IVIG (1 g/kg) sono state somministrate ai neonati ogni quindici giorni subito dopo la nascita fino alla negativizzazione degli anticorpi materni passivi. Analisi statistica: Wilcoxon, Mann-Whitney U, ANOVA e Spearman tests. Il valore di p<0,05 è stato considerato significativo.
Risultati e Conclusioni. Parte I: La specificità epitopica dell’anticorpo anti-p200 è stata localizzata nella posizione 233. Tale epitopo potrebbe essere utile per identificare la specificità anticorpale strettamente associata allo sviluppo del CHB e costituire quindi uno strumento per individuare le gravidanze ad alto rischio per CHB. Inoltre potrebbe contribuire a chiarire il ruolo di questo anticorpo nella patogenesi del CHB.
Parte II: Abbiamo sviluppato un modello animale del CHB con una semplice tecnica di trasferimento passivo di IgG umane purificate da un paziente con CHB fetale. Gli alti livelli (4 mg) degli anticorpi anti-Ro/SSA ed anti-La/SSB hanno indotto bradicardia, prolungamento dell’intervallo PR e una depressione delle funzione cardiaca nel animale. Invece, i bassi livelli (2 mg) hanno determinato solo una diminuzione della funzione cardiaca. In questo modo è stato dimostrato la patogenicità degli anticorpi anti-Ro/SSA ed anti-La/SSB sul sistema di conduzione cardiaco.
Parte III: I risultati ottenuti da queste serie di casi sono i seguenti: a) l’efficacia nel trattamento del CHB di 2° grado, e b) la sicurezza della plasmaferesi e delle IVIG. Tuttavia il basso numero di casi trattati, e il follow-up relativamente breve (media 22,7 mesi ± 10,4 DS, range 12-42 mesi), come anche l'alto costo della procedura possono essere considerati limiti.
Parte IV: La plasmaferesi riduce i livelli degli anticorpi anti-Ro52, anti-p200 e anti-La. Tuttavia, un decremento significativo anticorpale non è stato dimostrato nelle pazienti con livelli molto alti di anticorpi anti-Ro52

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Tipo di EPrint:Tesi di dottorato
Relatore:Ruffatti, Ariela
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE REUMATOLOGICHE
Data di deposito della tesi:29 Gennaio 2013
Anno di Pubblicazione:29 Gennaio 2013
Parole chiave (italiano / inglese):blocco cardiaco congenito, anticorpi anti-Ro/SSA, anticorpi anti-La/SSB/ congenital heart block, anti-Ro/SSA antibodies, anti-La/SSB antibodies
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/16 Reumatologia
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:5642
Depositato il:16 Ott 2013 09:33
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