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1.  Antenatal and postnatal combined therapy for autoantibody-related congenital atrioventricular block 
Background
Autoantibody-related congenital heart block (CHB) is an autoimmune condition in which trans placental passage of maternal autoantibodies cause damage to the developing heart conduction system of the foetus.
Case presentation
We report a case of an Italian 31–year-old woman, in a good clinical status, referred to our Centre at 26 weeks of her first pregnancy, because of foetal bradycardia, found during routine foetal ultrasonography. Foetal echocardiography revealed a 3rd degree CHB, without any anatomical defects. Despite the mother was asymptomatic for autoimmune disease, anti-Ro/La were searched for, because of the hypothesis of autoantibody-related CHB. High title of maternal anti-Ro/SSA antibodies was found and diagnosis of an autoantibody-related CHB was made. A combination treatment protocol of the mother was started with oral betamethasone, plasmapheresis and IVIG. An emergency C-section was performed at 32 + 3 weeks of gestation because of a non-reassuring cardiotocography pattern. A male newborn (BW 1515 g, NGA, Apgar 8–10) was treated since birth with high-flow O2 for mild RDS. IVIG administration was started at one week, and then every two weeks, until complete disappearance of maternal antibodies from blood. Because of persistent low ventricular rate (<60/min), seven days following birth, pacemaker implantation was performed. The baby is now at 40th week with no signs of cardiac failure and free of any medications.
Conclusion
Up to date, no guidelines have been published for the treatment of “in utero-CHB” and only anecdotal reports are available. It has been stated that a combination therapy protocol is effective in reversing a 2nd degree CHB, but not for 3rd degree CHB. In cases of foetal bradycardia, weekly foetal echocardiographic monitoring needs to be performed and in cases of 2nd degree CHB and 3rd degree CHB maternal therapy could be suggested, as in our case, to avoid foetal heart failure. In cases of 3rd degree CHB often pacemaker implantation is needed.
doi:10.1186/1471-2393-13-220
PMCID: PMC4219454  PMID: 24286473
Autoantibody-associated congenital heart block; Combination therapy protocol of plasmapheresis, intravenous immunoglobulin and betamethasone in congenital heart block; Pacemaker implantation in newborn; Foetal cardiac arrhythmia detection; Foetal ecochardiography; Neonatal counselling
2.  Congenital Heart Block Maternal Sera Autoantibodies Target an Extracellular Epitope on the α1G T-Type Calcium Channel in Human Fetal Hearts 
PLoS ONE  2013;8(9):e72668.
Background
Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.
Methodology/Principal Findings
We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18–22.6 weeks gestation). Using human fetal hearts (20–22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305–319 of the extracellular loop linking transmembrane segments S5–S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.
Conclusions/Significance
Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.
doi:10.1371/journal.pone.0072668
PMCID: PMC3767782  PMID: 24039792
3.  Congenital Heart Block: Identification of Autoantibody Binding Site on the Extracellular Loop (Domain I, S5–S6) of α 1D L-type Ca Channel 
Journal of autoimmunity  2009;34(2):80.
Congenital heart block (CHB) is an autoimmune disease associated with autoantibodies against intracellular ribo-nucleoproteins SSB/La and SSA/Ro. The hallmark of CHB is complete atrioventricular block. We have recently established that anti-SSA/Ro -SSB/La autoantibodies inhibit α1D L-type Ca current, ICa-L, and cross-react with the α1D Ca channel protein. This study aims at identifying the possible binding sites on α1D protein for autoantibodies from sera of mothers with CHB children. GST fusion proteins of the extracellular regions between the transmembrane segments (S5–S6) of each of the four α1D Ca channel protein domains I-IV were prepared and tested for reactivity with sera from mothers with CHB children and controls using ELISA. Sera containing anti-Ro/La autoantibodies from 118 mothers with CHB children and from 15 mothers with anti-Ro/La autoantibodies but have healthy children, and from 28 healthy mothers without anti-Ro/La autoantibodies and healthy children were evaluated. Seventeen of 118 (14.4%) sera from mothers with CHB children reacted with the extracellular loop of domain I S5–S6 region (E1). In contrast, only 2 of 28 (7%) of sera from healthy mothers (- anti-Ro/La) and healthy children reacted with E1 loop and none (0 of 15) of sera from healthy mothers (+ anti-Ro/La) and healthy children reacted with the E1 loop. Preincubation of E1 loop with the positive sera decreased the O.D reading establishing the specificity of the response. Electrophysiological characterization of the ELISA positive sera and purified IgG showed inhibition (44.1% and 49.8%, respectively) of the α1D ICa-L expressed in tsA201 cells. The inhibition was abolished when the sera were pre-incubated with E1 fusion protein. The results identified the extra-cellular loop of domain I S5–S6 of L-type Ca channel α1D subunit as a target for autoantibodies from a subset of mothers with CHB children. This novel finding provides insights into the potential development of therapeutic peptides that could bind to the pathogenic antibodies and prevent CHB.
doi:10.1016/j.jaut.2009.06.005
PMCID: PMC2822065  PMID: 19640679
Autoantibodies; calcium; heart block; ion channels; sinoatrial node
4.  Evaluation of Fetuses in the Preventive IVIG Therapy for Congenital Heart Block (PITCH) study 
Arthritis and rheumatism  2010;62(4):1138-1146.
Objective
The recurrence rate of anti-SSA/Ro associated congenital heart block (CHB) is 17%. Reversal of 3rd degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, IVIG was evaluated as a preventative therapy for CHB.
Methods
A multicenter open-label study based on Simon’s 2-stage optimal design was initiated. Enrollment criteria included: maternal anti-SSA/Ro antibody, a previous child with CHB/rash,
Results
Twenty mothers completed the IVIG protocol before reaching the pre-determined stopping rule of three cases of advanced CHB. CHB was detected at 19, 20 and 25 weeks; none followed an abnormal PR interval. One of these mothers had two previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal antibody titers to SSA/Ro, SSB/La, or Ro52 were detected over the course of therapy or at delivery. There were no safety issues.
Conclusions
IVIG at doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers. Having established safety with this protocol and feasibility of patient enrollment, subsequent preventative studies may be considered, perhaps to include higher doses of IVIG.
doi:10.1002/art.27308
PMCID: PMC3214993  PMID: 20391423
Congenital Heart Block; Intravenous Immunoglobulin; anti-SSA/Ro antibodies; neonatal lupus
Congenital heart block (CHB) is a passively acquired autoimmune disease due to the transfer of maternal autoantibodies anti-SSA/Ro –SSB/La to the fetus resulting in atrioventricular (AV) block and sinus bradycardia. We previously established a murine model for CHB where pups born to immunized wild type (WT) mothers exhibited electrocardiographic abnormalities similar to those seen in CHB and demonstrated inhibition of L-type Ca channels (LTCC) by maternal antibodies. Here, we hypothesize that overexpression of LTCC should rescue, whereas knockout of LTCC should worsen the electrocardiographic abnormalities in mice.
Methods and Results
Transgenic (TG) mice were immunized with SSA/Ro and SSB/La antigens. Pups born to immunized WT mothers had significantly greater sinus bradycardia and AV block compared to pups from nonimmunized WT. TG pups overexpressing LTCC had significantly less sinus bradycardia and AV block compared to their non-TG littermates and to pups born to immunized WT mothers. All LTCC knockout pups born to immunized mothers had sinus bradycardia, advanced degree of AV block and decreased fetal parity. No sinus bradycardia or AV block were manifested in pups from control nonimmunized WT mothers. IgG from mothers with CHB children, but not normal IgG, completely inhibited intracellular Ca transient ([Ca]iT) amplitude.
Conclusions
Cardiac specific overexpression of LTCC significantly reduced the incidence of AV block and sinus bradycardia in pups exposed to anti-SSA/Ro -SSB/La autoantibodies, whereas exposure of LTCC knockout pups to these autoantibodies significantly worsened the electrocardiographic abnormalities. These findings support the hypothesis that maternal antibodies inhibit LTCC and [Ca]iT thus contributing to the development of CHB. Altogether, the results are relevant to the development of novel therapies for CHB.
doi:10.1111/j.1540-8167.2011.02032.x
PMCID: PMC3135711  PMID: 21352396
congenital heart block; calcium channels; systemic lupus erythematosis; autoantibodies; genetics
Arthritis and rheumatism  2011;63(9):2783-2789.
Objective
Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ~18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype: antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB.
Methods
We studied 16 anti-Ro/SSA and anti-La/ SSB–positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349–364aa of La/SSB (idiotype) and its antiidiotypic antibodies.
Results
Following IVIG treatment, serum titers of anti-La(349–364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349–364) was observed. The Id: anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P < 0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349–364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of <1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied.
Conclusion
This is the first study in humans to demonstrate that IVIG influences the Id–anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.
doi:10.1002/art.30464
PMCID: PMC3551293  PMID: 21618202
Journal of internal medicine  2009;265(6):653-662.
One of the strongest associations with autoantibodies directed to components of the SSA/Ro-SSB/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. This risk is 10-fold higher in women who have had a previously affected child with CHB. Anti-Ro/La antibodies are necessary but insufficient to cause disease. In vitro and in vivo experiments suggest that the pathogenesis involves exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGFβ expression and extensive fibrosis in the conducting system and in some cases surrounding myocardium. A disturbing observation is the rapidity of disease progression, with advanced heart block and life-threatening cardiomyopathy observed <2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal has never been achieved, despite dexamethasone. Current strategies include the evaluation of an early echocardiographic marker of injury, such as a prolonged PR interval and the use of IVIG as a preventative measure for pregnancies of mothers with previously affected children.
doi:10.1111/j.1365-2796.2009.02100.x
PMCID: PMC3551292  PMID: 19493059
anti-Ro/La antibodies; congenital heart block; PR interval
Congenital heart block (CHB) is the most severe manifestation of neonatal lupus which can develop into a lethal atrioventricular (AV) block. Complete congenital foetal heart block related to maternal anti-Ro/SSA autoanti­bodies typically develops between 20 and 24 weeks of gestation. CHB with a structurally normal heart is frequently associated with maternal autoantibodies to Ro/SSA and La/SSB. We are presenting a case of foetal complete CHB with high maternal Ro/SSA and La/SSB titre with favourable outcome.
PMCID: PMC4086001  PMID: 25009724
Congenital heart block; SLE; Ro/SSA; La/SSB; Dexamethasone
Arthritis and rheumatism  2010;62(10):3119-3121.
Anti-SSA/Ro antibodies are necessary but not sufficient to provoke autoimmune-associated congenital heart block (CHB). Genetic factors are likely contributory. Accordingly, HLA-related candidates and single-nucleotide polymorphisms in the promoter region of tumor necrosis factor α and codon 10 in transforming growth factor β1 (TGFβ1) were evaluated in a unique family: the surrogate mother (anti-SSA/Ro positive), the biologic father, and the CHB-affected child (product of ovodonation). There was an HLA mismatch between the affected child and the surrogate mother. However, both the biologic and the surrogate mothers shared DQ2 and the profibrosing leucine polymorphism at codon 10 of TGFβ. In conclusion, we observed that CHB can develop in a genetically unrelated child exposed in utero to anti-SSA/Ro antibodies. Testing for anti-SSA/Ro antibodies might be considered in women undergoing artificial fertilization. It is possible that there is no direct association of maternal genes beyond a contributory role in generating the autoantibody.
doi:10.1002/art.27575
PMCID: PMC3931307  PMID: 20499382
Journal of Clinical Investigation  2006;116(9):2413-2422.
The role of cardiocytes in physiologic removal of apoptotic cells and the subsequent effect of surface binding by anti-SSA/Ro and -SSB/La antibodies was addressed. Initial experiments evaluated induction of apoptosis by extrinsic and intrinsic pathways. Nuclear injury and the translocation of SSA/Ro and SSB/La antigens to the fetal cardiocyte plasma membrane were common downstream events of Fas and TNF receptor ligation, requiring caspase activation. As assessed by phase-contrast and confirmed by confocal microscopy, coculturing of healthy cardiocytes with cardiocytes rendered apoptotic via extrinsic pathways revealed a clearance mechanism that to our knowledge has not previously been described. Cultured fetal cardiocytes expressed phosphatidylserine receptors (PSRs), as did cardiac tissue from a fetus with congenital heart block (CHB) and an age-matched control. Phagocytic uptake was blocked by anti-PSR antibodies and was significantly inhibited following preincubation of apoptotic cardiocytes with chicken and murine anti-SSA/Ro and -SSB/La antibodies, with IgG from an anti-SSA/Ro– and -SSB/La–positive mother of a CHB child, but not with anti–HLA class I antibody. In a murine model, anti-Ro60 bound and inhibited uptake of apoptotic cardiocytes from wild-type but not Ro60-knockout mice. Our results suggest that resident cardiocytes participate in physiologic clearance of apoptotic cardiocytes but that clearance is inhibited by opsonization via maternal autoantibodies, resulting in accumulation of apoptotic cells, promoting inflammation and subsequent scarring.
doi:10.1172/JCI27803
PMCID: PMC1533875  PMID: 16906225
The American Journal of Cardiology  2007;100(4):661-665.
Terbutaline is used to treat fetal bradycardia in the setting of complete heart block (CHB); however, little is known of its effects on atrial and ventricular beat rates or patterns of heart rate (HR) acceleration. Fetal atrial and ventricular beat rates were compared before and after transplacental terbutaline treatment (10 to 30 mg/day) by fetal echocardiography in 17 fetuses with CHB caused by immune-mediated damage to a normal conduction system (isoimmune, n = 8) or a congenitally malformed conduction system associated with left atrial isomerism (LAI, n = 9). While receiving terbutaline, 9 of the 17 fetuses underwent fetal magnetocardiography (fMCG) to assess maternal HR and rhythm, patterns of fetal HR acceleration, and correlation between fetal atrial and ventricular accelerations (i.e., AV correlation). Maternal HR and fetal atrial and ventricular beat rates increased with terbutaline. However, terbutaline's effects were greater on the atrial pacemaker(s) in fetuses with isoimmune CHB and greater on the ventricular pacemaker(s) in those with LAI-associated CHB. Patterns of fetal HR acceleration also differed between isoimmune and LAI CHB. Finally, despite increasing HR, terbutaline did not restore the normal coordinated response between atrial and ventricular accelerations in isoimmune or LAI CHB. In conclusion, the pathophysiologic heterogeneity of CHB is reflected in the differing effect of terbutaline on the atrial and ventricular pacemaker(s) and varying patterns of HR acceleration. However, regardless of the cause of CHB, terbutaline augments HR but not AV correlation, suggesting that its effects are determined by the conduction system defect rather than the autonomic control of the developing heart.
doi:10.1016/j.amjcard.2007.03.081
PMCID: PMC3305282  PMID: 17697825
Anti-Ro/SSA antibodies are associated with neonatal lupus (congenital heart block (CHB), neonatal transient skin rash, hematological and hepatic abnormalities), but do not negatively affects other gestational outcomes, and the general outcome of these pregnancies is now good, when followed by experienced multidisciplinary teams. The prevalence of CHB, defined as an atrioventricular block diagnosed in utero, at birth, or within the neonatal period (0–27 days after birth), in the offspring of an anti-Ro/SSA-positive women is 1–2%, of neonatal lupus rash around 10–20%, while laboratory abnormalities in asymptomatic babies can be detected in up to 27% of cases. The risk of recurrence of CHB is ten times higher. Most of the mothers are asymptomatic at delivery and are identified only by the birth of an affected child. Half of these asymptomatic women develop symptoms of a rheumatic disease, most commonly arthralgias and xerophtalmia, but few develop lupus nephritis. A standard therapy for CHB is still matter of investigation, although fluorinated corticosteroids have been reported to be effective for associated cardiomyopathy. Serial echocardiograms and obstetric sonograms, performed at least every 1–2 weeks starting from the 16th week of gestational age, are recommended in anti-Ro/SSA-positive pregnant women to detect early fetal abnormalities that might be a target of preventive therapy.
doi:10.1007/s12016-009-8190-6
PMCID: PMC3558034  PMID: 20012231
Heart block/congenital; Neonatal lupus; Anti-Ro/SSA antibodies
In congenital heart block (CHB), binding of maternal anti-SSA/Ro antibodies to fetal apoptotic cardiocytes impairs their removal by healthy cardiocytes and increases uPA/uPAR-dependent plasmin activation. Since the uPA/uPAR system plays a role in TGF beta activation, we evaluated whether anti-Ro binding to apoptotic cardiocytes enhances plasmin-mediated activation of TGF beta thereby promoting a profibrosing phenotype. Supernatants from co-cultures of healthy cardiocytes and apoptotic cardiocytes bound by IgG from a mother whose child had CHB (apo-CHB-IgG) exhibited significantly increased levels of active TGF beta compared to supernatants from co-cultures of healthy cardiocytes and apoptotic cardiocytes preincubated with IgG (apo-nl-IgG) from a healthy donor. Treatment of the culture medium with anti-TGF beta antibody or TGF beta inhibitor (SB431542) abrogated the luciferase response thereby confirming TGF beta dependency. Increased uPA levels and activity were present in supernatants generated from cocultures of healthy cardiocytes and apo-CHB-IgG cardiocytes compared to healthy cardiocytes and and apo nl-IgG cardiocytes, respectively. Treatment of apo-CHB-IgG cardiocytes with anti-uPAR or anti-uPA antibodies or plasmin inhibitor aprotinin prior to coculturing with healthy cardiocytes attenuated TGF beta activation. Supernatants derived from cocultures of healthy cardiocytes and apo-CHB-IgG cardiocytes promoted Smad2 phosphorylation and fibroblast transdifferentiation as evidenced by increased SMAc and collagen expression, which decreased when fibroblasts were treated with supernatants from cocultures pretreated with uPAR antibodies. These data suggest that binding of anti-Ro antibodies to apoptotic cardiocytes triggers TGF beta activation, by virtue of increasing uPAR-dependent uPA activity, thus initiating and amplifying a cascade of events that promote myofibroblast transdifferentiation and scar.
doi:10.4049/jimmunol.1101288
PMCID: PMC3208032  PMID: 22013113
Background. The presence of anti-SSA/Ro and anti-SSB/La antibodies during pregnancy is associated with fetal congenital heart block (CHB), which is primarily diagnosed through fetal echocardiography. Conclusive information about the complete electrophysiology of the fetal cardiac conducting system is still lacking. In addition to echocardiography, fetal magnetocardiography (fMCG) can be used. fMCG is the magnetic analogue of the fetal electrocardiogram (ECG). Patients and Methods. Forty-eight pregnant women were enrolled in an observational study; 16 of them tested positive for anti-SSA/Ro and anti-SSB/La antibodies. In addition to routine fetal echocardiography, fMCG was used. Fetal cardiac time intervals (fCTIs) were extracted from the magnetic recordings by predefined procedures. ECGs in the neonates of the study group were performed within the first month after delivery. Results. The PQ segment of the fCTI was significantly prolonged in the study group (P = 0.007), representing a delay of the electrical impulse in the atrioventricular (AV) node. Other fCTIs were within normal range. None of the anti-SSA/Ro and/or anti-SSB/La fetuses progressed to a more advanced heart block during pregnancy or after birth. Conclusion. The study identified a low-risk population within antibody positive mothers, where PQ segment prolongation is associated with a lack of progression of the disease.
doi:10.1155/2012/432176
PMCID: PMC3539448  PMID: 23320018
Background
Good and reliable atrial sensing is a fundamental part of atrioventricular (AV) synchrony in dual chamber pacemakers. Due to the floating nature of atrial sensing electrode in single pass dual chamber pacemakers (VDD) compared with two-lead dual chamber pacemakers (DDD), they are more prone to atrial under-sensing and the resulting loss of AV synchrony. We hypothesized that there is a relation between the chronicity of AV block and the amplitude of intracardiac atrial signal amplitudes (IASA).
Methods
Detailed demographic, electrocardiographic and echocardiographic data were recorded in 34 consecutive patients with congenital and acquired complete heart block (CHB). The intracardiac atrial signal amplitudes (IASA) were recorded at implantation time, 48 hours and 2 months post-implantation and compared between the two groups of patients.
Results
The mean age of the study group was 38.73±12.53 years (congenital: 30.08±11.07, acquired: 47.38±6.5). There were no important differences in left atrial or ventricular sizes and in P-wave amplitude in lead II, but the IASA was significantly higher in the congenital group at implantation time (5.21±1.86 vs. 3.38±0.84 mV, P<0.001) and during the follow-up.
Conclusion
The intracardiac atrial signal amplitudes were higher in congenital CHB compared with the acquired CHB. Chronicity (and may be the congenital type) of CHB may be an affecting factor in case selection for VDD pacemaker implantation.
PMCID: PMC2974332  PMID: 21151383
Atrial signal amplitude; Congenital CHB; VDD pacemaker
The Journal of rheumatology  2009;36(8):1744-1748.
Objective
To study anti-Ro/La-negative congenital heart block (CHB).
Methods
Forty-five fetuses with CHB were evaluated by analysis of anti-Ro/La antibodies using sensitive laboratory methods.
Results
There were 9 cases of anti-Ro/La-negative CHB; 3 died (33.3%). Only 3 (33.3%) were complete in utero and 5 (55.5%) were unstable. No specific etiology was diagnosed. Six infants (66.6%) were given pacemakers. There were 36 cases of anti-Ro/La-positive CHB. All except 2 infants (94.4%) had complete atrioventricular block in utero. Ten died (27.8%), one (2.7%) developed severe dilated cardiomyopathy, and 26 (72.2%) were given pacemakers.
Conclusion
Nine of the 45 consecutive CHB cases (20%) were anti-Ro/La-negative with no known cause. They were less stable and complete than the anti-Ro/La positive cases.
doi:10.3899/jrheum.080737
PMCID: PMC2798588  PMID: 19567621
HEART BLOCK; ANTINUCLEAR ANTIBODIES; AUTOIMMUNE DISEASES
Annals of the Rheumatic Diseases  2006;65(11):1422-1426.
Background
Antenatal and postnatal treatment with dexamethasone (DEX) may negatively affect the neuropsychological development in children. Maternal anti‐Ro/Sjögren's syndrome A (SSA) antibodies may also be associated with learning disabilities in offspring.
Objective
To assess neuropsychological development in babies exposed to very high dosages of DEX in utero, whose mothers were anti‐Ro/SSA positive.
Methods
13 children with congenital complete heart block (CHB) (11 exposed and 2 not exposed to DEX) and 3 healthy siblings, all of anti‐Ro/SSA‐positive women, were evaluated. 11 preschool‐aged children (5 boys) were assessed using Griffiths Mental Development Scales. 5 school‐aged children (2 boys) were examined using Wechsler Intelligence Scale for Children—Revised to check IQ and reading tests to explore the existence of learning disabilities or dyslexia. None of the children had had major neonatal complications, although those with CHB had to be paced at different intervals from birth.
Results
The children had been exposed in utero to a mean total dose of 186.6 mg DEX. IQ levels were always normal (mean IQ 105.1, standard deviation (SD) 9.5). Only one child had a learning disability, of borderline clinical significance, but this child had never been exposed to DEX.
Conclusion
No negative effects were found on the neuropsychological development in this cohort of children, even if they had been exposed to maternal anti‐Ro/SSA antibodies and to very high dosages of DEX (much higher than those used to improve fetal lung maturity). These findings might be of interest in view of the large number of infants exposed in the past to repeated antenatal courses of steroids.
doi:10.1136/ard.2005.049866
PMCID: PMC1798357  PMID: 16504990
Human maternal autoantibodies can trigger autoimmune diseases such as congenital heart block (CHB) in the progeny of women with lupus or Sjogren’s disease. The pathogenic effect of early autoantibody (autoAb) exposure has been investigated in a murine neonatal autoimmune ovarian disease (nAOD) model triggered by a unique ZP3 antibody. Although immune complexes (IC) are formed in adult and neonatal ovaries, ZP3 antibody triggers severe nAOD only in <7-day-old neonatal mice. Propensity to nAOD is due to the uniquely hyper-responsive neonatal natural killer (NK) cells that lack the inhibitory Ly49C/I receptors. In nAOD, the neonatal NK cells directly mediate ovarian inflammation and oocyte depletion while simultaneously promoting de novo pathogenic ovarian-specific T cell responses. Resistance to nAOD in older mice results from the emergence of the Ly49C/I+ NK cells that regulate effector NK cells and from CD25+ regulatory T cell control. In preliminary studies, FcγRIII+ NK cells as well as the ovarian resident FcγRIII+ macrophages and/or dendritic cells were found to be as indispensable players. Activated by ovarian IC, they migrate to lymphoid organs where NK cell priming occurs. Remarkably, the findings in nAOD are very similar to those reported for neonatal responses to a retrovirus and its cognate antibody that lead to long-lasting immunity. Studies on nAOD therefore provide insights into maternal autoAb-mediated neonatal autoimmunity, including CHB, while simultaneously uncovering new properties of the neonatal innate and adaptive responses, lethality of premature infant infection, and novel neonatal antiviral vaccine design.
doi:10.3389/fimmu.2014.00242
PMCID: PMC4035566  PMID: 24904590
NK cells; Ly49 receptors; neonatal immunology; immune complex; autoimmune ovarian disease; regulatory T cells; congenital heart block; neonatal viral immunity
Activation of TLR by ssRNA after FcγR-mediated phagocytosis of immune complexes (IC) may be relevant in autoimmune-associated congenital heart block (CHB) where the obligate factor is a maternal anti-SSA/Ro Ab and the fetal factors, protein/RNA on an apoptotic cardiocyte and infiltrating macrophages. This study addressed the hypothesis that Ro60-associated ssRNAs link macrophage activation to fibrosis via TLR engagement. Both macrophage transfection with noncoding ssRNA that bind Ro60 and an IC generated by incubation of Ro60-ssRNA with an IgG fraction from a CHB mother or affinity purified anti-Ro60 significantly increased TNF-α secretion, an effect not observed using control RNAs or normal IgG. Dependence on TLR was supported by the significant inhibition of TNF-α release by IRS661 and chloroquine. The requirement for FcγRIIIa-mediated delivery was provided by inhibition with an anti-CD16a Ab. Fibrosis markers were noticeably increased in fetal cardiac fibroblasts after incubation with supernatants generated from macrophages transfected with ssRNA or incubated with the IC. Supernatants generated from macrophages with ssRNA in the presence of IRS661 or chloroquine did not cause fibrosis. In a CHB heart, but not a healthy heart, TLR7 immunostaining was localized to a region near the atrioventricular groove at a site enriched in mononuclear cells and fibrosis. These data support a novel injury model in CHB, whereby endogenous ligand, Ro60-associated ssRNA, forges a nexus between TLR ligation and fibrosis instigated by binding of anti-Ro Abs to the target protein likely accessible via apoptosis.
doi:10.4049/jimmunol.0902248
PMCID: PMC3551297  PMID: 20089705
Congenital heart block (CHB) is a conduction abnormality that affects hearts of fetuses and/or newborn to mothers with autoantibodies reactive with the intracellular soluble ribonucleoproteins 48kD La, 52kD Ro, and 60kD Ro. CHB carries substantial mortality and morbidity, with more than 60% of affected children requiring lifelong pacemakers. Several hypotheses have been proposed to explain the pathogenesis of CHB. These can be grouped under three main hypotheses: Apoptosis, Serotoninergic and Ca channel hypothesis. Here we discuss these hypotheses and provide recent scientific thinking that will most likely dominate the future of this field of research.
doi:10.1111/j.1365-3083.2010.02439.x
PMCID: PMC2944231  PMID: 20696020
Annals of Pediatric Cardiology  2013;6(2):182-184.
Anti-Ro/La negative congenital heart block (CHB) is uncommon. We report one such case of CHB, with no associated structural heart disease or maternal autoantibodies. The heart block reverted to sinus rhythm spontaneously at two weeks of age, and the patient remains in sinus rhythm at a one year followup. Whether patients with antibody negative complete heart block have a different clinical course is conjectural.
doi:10.4103/0974-2069.115278
PMCID: PMC3957454  PMID: 24688242
Anti Ro/La antibody; congenital heart block; neonatal bradycardia
Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200–239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.
doi:10.1084/jem.20041859
PMCID: PMC2212767  PMID: 15630133
British Medical Journal  1979;1(6173):1235-1238.
The association between infants with congenital heart block (CHB) and the presence or later development of maternal systemic lupus erythematosus or other connective-tissue disease (CTD) was reviewed in 67 cases. In 24 cases CHB was diagnosed at or before birth. Of nine necropsies on affected infants, seven showed endomyocardial fibrosis. The results suggest that one in three mothers who deliver babies with CHB have or will develop CTD. The association is probably explained by placental transfer of a maternal antibody. Awareness of the association may lead to prevention of the birth of children with CHB and better neonatal care of affected children.
PMCID: PMC1598992  PMID: 455010
Arthritis Research & Therapy  2005;7(2):69-73.
Apart from complete and incomplete congenital heart block (CHB), new cardiac manifestations related to anti-SSA/Ro antibodies have been reported in children born to mothers bearing these antibodies. These manifestations include transient fetal first-degree heart block, prolongation of corrected QT (QTc) interval, sinus bradycardia, late-onset cardiomyopathy, endocardial fibroelastosis and cardiac malformations. Anti-SSA/Ro antibodies are not considered pathogenic to the adult heart, but a prolongation of the QTc interval has recently been reported in adult patients and is still a matter of debate. Treatment of CHB is not well established and needs to be assessed carefully. The risks and benefits of prenatal fluorinated steroids are discussed.
doi:10.1186/ar1690
PMCID: PMC1065339  PMID: 15743492
Arthritis Research & Therapy  2003;5(6):266-270.
Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often referred to as a model of passively acquired autoimmunity. In essence, this disease encompasses two patients, both the mother and her child. The signature histologic lesion of autoimmune-associated congenital heart block is fibrosis of the conducting tissue, and in some cases the surrounding myocardium. It is astounding how rapid and, in most cases, irreversible is the fibrotic response to injury. The mechanism by which maternal anti-SSA/Ro–SSB/La antibodies initiate and perpetuate inflammation, and eventuate in scarring of the atrioventricular node, is not yet defined. In vitro and in vivo studies suggest that one pathologic cascade leading to scarring may be initiated via apoptosis, resulting in translocation of SSA/Ro–SSB/La antigens and subsequent surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors that transdifferentiate fibroblasts into myofibroblasts, a scarring phenotype. Dissecting the individual components in this fibrotic pathway should provide insights into the rarity of irreversible injury and should form the basis of rational approaches to prevention and treatment.
doi:10.1186/ar763
PMCID: PMC333420  PMID: 14680501
anti-SSA/Ro and SSB/La antibodies; congenital heart block; myofibroblasts; neonatal lupus

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