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Maternal autoantibodies and congenital heart block: mediators, markers, and therapeutic approach

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Maternal autoantibodies: identification of the candidate targets

Bridging the gap from identification of the target antigens recognized by the maternal autoantibodies to the mechanism by which these antibodies affect clinical disease represents a major challenge. Although the necessity of anti—SSA/Ro-SSB/La antibodies is supported by their presence in >85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart (3), when clinicians applied this testing to their pregnant patients, the risk for a woman with the

Evaluating the fine specificities of the maternal autoantibody response

The use of serologic testing to identify the mother at highest risk for having a child with CHB is particularly challenging, because it is difficult to assemble a control group of mothers against whom a particular antibody profile will be compared. The challenge is to match on maternal diagnosis, which is not straightforward because most of the mothers with affected children are either asymptomatic or have an undifferentiated autoimmune disease 10, 43, 44 that may subsequently progress to SS 20

Considerations for therapeutic intervention

The substantial morbidity and mortality associated with CHB 10, 12, 58, 59 and the readily available technology for identification of CHB in utero have prompted the search for effective therapies. Ideally, because CHB is most often identified between 18 and 24 weeks of gestation 10, 11, intrauterine therapy should be possible. Firm guidelines for the obstetric and rheumatologic management of the fetus identified with CHB, and the fetus with a normal heartbeat but at high risk for developing

Jill P. Buyon, MD: Professor of Medicine

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References (82)

  • J Copel et al.

    Successful in utero therapy of fetal heart block

    Am J Obstet Gynecol

    (1995)
  • I.Z Beitins et al.

    The transplacental passage of prednisone and prednisolone in pregnancy near term

    J Pediatr

    (1972)
  • D Rosenthal et al.

    A new therapeutic approach to the fetus with congenital complete heart blockPreemptive, targeted therapy with dexamethasone

    Obstet Gynecol

    (1998)
  • K.L Harkavy et al.

    Dexamethasone therapy for chronic lung disease in ventilator- and oxygen-dependent infantsa controlled trial

    J Pediatr

    (1989)
  • J.B Van Goudoever et al.

    Effect of dexamethasone on protein metabolism in infants with bronchopulmonary dysplasia

    J Pediatr

    (1994)
  • T.F Yeh et al.

    Early postnatal dexamethasone therapy in premature infants with severe respiratory distress syndromeA double-blind, controlled study

    J Pediatr

    (1990)
  • A.H Jobe

    Glucocorticoids in perinatal medicineMisguided rockets?

    J Pediatr

    (2000)
  • J.S Scott et al.

    Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block

    N Engl J Med

    (1983)
  • L.A Lee et al.

    Autoantibodies to SS-A/Ro in congenital heart block

    Arthritis Rheum

    (1983)
  • J.P Buyon

    Neonatal lupus syndromes

  • L.A Lee

    Neonatal lupus erythematosus

    J Invest Derm

    (1993)
  • J.P Buyon et al.

    Congenital complete heart blockA human model of passively acquired autoimmune injury

    Arthritis Rheum

    (1990)
  • J.P Buyon et al.

    In utero identification and therapy of congenital heart block (CHB)

    Lupus

    (1995)
  • G Herreman et al.

    Maternal connective tissue disease and congenital heart block

    N Engl J Med

    (1985)
  • J Buyon et al.

    Intra-uterine therapy of presumptive fetal myocarditis with heart block occurring in a mother with systemic lupus erythematosus and a predominance of La (SSB) antibodies

    Arthritis Rheum

    (1987)
  • A Brucato et al.

    Risk of congenital congenital heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis

    Arthritis Rheum

    (2001)
  • J Waltuck et al.

    Autoantibody-associated congenital heart blockOutcome in mothers and children

    Ann Intern Med

    (1994)
  • E.D Silverman

    Congenital heart block and neonatal lupus erythematosusPrevention is the goal

    J Rheumatol

    (1993)
  • D.D.G Solomon et al.

    Birth order, gender and recurrence rate in autoantibody-associated congenital heart blockImplications for pathogenesis and family counseling

    Lupus

    (2003)
  • M Reichlin et al.

    Concentration of autoantibodies to native 60-kd Ro/SS-A and denatured 52-kd Ro/SS-A in eluates from the heart of a child who died with congenital complete heart block

    Arthritis Rheum

    (1994)
  • E Alexander et al.

    Anti-Ro/SS-A antibodies in the pathophysiology of congenital heart block in neonatal lupus syndrome, an experimental modelIn vitro electrophysiologic and immunocytochemical studies

    Arthritis Rheum

    (1992)
  • S Garcia et al.

    Cellular mechanism of the conduction abnormalities induced by serum from anti-Ro/SSA-positive patients in rabbit hearts

    J Clin Invest

    (1994)
  • M Boutjdir et al.

    Serum and IgG from the mother of a child with congenital heart block induce conduction abnormalities and inhibit L-type calcium channels in a rat heart model

    Pediatr Res

    (1998)
  • P Eftekhari et al.

    Anti-Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block

    Eur J Immunol

    (2000)
  • H Julkunen et al.

    Isolated congenital heart blockLong-term outcome of mothers and characterization of the immune response to SS-A/Ro and to SS-B/La

    Arthritis Rheum

    (1993)
  • J.P Buyon et al.

    Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their childrenComparison of ELISA and immunoblot to measure anti-SS-A/Ro and anti-SS-B/La antibodies

    Arthritis Rheum

    (1993)
  • S Riemersma et al.

    Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine receptor function

    J Clin Invest

    (1996)
  • E.K.L Chan et al.

    52-kD SS-A/RoGenomic structure and identification of an alternatively spliced transcript encoding a novel leucine zipper-minus autoantigen expressed in fetal and adult heart

    J Exp Med

    (1995)
  • J.P Buyon et al.

    Cardiac expression of 52β, an alternative transcript of the congenital heart block-associated 52-kD SS-A/Ro autoantigen, is maximal during fetal development

    Arthritis Rheum

    (1997)
  • H.B Tran et al.

    Subcellular redistribution of La/SSB autoantigen during physiologic apoptosis in the fetal mouse heart and conduction systemA clue to the pathogenesis of congenital heart block

    Arthritis Rheum

    (2002)
  • H.B Tran et al.

    Anti-La/SSB antibodies transported across the placenta bind apoptotic cells in fetal organs targeted in neonatal lupus

    Arthritis Rheum

    (2002)
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    • Secreted autoantibody repertoires in Sjögren's syndrome and systemic lupus erythematosus: A proteomic approach

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      Direct autoantibody sequencing has revealed for the first time that humoral autoimmunity in these diseases is dominated by public (shared) sets of clonotypic autoantibodies. Ro60 is considered to be a primordial autoantigen involved in the initiation of systemic autoimmunity, with anti-Ro60 occurring years before clinical autoimmunity and becoming pathogenic on binding Ro60 on the surface of apoptotic fetal cardiomyocytes in congenital heart block [2,26,27]. A subset of anti-Ro60 in patients with linked anti-Ro60/La responses react on solid phase immunoassay with an apical peg-like structure on Ro60 that is expressed on intracellular Ro/La–RNP complexes [28].

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      It is the most severe complication that may affect the offspring of women with SS and it is attributed to anti-Ro/SSA and/or anti-La/SSB-mediated damage of the atrio-ventricular node. The occurrence rate of CHB has been estimated at approximately 2% in all infants born to women with anti-Ro/SSA antibodies [3–7] and 3% in all infants born to women with anti-La/SSB [8–10]. The recurrence rate in a mother with antibodies, who has a previous child affected, is approximately 16–18% [3,8,11]: it is nearly nine times higher than the risk for CHB in a primigravida with the candidate antibodies.

    • Nucleic acid-associated autoantigens: Pathogenic involvement and therapeutic potential

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      When mothers have connective tissue diseases with anti-Ro/SS-A antibodies, incidence of CHB is 1–2% in live births [273,274]. Tissue injury in CHB is thought to be mediated by the binding of maternal anti-Ro/La autoAbs to apoptotic cells in the developing fetal heart [275]. This may be particularly caused by Abs to Ro52, which may play a direct pathogenic role in congenital heart block by cross-reaction to the human serotoninergic 5-HT-4 receptor [6,276,277].

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      The mortality of CHB in utero and in the first months of life is an estimated 16-19%. A pacemaker is required in about 66% of cases in childhood and eventually almost 100% of children will require one by adulthood (120). Curative treatment of CHB is based on dexamethasone or betameth1asone therapy that crosses the placenta in an active form (124).

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    Jill P. Buyon, MD: Professor of Medicine

    Robert M. Clancy, PhD: Research Associate Professor.

    Supported by the United States National Institutes of Health/NIAMS Grants AR-42455 (to J.P.B.), AR-48409 (to R.M.C.), and contract AR-4-2220 for the Research Registry for Neonatal Lupus (directed by J.P.B.).

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