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Jill P Buyon

Publications and source records attributed to Jill P Buyon.

At least 19 recordsLinked to original sources
PubMed2006

Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block.

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.

Animals↗
PubMed2006

Autoimmunity as a result of escape from RNA surveillance.

In previous studies, we detected a frame shift mutation in the gene encoding the autoantigen La of a patient with systemic lupus erythematosus. The mutant La mRNA contains a premature termination codon. mRNAs that prematurely terminate translation should be eliminated by RNA quality control mechanisms. As we find Abs specific for the mutant La form in approximately 30% of sera from anti-La-positive patients, we expected that mutant La mRNAs circumvent RNA control and the expression of mutant La protein could become harmful. Indeed, real-time PCR, immunostaining, and immunoblotting data of mice transgenic for the mutant La form show that mutant La mRNAs are not repressed in these animals and are translated to mutant La protein. In addition to the mutant La protein, we detected a minor portion of native human La in the mutant La-transgenic mice. Therefore, ribosomal frame shifting may allow the mutant La mRNA to escape from RNA control. Interestingly, expression of the mutant La mRNA results in a lupus-like disease in the experimental mice. Consequently, escape of mutant La mRNA from RNA control can have two effects: it 1) results in the expression of an immunogenic (neo)epitope, and 2) predisposes to autoimmunity.

3T3 Cells↗
PubMed2006

Anti-La/SSB antiidiotypic antibodies in maternal serum: a marker of low risk for neonatal lupus in an offspring.

OBJECTIVE: The anti-La/SSB response to major B cell epitopes of La/SSB can be blocked by an active idiotypic/antiidiotypic network, which can be identified using synthetic complementary epitopes deduced from the sequence of the major B cell epitopes of the molecule. This study evaluated the role of this network in pregnant women with anti-Ro/SSA and/or anti-La/SSB antibodies in the development of neonatal lupus syndrome (NLS). METHODS: Sixty-three serum samples collected from anti-Ro/anti-La-positive women during pregnancy or within 6 months after delivery were obtained from the Research Registry for Neonatal Lupus and the PR Interval Dexamethasone Evaluation study. These samples, as well as 30 sera from healthy individuals, were tested in a blinded manner by enzyme-linked immunosorbent assay against synthetic peptides corresponding to major B cell epitopes and complementary epitopes of La/SSB. RESULTS: Sera from mothers giving birth to a healthy child and having no history of a child with NLS exhibited higher antiidiotypic antibody activity compared with mothers carrying a child with NLS (P < 0.0001) or mothers giving birth to a healthy child but who previously gave birth to a child with NLS (P = 0.0151). Sera from mothers of healthy children, which exhibited no apparent epitope activity against amino acids 349-364, revealed a significantly greater frequency of hidden anti-349-364aa epitope responses, blocked by antiidiotypic antibodies, as compared with sera from women pregnant with an affected child (P = 0.0094). CONCLUSION: The presence of antiidiotypic antibodies to autoantibodies against La/SSB may protect the fetus by blocking pathogenic maternal autoantibodies. Testing for these antiidiotypic responses may be useful in predicting a decreased risk of NLS.

Adult↗
PubMed2006

The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Serial measurements of anti-double-stranded DNA (anti-dsDNA) and complement are routine in the management of systemic lupus erythematosus (SLE), but their utility as biomarkers in preemptive treatment to prevent flares remains a subject of controversy. We hypothesized that concomitant elevation of anti-dsDNA and C3a can predict SLE activity in patients with stable or inactive disease and that short-term treatment with corticosteroids can avert flares. METHODS: In this prospective, randomized, double-blind, placebo-controlled trial, 154 patients were evaluated monthly for up to 18 months, with measurements of C3a, C3, C4, CH50, and anti-dsDNA levels. Patients who remained clinically stable but showed serologic evidence of an SLE flare (elevation of both the anti-dsDNA level by 25% and the C3a level by 50% over the previous 1-2 monthly visits) were randomized to receive either prednisone or placebo therapy at a dosage of 30 mg/day for 2 weeks, 20 mg/day for 1 week, and 10 mg/day for 1 week. RESULTS: Forty-one patients (21 randomized to prednisone and 20 randomized to placebo) experienced a serologic flare. Analysis of severe flares occurring 40 mg/day and/or the addition of an immunosuppressive agent. Furthermore, improvement in scores on the Systemic Lupus Erythematosus Disease Activity Index, decreased levels of anti-dsDNA antibodies, and increased levels of C4 occurred 1 month after initiation of prednisone treatment. CONCLUSION: These preliminary data support our hypothesis that in a subset of clinically stable SLE patients with a combination of elevated C3a and anti-dsDNA levels, short-term corticosteroid therapy may avert a severe flare.

Acute Disease↗
PubMed2005

Combined oral contraceptives in women with systemic lupus erythematosus.

BACKGROUND: Oral contraceptives are rarely prescribed for women with systemic lupus erythematosus, because of concern about potential negative side effects. In this double-blind, randomized, noninferiority trial, we prospectively evaluated the effect of oral contraceptives on lupus activity in premenopausal women with systemic lupus erythematosus. METHODS: A total of 183 women with inactive (76 percent) or stable active (24 percent) systemic lupus erythematosus at 15 U.S. sites were randomly assigned to receive either oral contraceptives (triphasic ethinyl estradiol at a dose of 35 microg plus norethindrone at a dose of 0.5 to 1 mg for 12 cycles of 28 days each; 91 women) or placebo (92 women) and were evaluated at months 1, 2, 3, 6, 9, and 12. Subjects were excluded if they had moderate or high levels of anticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. RESULTS: The primary end point, a severe lupus flare, occurred in 7 of 91 subjects receiving oral contraceptives (7.7 percent) as compared with 7 of 92 subjects receiving placebo (7.6 percent). The 12-month rates of severe flare were similar: 0.084 for the group receiving oral contraceptives and 0.087 for the placebo group (P=0.95; upper limit of the one-sided 95 percent confidence interval for this difference, 0.069, which is within the prespecified 9 percent margin for noninferiority). Rates of mild or moderate flares were 1.40 flares per person-year for subjects receiving oral contraceptives and 1.44 flares per person-year for subjects receiving placebo (relative risk, 0.98; P=0.86). In the group that was randomized to receive oral contraceptives, there was one deep venous thrombosis and one clotted graft; in the placebo group, there was one deep venous thrombosis, one ocular thrombosis, one superficial thrombophlebitis, and one death (after cessation of the trial). CONCLUSIONS: Our study indicates that oral contraceptives do not increase the risk of flare among women with systemic lupus erythematosus whose disease is stable.

Adolescent↗
PubMed2005

The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial.

BACKGROUND: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE). OBJECTIVE: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE. DESIGN: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002. SETTING: 16 university-affiliated rheumatology clinics or practices in 11 U.S. states. PATIENTS: 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE. INTERVENTIONS: 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group. MEASUREMENTS: The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite. RESULTS: Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis. LIMITATIONS: Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis. CONCLUSIONS: Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo.

Adolescent↗
PubMed2005

Maternal antibody responses to the 52-kd SSA/RO p200 peptide and the development of fetal conduction defects.

OBJECTIVE: To identify a finer level of antibody specificity for risk of congenital heart block (CHB) than reactivity to 52-kd SSA/Ro (Ro 52). METHODS: Serum from mothers enrolled in the Research Registry for Neonatal Lupus and the observational PR Interval and Dexamethasone Evaluation (PRIDE) study was evaluated for reactivity against peptide aa200-239 of Ro 52 (p200), recently reported to be associated with a higher risk of CHB. RESULTS: The majority of 156 Ro 52-positive sera tested were reactive with p200 (>3 SD above control), irrespective of the clinical status of the child. Optical density (OD) values of p200 did not differ significantly among mothers of children with CHB (mean +/- SD 0.187 +/- 0.363), mothers of children with rash (mean +/- SD 0.176 +/- 0.356), and mothers of children without neonatal lupus (mean +/- SD 0.229 +/- 0.315). Reactivity against p200 was found in 80 of 104 mothers of children with CHB (77%), 24 of 30 mothers of children with rash (80%), and 21 of 22 mothers who delivered healthy children and had no children with neonatal lupus (95%) (P not significant for all comparisons). Sera from 4 mothers of children with CHB with varied p200 titers (OD range 0.025-1.818) bound to the surface of non-permeabilized apoptotic, but not proliferating, human fetal cardiocytes. In 32 Ro 52-positive women who completed the PRIDE study (22 with no child with neonatal lupus, 7 with a child with CHB, and 3 with a child with rash) in whom p200 levels were determined during pregnancy, the correlation between level of p200 (OD range 0.000-1.170) and maximal fetal PR interval (range 115-168 msec) was not significant (rho = 0.107, P = 0.58). CONCLUSION: Reactivity to p200 is a dominant but not uniform anti-Ro 52 response in women whose children have CHB. Since exposure to this antibody specificity was observed with a similar frequency in children without CHB born to mothers with anti-Ro 52, additional factors are necessary to convert risk to disease expression.

Antibodies, Antinuclear↗
PubMed2005

Exposure and binding of selected immunodominant La/SSB epitopes on human apoptotic cells.

OBJECTIVE: Opsonization of apoptotic cells by autoantibodies bound to surface membrane-translocated La/SSB antigens may initiate tissue damage in the setting of congenital heart block. By injecting pregnant mice with human anti-La antibodies, we previously demonstrated the formation of IgG-apoptotic cell complexes in the developing mouse fetus; however, the binding of anti-La antibodies to human-specific epitopes could not be addressed. Accordingly, the objective of the current study was to delineate the epitope specificity of human La antibodies that are exposed on the surface of apoptotic cells. METHODS: We used fluorescence microscopy and flow cytometry to assess the binding of human anti-La antibodies affinity purified against immunodominant epitopes of La to human cells undergoing spontaneous apoptosis, in a murine xenograft model in vivo and in cultured human fetal cardiocytes rendered apoptotic in vitro, respectively. RESULTS: Anti-La antibodies bound to immunodominant epitopes of La within the NH(2)-terminus and the RNA recognition motif (RRM) region of apoptotic human cells, in both xenografts and fetal cardiocytes. In contrast, human antibodies affinity purified against the COOH-terminal La epitope did not bind apoptotic cells in either model. This defines the topology of redistributed La during apoptosis, with surface exposure of the NH(2)-terminus and RRM regions. The potential importance of anti-La NH(2)-terminal and anti-La RRM specificity was confirmed by detection of this reactivity in mothers of children with congenital heart block. CONCLUSION: These findings provide insight into both the molecular modification of the La autoantigen during apoptosis and the specificity of antibodies capable of binding to surface-exposed La. Subsequent formation of surface immune complexes may lead to tissue injury in patients with autoimmune diseases such as congenital heart block.

Animals↗
PubMed2005

Autoantibody-associated congenital heart block: TGFbeta and the road to scar.

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus (NL), often referred to as a model of passively acquired autoimmunity. The signature histologic lesion of autoimmune congenital heart block (CHB) is fibrosis of the conducting tissue and, in some cases, the surrounding myocardium. It is astounding how rapid, and in most cases, irreversible, the fibrotic response to injury is. The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and finally eventuate in atrioventricular (AV) nodal scarring 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 the translocation of SSA/Ro-SSB/La antigens and surface binding by maternal autoantibodies. Subsequently, the Fc portion of the bound immunoglobulin engages Fcgamma receptors on tissue macrophages, resulting in the release of TGFbeta at a threshold that favors a pro-fibrotic milieu and irreversible scarring. This cascade also involves a tissue-specific activation of TGFbeta, which promotes the transdifferentiation of fibroblasts into myofibroblasts, a scarring phenotype. Phagocytosis of opsonized apoptotic cardiocytes is distinct from macrophage pathways engaged in physiologic clearance of dying tissue, which also results in the release of TGFbeta but in the latter case appropriately serves to dampen inflammation. Downregulation of TGFbeta (activation/secretion pathway) may provide the basis of a novel approach to treatment of CHB in the future.

Atrioventricular Node↗
PubMed2005

The role of biomarkers in the assessment of lupus.

Although considered a prototypic autoimmune disease, the hallmark of systemic lupus erythematosus (SLE) is its heterogeneity. Accordingly, manifestations can vary widely from person to person, with the potential involvement of virtually any bodily organ. Furthermore, the genetic abnormalities underlying this condition are complicated, with diverse genetic polymorphisms described in different ethnic groups, strongly suggesting that the actual pathology underlying the immunologic disarray might not be the same for each patient. Evolving concepts of genetics and immunity have clarified that patients can carry unique arrays of exacerbating and protective factors. These factors, in conjunction with variable environmental triggers for SLE, probably determine the sequelae that an individual experiences. Therefore, it is not surprising that the clinical manifestations are diverse, the temporal sequence of organ involvement often unpredictable, and that the flares of inflammatory activity that characterize SLE can either remit without consequence or leave permanent damage in their wake. It is widely accepted that the current standard of care for SLE patients is inadequate. Programs to develop and test new drug and/or device therapies have been ongoing since the mid-1990s but have encountered formidable obstacles. With the current burst of drug discovery and the advent of several large international trials of promising new agents, the challenge to overcome these obstacles has never been greater. A burgeoning literature in the past decades nevertheless suggests that despite the complexities of the many immunologic pathways that impact on SLE, characteristic biologic markers are emerging as potential signposts that can characterize patient subgroups, predict prognosis, mark the exacerbations and remissions of SLE flares, and serve as endpoints in the determination of the dosing and timing of immune-modulating treatments. Several of the promising biomarkers are addressed in this chapter.

Biomarkers↗
PubMed2005

Autoantibodies against the serotoninergic 5-HT4 receptor and congenital heart block: a reassessment.

The specificity of autoantibodies against the serotoninergic 5-HT4 receptor in congenital heart block has led to conflicting observations. In order to clarify the situation, a collaborative effort was undertaken to discover the reasons for these discrepancies and to reassess the importance of such autoantibodies by making use of the Research Registry for Neonatal Lupus. Sera from 128 patients (101 anti-SSA/Ro52 positive mothers among which 74 have children with congenital heart block (CHB), 9 anti-SSA/Ro52 negative patients of which 1 had a child with heart block and 18 healthy donors) were assessed in a single blind test using an ELISA coated with a 5-HT4 receptor-derived peptide. Discrepancies between previous observations in our two groups could be ascribed to small differences in the set up of the assay. Of the 75 sera from mothers of children with CHB, 12 were reactive with the 5-HT4 peptide. Four sera among which three were from 35 Ro52 negative mothers without affected children as well as 2 in the 18 controls were positive. Interestingly, in 1 mother with an isolated child with CHB but who had no detectable anti-SSA/Ro52 antibodies and 1 mother with a child with a structural heart block and no detectable antibodies to any component of SSA/Ro, reactivity with the 5-HT4 receptor was noted. While 5-HT4 receptor autoantibodies do not have the predictive value of anti-Ro52 autoantibodies, the presence of these antibodies in a minor subset of mothers whose children have CHB suggests an additional risk factor which may contribute to the pathogenesis of disease.

Amino Acid Sequence↗
PubMed2005

Neonatal lupus: basic research and clinical perspectives.

Neonatal lupus, although quite rare, carries a significant mortality and morbidity when the fetal heart is the targeted organ. Anti-SSA/Ro-SSB/La antibodies are present in more than 85% of mothers whose fetuses are identified with congenital heart block (CHB) in a structurally normal heart, but the risk for a woman who has the candidate antibodies to have a child who has CHB is approximately 2%. Although the precise pathogenic mechanism of injury remains unknown, it is clear that the antibodies alone are insufficient to cause disease, and fetal factors are likely contributory. In vivo and in vitro evidence supports a pathologic cascade, involving apoptosis of cardiocytes, surface translocation of Ro and La antigens, binding of maternal autoantibodies, secretion of profibrosing factors (eg, tumor growth factor ) from the scavenging macrophages, and modulation of cardiac fibroblasts to a myofibroblast-scarring phenotype. The spectrum of cardiac abnormalities encompasses varying degrees of block identified in utero and late-onset cardiomyopathy. Better echocardiographic measurements that identify first-degree block in utero may be the optimal approach for pregnant women at risk; prophylactic therapies, including treatment with intravenous immunoglobulin, await larger trials.

Female↗
PubMed2005

Shedding of endothelial protein C receptor contributes to vasculopathy and renal injury in lupus: in vivo and in vitro evidence.

BACKGROUND: Candidate biomarkers for vasculopathy in systemic lupus erythematosus (SLE) include circulating endothelial cells and the recently identified endothelial protein C receptor (EPCR) which, when shed, promotes a thrombotic diathesis. This study sought correlation between plasma levels of soluble EPCR and disease manifestation/severity, with a focus on lupus nephritis. METHODS: In 81 SLE patients (evaluated cross-sectionally and longitudinally) and 59 healthy controls, levels of soluble EPCR and soluble E-selectin were assessed by sandwich enzyme-linked immunosorbent assay (ELISA), circulating endothelial cells isolated by immunomagnetic separation, and EPCR gene polymorphisms determined. Mechanisms of vascular injury were addressed in vitro in human aortic endothelial cells (HAEC) cultured in the presence and absence of interferon-gamma (IFN-gamma). RESULTS: The mean level of soluble EPCR was significantly higher in SLE patients (263 +/- 13 ng/mL) than controls (174 +/- 11 ng/mL) (P < 0.0001). Patients with active or past renal involvement had significantly higher mean soluble EPCR levels (306 +/- 21 ng/mL) (N= 40) than patients without nephritis (228 +/- 14 ng/mL) (N= 41) (P= 0.0033). Mean soluble EPCR correlated positively with serum creatinine (R= 0.3429, P < 0.0001). The prevalence of the enhanced-shedding EPCR polymorphism A6936G was higher in SLE (41%) (N= 27) than controls (7%) (N= 29) (P= 0.0039). Patient and control plasma were also interrogated for soluble E-selectin, a comparator plasma marker. The results suggest that soluble E-selectin and soluble EPCR are not equivalent end points of vasculopathy and endothelial perturbation in SLE. Although in SLE patients the absence or diminished expression of membrane EPCR on circulating endothelial cells varied, the rare circulating endothelial cells detected in controls invariably expressed membrane-bound EPCR. IFN-gamma-treated HAEC expressed less membrane-bound EPCR [133 relative fluorescence units (rfu)] than untreated HAEC (275 rfu); more soluble EPCR was detected in IFN-gamma-treated (1.1 ng/10(6) cells) than untreated HAEC (0.65 ng/10(6) cells) (P= 0.027). CONCLUSION: The results obtained from this cross-sectional/longitudinal study support the hypothesis that the vascular dysfunction characteristic of SLE may be related to a dramatically altered distribution of EPCR, both soluble and membrane-bound forms.

Adolescent↗
PubMed2005

Circulating endothelial cells. Biomarker of vascular disease.

Recent research has recognised new populations of non-hematopoietic cells in the blood. One of these, circulating endothelial cells (CECs), often defined by the expression of membrane glycoprotein CD146, are rarely found in the blood in health, but raised numbers are present in a wide variety of human conditions, including inflammatory, immune, infectious, neoplastic and cardiovascular disease, and seem likely to be evidence of profound vascular insult. An additional population are endothelial progenitor cells, defined by the co-expression of endothelial and immaturity cell surface molecules and also by the ability to form colonies in vitro. Although increased numbers of CECs correlate with other markers of vascular disease, questions remain regarding the precise definition, cell biology and origin of CECs. For example, they may be damaged, necrotic or apopototic, or alive, and could possess procoagulant and/or proinflammatory properties. However, since these cells seem to be representative of in situ endothelium, their phenotype may provide useful information. Indeed, whatever their phenotype, there is growing evidence that CECs may well be a novel biomarker, the measurement of which will have utility in various clinical settings related to vascular injury. Despite this promise, progress is impeded by the diversity of methodologies used to detect these cells. Accordingly, results are sometimes inconclusive and even conflicting. Nevertheless, increased CECs predict adverse cardiovascular events in acute coronary syndromes, suggesting they may move from being simply a research index to having a role in the clinic. The objective of the present communication is to condense existing data on CECs, briefly compare them with progenitor cells, and summarise possible mechanism(s) by which they may contribute to vascular pathology.

Animals↗
PubMed2004

Autoimmune-associated congenital heart block: dissecting the cascade from immunologic insult to relentless fibrosis.

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often described as a model of passively acquired autoimmunity. The signature histologic lesion of autoimmune congenital heart block (CHB) is fibrosis of the conducting tissue and, in some cases, the surrounding myocardium. Although anti-SSA/Ro-SSB/La antibodies are detected in > 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, the risk for a woman with the candidate antibodies to have a child with CHB is 2%. The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and finally eventuate in atrioventricular nodal scarring is not yet defined, but it is clear that the antibodies alone are insufficient to cause disease and fetal factors are likely contributory. Previous in vitro and in vivo studies suggest that the pathologic cascade is initiated via apoptosis, resulting in translocation of SSA/Ro-SSB/La antigens to the cell surface where they are bound by maternal autoantibodies. Subsequently, the Fc portion of the bound immunoglobulin engages Fcgamma receptors on tissue macrophages, resulting in release of TGF-beta at a threshold favoring a profibrotic milieu and irreversible scarring. This cascade also involves tissue-specific activation of TGF-beta, which promotes the modulation of fibroblasts into myofibroblasts, a scarring phenotype. Recent findings point to genetic polymorphisms that promote high production of TGF-beta as possible fetal risk factors for CHB. Further elucidation of maternal and fetal contributory factors should provide insight into the pathogenesis of CHB and the rarity of irreversible injury.

Animals↗