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Antibody-initiated organ injury: apoptosis, inflammation and fibrosis in neonatal lupus

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus (NL). Although congenital heart block (CHB) and neonatal rash are strongly associated with maternal anti-Ro antibodies, the former occurs earlier and is permanent, and the latter is transient. Defining the pathogenicity of maternal antibodies in both manifestations must account for accessibility of the intracellular target antigen(s). In vitro studies suggest that one pathologic cascade leading to scarring of the conduction system may be initiated via apoptosis of the cardiocytes, resulting in translocation of Ro/La antigens and subsequent surface binding by maternal autoantibodies [1]. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors not only supporting an inflammatory response (secretion of tumor necrosis factor alpha [TNF-α]), but a fibrotic response (secretion of transforming growth factor beta [TGF-β]). The latter results in the transdifferentiation of fibroblasts into myofibroblasts, a scarring phenotype. In vivo studies support the molecular scenario identified in the co-culturing experiments. Based on immunohistochemistry of four fetal hearts identified in utero with CHB or isolated myocarditis, apoptosis was most extensive in fetuses dying early and was most pronounced in regions containing conduction tissue [2]. Deposition of IgG was observed in the CHB/myocarditis fetuses and colocalized to the apoptotic cells. Giant cells and macrophages (frequently seen proximal to IgG) were present in septal and thickened fibrous subendocardial regions, most apparent in the youngest fetuses. Septal tissue also revealed extensive areas of fibrosis and microcalcification in which a predominant smooth muscle actin-positive infiltrate (myofibroblast scarring phenotype) was observed [2]. TGF-β was expressed in septal regions and was present extracellularly in the fibrous matrix and intracellularly in macrophage infiltrates [3]. The detection of nuclear SMAD2 and PAI-1 provided strong evidence for TGF-β activation. Assessment of fetal genetic factors revealed that the TGF-β polymorphism Leu10 (associated with increased fibrosis) was significantly higher in CHB children (genotypic frequency, 60%; allelic frequency, 78%) than unaffected offspring (genotypic frequency, 29%, P = 0.016; allelic frequency, 56%, P = 0.011) [3]. With regard to NL rash, the immunohistology of biopsies taken from the lesional skin of three affected children revealed prominent TNF-α staining (cell-associated and extracellular) in the epidermal region and dermal-epidermal junction as well as the deeper fibroblast zone and adnexa [4]. The -308A allele (associated with higher production of TNF-α), HLA DRQB1*02, and HLA DRB1*03 were each present in the majority of children with rash (64%, 68%, and 64%, respectively). The frequency of all three 6p alleles together in one individual was significantly greater in the children with rash compared with children exposed to maternal anti-SSA/Ro antibodies who had either CHB or no manifestation of NL (59% versus 30%, P = 0.02) [4]. In summary, although maternal antibodies are common to both manifestations of NL, the genetic fetal factor in rash appears to be maternally derived [4] and that in CHB paternally derived [3]. TNF-α may be one of several factors that amplify susceptibility, particularly in NL rash; however, the genetic studies, backed by the histological data, more convincingly link TGF-β to the pathogenesis of CHB. This profibrosing cytokine and its secretion/activation circuitry may provide a novel direction for evaluating fetal factors in the development of a robust animal model of CHB as well as therapeutic strategies in humans.


  1. Buyon JP, Clancy RM: Maternal autoantibodies and congenital heart block: mediators, markers and therapeutic approach. Semin Arthritis Rheum. 2003, 33: 140-154. 10.1016/j.semarthrit.2003.09.002.

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  2. Clancy RM, Kapur RP, Molad Y, Askanase AD, Buyon JP: Immunohistologic evidence supports apoptosis, IgG deposition and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block. Arthritis Rheum. 2004, 50: 173-182. 10.1002/art.11430.

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Supported in part by NIH grants AR42455 (JPB) and AR48409 (RMC), and by patient data/materials from the Research Registry for Neonatal Lupus (NIAMS contract AR4-2220).

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Buyon, J., Clancy, R. Antibody-initiated organ injury: apoptosis, inflammation and fibrosis in neonatal lupus. Arthritis Res Ther 6 (Suppl 3), 31 (2004).

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