Pathogenesis

The available evidence points strongly to autoantibodies as the cause of NLE. Maternal autoantibodies are uniformly present in NLE, and they are of a distinct family of autoantibodies. Disease activity resolves as the maternal autoantibodies are metabolized. Antibody deposits in tissues have been shown to represent anti-Ro/SSA (Lee et al. 1989, Reichlin et al. 1994).

The autoantibodies most closely linked to NLE are antibodies to 60-kDa Ro/SSA and antibodies to 52-kDa Ro/SSA (Lee et al. 1994). Several investigators have attempted to reproduce disease using infused anti-Ro/SSA. Isolated rabbit cardiac muscle has been shown to develop abnormalities of repolarization when infused with anti-Ro/SSA-containing serum (likely representing a combination of anti-60-kDa Ro/SSA and anti-52-kDa Ro/SSA) (Alexander et al. 1992). Isolated rabbit hearts and isolated rat hearts perfused with anti-Ro-containing serum and anti-52-kDa Ro/SSA developed heart block (Boutjdir et al. 1998, Garcia et al. 1994,Viana et al. 1998). Some newborn mice whose mothers received anti-Ro/SSA and/or La/SSB-containing IgG during pregnancy experienced bradycardia and prolonged PR interval (Mazel et al. 1999). An interaction of NLE maternal IgG with human fetal cardiac sarcolemma and with human L-type calcium channel alpha (1C) protein has been demonstrated (Qu et al. 2001).

The 60- and 52-kDa Ro/SSA proteins are apparently expressed ubiquitously, and it has not been clear why the disease process in NLE is apparently limited to only a few organs. It has been proposed that tissue specificity may be conferred by cross-reac-tivitybetween 52-kDa Ro/SSA and the 5-HT4 serotoninergic receptor (Eftekhari et al. 2000). Pups from mice immunized with anti-5HT4 receptor peptides developed bradycardia, incomplete atrioventricular block, prolonged QT, skin lesions, and neu-romotor problems (Eftekhari et al. 2001). One group reported that NLE serum samples contain, independent of anti-Ro, autoantibodies to neonatal heart M1 muscarinic acetylcholine receptor (Borda and Sterin-Borda 2001). The finding of expression of different isoforms of 52-kDa Ro/SSA at different times during cardiac development led to a proposed link between expression of specific 52-kDa Ro/SSA isoforms and the development of congenital heart block (Buyon et al. 1997). RNAs associated with 60-kDa Ro/SSA are also expressed differentially during development (Fraire-Velzquez et al. 1999).

Genetic factors that have been identified as contributors to NLE include genes of the major histocompatibility complex (MHC) and C4 (Lee et al. 1983, Miyagawa et al. 1997,1999, Watson et al. 1992). These associations are noted in NLE mothers and may in part be related to increased risk for production of anti-Ro/SSA autoantibodies. Genetic factors that contribute to determining which babies exposed to maternal anti-Ro/SSA autoantibodies will be affected and which will not have not yet been completely established, but there is emerging evidence that tumor necrosis factor (TNF)-a and transforming growth factor (TGF)-p polymorphisms may contribute (Clancy et al. 2003).

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