| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
and TGF-
1 to the Pathogenesis of Autoimmune-Associated Congenital Heart Block 1
* Hospital for Joint Diseases, New York University School of Medicine, Department of Rheumatology, New York, NY 10003;
Children’s Hospital and Regional Medical Center, Department of Laboratories, and University of Washington, Seattle, WA 98105; and
Rabin Medical Center, Rheumatology Unit, Petah-Tikva, Israel
Although Abs to SSA/Ro-SSB/La are necessary for the development of congenital heart block (CHB), the low frequency suggests that fetal factors are contributory. Because CHB involves a cascade from inflammation to scarring, polymorphisms of the TNF-
promoter region and codons 10 and 25 of the TGF-
gene were evaluated in 88 children (40 CHB, 17 rash, 31 unaffected siblings) and 74 mothers from the Research Registry for Neonatal Lupus (NL). Cytokine expression was assessed in autopsy material from two fetuses with CHB. Significantly increased frequency of the -308A (high-producer) allele of TNF- was observed in all NL groups compared with controls. In contrast, the TGF- 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) and controls, while there were no significant differences between controls and other NL groups. For the TGF- polymorphism, Arg25, there were no significant differences between NL groups and controls. In fetal CHB hearts, protein expression of TGF-, but not TNF-, was demonstrated in septal regions, extracellularly in the fibrous matrix, and intracellularly in macrophage infiltrates. Age-matched fetal hearts from voluntary terminations expressed neither cytokine. TNF- may be one of several factors that amplify susceptibility; however, the genetic studies, backed by the histological data, more convincingly link TGF- 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.
This article has been cited by other articles:
|
|
 |
|
  T L Rivera, P M Izmirly, B K Birnbaum, P Byrne, J B Brauth, M Katholi, M Y Kim, J Fischer, R M Clancy, and J P Buyon Disease progression in mothers of children enrolled in the Research Registry for Neonatal Lupus Ann Rheum Dis, June 1, 2009; 68(6): 828 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Suarez, P Lopez, L Mozo, and C Gutierrez Differential effect of IL10 and TNF{alpha} genotypes on determining susceptibility to discoid and systemic lupus erythematosus Ann Rheum Dis, November 1, 2005; 64(11): 1605 - 1610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N Costedoat-Chalumeau, S Georgin-Lavialle, Z Amoura, and J-C Piette Anti-SSA/Ro and anti-SSB/La antibody-mediated congenital heart block Lupus, September 1, 2005; 14(9): 660 - 664. [Abstract] [PDF]
|
|
|
|
|
|
J P Buyon, A Rupel, and R M Clancy Neonatal lupus syndromes Lupus, September 1, 2004; 13(9): 705 - 712. [Abstract] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
