title: Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects.
abstract: BACKGROUND
  Periconceptional supplementation with folic acid results in a significant reduction in the incidence of neural tube defects (NTDs). Nonetheless, NTDs remain a leading cause of perinatal morbidity and mortality worldwide, and the mechanism(s) by which folate exerts its protective effects are unknown. Homocysteine is an amino acid that accumulates under conditions of folate-deficiency, and is suggested as a risk factor for NTDs. One proposed mechanism of homocysteine toxicity is its accumulation into proteins in a process termed homocysteinylation.
  
  
  RESULTS
  Herein, we used a folate-deficient diet in pregnant mice to demonstrate that there is: (i) a significant inverse correlation between maternal serum folate levels and serum homocysteine; (ii) a significant positive correlation between serum homocysteine levels and titers of autoantibodies against homocysteinylated protein; and (iii) a significant increase in congenital malformations and NTDs in mice deficient in serum folate. Furthermore, in mice administered the folate-deplete diet before conception, supplementation with folic acid during the gestational period completely rescued the embryos from congenital defects, and resulted in homocysteinylated protein titers at term that are comparable to that of mice administered a folate-replete diet throughout both the pre- and postconception period. These results demonstrate that a low-folate diet that induces NTDs also increases protein homocysteinylation and the subsequent generation of autoantibodies against homocysteinylated proteins.
  
  
  CONCLUSIONS
  These data support the hypotheses that homocysteinylation results in neo-self antigen formation under conditions of maternal folate deficiency, and that this process is reversible with folic acid supplementation.
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.|School of Medicine, University of Queensland, Brisbane, Australia.
authors.forename: Kerina J
authors.initials: KJ
authors.lastname: Denny
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Christina F
authors.initials: CF
authors.lastname: Kelly
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Katey L
authors.initials: KL
authors.lastname: Witham
authors.affiliation: Department of Nutritional Sciences, The University of Texas, Austin, Texas.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cabrera
authors.affiliation: Department of Nutritional Sciences, The University of Texas, Austin, Texas.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Jeanes
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001798:Blood Proteins / Q000276:immunology / Q000378:metabolism*; D004032:Diet; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood* / Q000276:immunology; D005494:Folic Acid Deficiency / Q000097:blood / Q000150:complications* / Q000276:immunology / Q000473:pathology; D005865:Gestational Age; D006710:Homocysteine / Q000096:biosynthesis / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009436:Neural Tube Defects / Q000097:blood / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D011247:Pregnancy; D011499:Protein Processing, Post-Translational
chemical_list: D001323:Autoantibodies; D001798:Blood Proteins; D006710:Homocysteine; D005492:Folic Acid
keywords: autoantibodies; folate; folate-deficient diet; homocysteine; neural tube defects; pregnancy