Neural tube defects, folate, and immune modulation

Abstract

Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored.

Keywords: C5a; complement; folate; neural tube defects; neurulation.

Figure 1

The connecting links between neural tube defects (NTDs), immune factors, and folate. Many lines of evidence now link two of the three hubs, while recent evidence shows that knockout or inhibition of the innate immune complement receptor, C5aR, leads to neural tube defects under conditions of folate deficiency (Denny et al., 2013). Notes contained in blue boxes relate to positive relationships, notes in red boxes relate to inverse or negative relationships. ¹ Denny et al. (2013). ² Girardi et al. (2008). ³ Lomaga et al. (2000); McGrath et al. (1999); McLin et al. (2008); Phelan et al. (2005); Regnier et al. (2002); Tissir et al. (2004). ⁴ Torchinsky et al. (1997); Hrubec et al. (2006). ⁵ Greene et al. (2009b). ⁶ Spiegelstein et al. (2004). ⁷ Smithells et al. (1976). ⁸ Duthie et al. (2010). ⁹ Cabrera et al. (2008). ¹⁰ Hammons et al. (2009). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]