Role of major histocompatibility complex class III genes in recurrent spontaneous abortions

Increased parental Human Leukocyte Antigen (HLA) sharing has been repeatedly reported in recurrent spontaneous abortions (RSA). Parental HLA sharing increases the chance of feto-maternal histocompatibility and potentially affects maternal allo-recognition of the fetus. However, strong linkage disequilibrium across the whole Major Histocompatibility Complex (MHC) region makes it difficult to interpret parental HLA sharing conclusively. It is not known whether the shared HLA gene as such or an unknown gene(s) in linkage disequilibrium or a combination of several loci are causing the disease. Interestingly, in mouse and rat MHC-linked, recessive genes are known to control the reproduction, development and growth of the fetus. Human analogs have not been identified. Compared to HLA genes, MHC Class III has been studied much less in RSA. However, there are some observations of an increased number of unexpressed complement C4 alleles in RSA spouses. Complement C4 genes are located in a chromosomal region characterized by extremely high gene density and frequent gene rearrangements. C4 "null" alleles can act as markers of gene rearrangements in Class III unfavorable for pregnancy outcome. Many of the novel genes located in this region by sequencing serve as new candidates for RSA, since they have housekeeping functions and some of them are highly expressed in human reproductive organs.