Theoretical considerations support the hypothesis that functionally relevant genes were not positively selected for symptomatic chronic inflammatory diseases (CIDs) because of 3 major reasons: 1) high negative selection pressure with loss of reproducibility; 2) no selection pressure at all (many CIDs of today manifest in higher ages, and due to low life expectancy of our ancestors, they did not suffer from CIDs that we know today); 3) there was no time for natural selection (various CIDs did not exist long enough). Nevertheless, genes can be transferred before outbreak of a CID and can confer an increased risk. However, these genes were positively selected for fitness in reproduction and survival at younger ages independent of a symptomatic CID (antagonistic pleiotropy). Thus, relevant genes were conserved for non-life-threatening inflammatory episodes (NOLTIES) such as infection or wound healing, which did not impede positive selection. Importantly, blastocyst implantation and embryogenesis are NOLTIES. We hypothesized that factors relevant in blastocyst implantation and embryogenesis are also found in active tissue inflammation of a CID.
Rheumatoid arthritis (RA) was used as a paradigmatic CID. An extensive database search in PubMed and OMIM of the U.S. National Library of Medicine was conducted.
Many important similarities between RA and blastocyst implantation/embryogenesis were found including stem cell pathways, hormonal pathways, angiogenesis, neuronal pathways, the wingless (Wnt) pathway, the Notch pathway, the TGF-beta superfamily, matrix metalloproteinases, and others.
It turned out that many factors of RA inflammation were borrowed from the non-life-threatening episode of blastocyst implantation and embryogenesis.