Could tolerance to DNA be broken in the gut in systemic lupus erythematosus?

The bacteria in the human colon outnumber the total number of nucleated cells in the human body by approximately 10:1. The DNA that the bacteria contain is enriched around 20-fold in immune stimulatory CpG motifs compared to the DNA of host cells. In addition, this DNA can have alternative more immunogeneic DNA structures and it may be presented to the immune system alongside other proinflammatory bacterial innate ligands such as LPS. To ensure that this immunostimulatory combination is not pathogenic, the luminal boundary of host tissues in the human gastrointestinal tract is protected by cells secreting bactericides together with the secreted enzyme DNASE1L3 that can break down bacterial DNA. Cells with RNA encoding DNASE1L3 are particularly abundant in the gut-associated lymphoid tissue where bacteria are specifically sampled into the body, alongside B cells noted for their T independent function. Importantly, individuals with loss of function mutations in DNASE1L3 develop anti-DNA antibodies and lupus symptoms. In this review, we explore the possibility that a perfect storm might break tolerance to DNA: when bacterial DNA from microbiota that is not digested by DNASE1L3 directly encounters B cells that are not necessarily restricted by T cell dependence.