Editors' ChoiceInflammation

Limited diversity sparks inflammation at the mucosal border

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Science Translational Medicine  23 Mar 2016:
Vol. 8, Issue 331, pp. 331ec47
DOI: 10.1126/scitranslmed.aaf6416

Immune deficiency is a clear risk for out-of-control microbial growth. Unexpectedly, many immune deficiency diseases also place patients at risk for aggressive autoimmune attack despite their low lymphocyte numbers. Now a new report from Rigoni and colleagues may have tied these features together, which could point the way to better symptom control and interventions.

The authors studied the disease Omenn Syndrome, an immune deficiency disease driven by decreased activity of the recombinase-activating gene (RAG) that is required for T and B lymphocyte development. In its absence, only small numbers of T and B cells with limited antigenic diversity are produced. In addition to infectious illness, patients with Omenn Syndrome suffer from severe inflammatory disease that affects the skin and gut, and also exhibit high levels of circulating IgE antibody. Using a mouse model, the investigators discovered that absent intestinal B cells and resulting decreased mucosal IgA promoted increased bacterial adherence to the gut luminal epithelium, increased translocation of lipopolysaccharide to the blood, and decreased bacterial diversity. This stimulatory environment led to T lymphocyte activation and decreased T regulatory cell function as the key drivers of disease pathology. Treatment of the mice with long-term antibiotic therapy diminished gut inflammation and also normalized serum IgE, a hallmark of Omenn Syndrome in patients. In addition, transfer of the abnormal gut microbiota to healthy mice by fecal transplant disrupted the recipients' immune function.

Overall, these findings point to a key relationship between a normally developed immune system and a healthy gut microbiota. When out of balance, systemic inflammatory disease may result, which can be addressed in part by antibiotic therapy. Other autoimmune and inflammatory diseases, including type 1 diabetes and graft-versus-host disease, also depend on this host-environment interaction. Understanding the specific microbiota involved and their proinflammatory products may enable us to promote proper and balanced diversity in the immune system and microbiota, which may dampen deleterious inflammation at the mucosal border.

R. Rigoni et al., Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. J. Exp. Med. 213, 355–375 (2016). [Abstract]

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