Why the body is sometimes attacked by its own immune system is largely a mystery. Work by Hirota et al. (page 41) suggests how an underlying genetic predisposition might combine with an environmental factor---specifically, an unrelated infection---to give rise to rheumatoid arthritis (RA) and possibly other autoimmune disorders.

Figure 1Pathogens encourage the production of self-reactive T cells, which cause autoimmune arthritis (purple, infiltrating cells).

A mouse model for RA, called SKG, has a single mutation in the ZAP-70 gene that causes an abundance of highly self-reactive T cells to enter the circulation. In a pathogen-free environment these mice are healthy, but when exposed to pathogens the mice develop autoimmune arthritis.

When these mice start to mount an immune response, such as that induced by a pathogen, their antigen-presenting cells (APCs) increase production of the IL-6 cytokine, the team shows. This IL-6 triggers the T cells to proliferate rapidly and differentiate into Th17 cells, which produce vast amounts of the proinflammatory cytokine IL-17. SKG mice that lacked either IL-17 or IL-6 were protected from arthritis.

Some potentially arthritogenic Th17 cells already exist in the pathogen-free mice due to the constant interaction between APCs and T cells. Activation of the Th17 cells is minimal without pathogen, but an increase in IL-6 during an immune response to a microbe, coupled with the constant exposure to self antigens, is just enough to tip these precariously balanced T cells into overdrive.

IL-17 levels have been shown to be high in a number of autoimmune disorders, including RA. Furthermore, mutation of a protein in the same pathway as ZAP-70 is a common genetic risk factor for RA. It is possible, therefore, that similar genetic and environmental factors also come together to produce RA in humans. ![](jem_iti_end.jpg)

[^1]: <ruth.williams@rockefeller.edu>
