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

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.

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.