TLR7 Ligands Induce Higher IFN-alpha Production in Females, The Journal of Immunology, 2006, 177: Pages 2088-2096, B. Berghöfer, T. Frommer, G. Haley, et. al.

Lupus affects women far more often than men, by a ratio of 9 to 1. New research has identified one reason why this may occur. At the basis of the research is the interplay between genes that we inherit, immune cells in the body, and the chemicals involved in inflammation.

Cytokines are chemical molecules that act as signals for the immune system to stimulate or dampen inflammation. Interferon alpha (IFN-alpha) has been identified as an important cytokine in lupus. Higher levels of IFN-alpha have been found in the blood of some people with lupus, and some cases of lupus have developed in patients who were given IFN-alpha for hepatitis or certain cancers.

Like other cytokines, IFN-alpha is produced and released by immune cells (white blood cells). These immune cells usually start producing agents like IFN-alpha after something triggers a switch by interacting with proteins on the surface of the white blood cell.

Each protein that sits on the surface of a white blood cell waiting to receive instructions from the outside world is called a receptor. Once they have been triggered, a series of chemical messages are sent into the cell to trigger more kinds of receptors inside the cell’s biologic machinery. Individual receptors accept only specific signals. There may be, however, several different types of signals that can initiate the same response inside the cell. So it is with IFN-alpha; cells can be triggered to start making this inflammatory cytoline through messages received at two different receptors, called TLR7 and TLR9.

A German research team examined the activity of these two receptors in blood samples donated by 344 healthy people, including 175 women and 169 men. White blood cells from these blood samples were stimulated with synthetic forms of both TLR7 and TLR9, and the resulting levels of IFN-alpha were measured. TLR9 and TLR7 both stimulated an increase in the production of IFN-alpha, with a stronger response through TLR9.

The response to TLR9 was the same in women and men. However, the increase of IFN-alpha triggered by TLR7 was significantly higher in women than men. The researchers looked at a number of factors that might be at work, such as estrogen receptors, and did not find the reasons for the difference. The researchers speculate that this difference in the activity of TLR7 between men and women might be one factor responsible for lupus in women and suggest that new treatments might be developed to block TLR7; this might mean different kinds of treatments could be optimal for women and men with lupus.