Andrew P. Fontenot

Linking Genetic Susceptibility and T Cell Activation in Beryllium-induced Disease

Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium (Be) exposure in the workplace. It is characterized by the accumulation of Be-specific CD4(+) T cells in the lung as well as persistent lung inflammation, culminating in the development of lung fibrosis. CBD occurs in 2 to 16% of Be-exposed workers depending on the individuals genetic susceptibility and the characteristics of the exposure. Genetic susceptibility to Be-induced disease has been linked to major histocompatibility complex class II molecules. In particular, HLA-DP alleles possessing a glutamic acid at the 69th position of the beta-chain (betaGlu69) are most strongly linked to disease susceptibility. The HLA-DP alleles that present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. However, the structural features of betaGlu69-containing HLA-DP molecules that explain the disease association remain unknown. We have recently crystallized HLA-DP2, which is the most prevalent of the betaGlu69-containing HLA-DP molecules. Its unique structure, which includes surface exposure of betaGlu69, provides an explanation of the genetic linkage between betaGlu69-containing HLA-DP alleles and Be-induced disease.

IL-17-Producing γδ T Cells in Auto-immune Disease

In both mice and humans, γδ T cells often represent a significant source of IL-17. Here we review the evidence that IL-17-producing γδ T cells contribute to auto-immune disease and discuss the role that they play in disease processes, including their influence on the development or activity of TH17 αβ T cells. Although IL-17-producing γδ T cells clearly can exacerbate auto-immune disease, in some systems they have instead been shown to play a protective role. The ability to produce IL-22 as well may be critical for this protective role.