Linking genetic susceptibility and T cell activation in beryllium-induced disease

Abstract

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.

Figure 1.

Immunopathogenesis of chronic beryllium disease. Following the inhalation of Be-containing particulates, antigen-presenting cells expressing a βGlu69-containing HLA-DP molecule present Be to CD4⁺ T cells resulting in T cell activation, proliferation, and Th1-type cytokine production.

Figure 2.

HLA-DP2 possesses a solvent-exposed acidic pocket which includes βGlu69. (A) The electrostatic surface charge of the HLA-DP2 molecule (with bound pDRA) is shown colored by the relative charge of the surface atoms (red, negative; blue, positive) (program GRASP). A wireframe representation of pDRA is shown with CPK coloring. (B) DP2 molecule is shown in the area between p4Leu and the DP2 β-chain α-helix with ribbon and wireframe representations of the DP2 β-chain (magenta) and pDRA (yellow coloring), respectively. Wireframe representations of the side chains of βGlu26, βGlu68, and βGlu69 are also shown.