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.
Falta
Michael T
MT
Division of Clinical Immunology (B164), University of Colorado Denver, 12700 East 19th Avenue, Aurora, CO 80045, USA.
Bowerman
Natalie A
NA
Dai
Shaodong
S
Kappler
John W
JW
Fontenot
Andrew P
AP
D001607:Berylliosis / Q000235:genetics* / Q000276:immunology*; D001608:Beryllium / Q000009:adverse effects*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006682:HLA-DP Antigens / Q000502:physiology*; D059868:HLA-DP beta-Chains; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*
D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D001608:Beryllium