HLA-DP allele-specific T cell responses to beryllium account for DP-associated susceptibility to chronic beryllium disease.
Occupational exposure to small molecules, such as metals, is frequently associated with hypersensitivity reactions. Chronic beryllium (Be) disease (CBD) is a multisystem granulomatous disease that primarily affects the lung, and occurs in approximately 3% of individuals exposed to this element. Immunogenetic studies have demonstrated a strong association between CBD and possession of alleles of HLA-DP containing glutamic acid (Glu) at position 69 in the HLA-DP beta-chain. T cell clones were raised from three patients with CBD in whom exposure occurred 10 and 30 years previously. Of 25 Be-specific clones that were obtained, all were restricted by HLA-DP alleles with Glu at DP beta69. Furthermore, the proliferative responses of the clones were absolutely dependent upon DP beta Glu(69) in that a single amino acid substitution at this position abolished the response. As befits a disease whose pathogenesis involves a delayed type hypersensitivity response, the large majority of Be-specific clones secreted IFN-gamma (Th1) and little or no IL-4 (Th2) cytokines. This study provides insights into the molecular basis of DP2-associated susceptibility to CBD.
Lombardi
G
G
Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom. g.lombardi@ic.ac.uk
Germain
C
C
Uren
J
J
Fiorillo
M T
MT
du Bois
R M
RM
Jones-Williams
W
W
Saltini
C
C
Sorrentino
R
R
Lechler
R
R
D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001607:Berylliosis / Q000235:genetics* / Q000276:immunology*; D001608:Beryllium / Q000276:immunology*; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D002908:Chronic Disease; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000235:genetics; D006682:HLA-DP Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006682:HLA-DP Antigens; D018698:Glutamic Acid; D001608:Beryllium