HLA-DP molecules bind cobalt: a possible explanation for the genetic association with hard metal disease

Metal dust inhalation induces an interstitial lung disease which may progre ss to pulmonary fibrosis (hard metal disease, HMD). Cobalt is believed to b e the pathogenic agent of HMD. A strong genetic association of HMD with som e HLA-DP alleles has been reported although the role of these molecules in the occurrence of the fibrotic disorder remains unclear. A possible explana tion of these findings is that HLA-DP but not other HLA class II molecules can bind cobalt. This could have as a consequence an HLA-DP-mediated specif ic activation of the immune system. To test this hypothesis, we have set up an in vitro binding assay using Co-57 and purified HLA-DP and -DR molecule s. The results indicate that HLA-DP but not HLA-DR molecules bind cobalt. M oreover, the presence of HLA-DP Glu beta 69, which is associated with susce ptibility to HMD, determines a higher metal uptake. Molecular modelling of HLA-DP2 molecules places the Glu beta 69 residue in a position relevant in determining peptide specificity. The possibility that binding of cobalt by HLA-DP molecules can interfere with their antigen presenting functions is d iscussed.