Toxicology 165 (2001) 27 – 38 Beryllium sensitivity is linked to HLA-DP genotype Zaolin Wang a , Georgia M Farris a , Lee S. Newman b , Yulin Shou a , Lisa A. Maier b , Hugh N. Smith a , Babetta L. Marrone a, * a B-2, M888, Bioscience Diision, Los Alamos National Laboratory, Los Alamos, NM 87545, USA b National Jewish Medical and Research Center and Uniersity of Colorado, Health Sciences Center, Dener, CO, USA Received 1 February 2001; received in revised form 30 April 2001; accepted 3 May 2001 Abstract Chronic beryllium disease (CBD) appears to arise from a combination of both exposure and genetic risk factors. A distinguishing feature of CBD is beryllium hypersensitivity, which can be measured in vitro by a lymphocyte proliferation test. The objective of this study was to determine whether certain allelic variations of the HLA-DPB1 gene, which had been observed previously in CBD, could be found in a group of individuals having beryllium hypersensitivity, but no symptoms of CBD. A flow cytometry-based Lymphocyte Proliferation Test combined with immunophenotyping (Immuno-LPT) was used to detect CD4 + and CD8 + T cell proliferation in response to in vitro stimulation with beryllium. The HLA-DPB1 haplotypes of the same individuals were determined by automated DNA sequencing. Twenty-two out of 25 beryllium-sensitive, non-CBD individuals were found to be carriers of the HLA-DPB1 gene having a substitution of a glutamic acid at position 69 in Exon 2 (Glu69), and a significantly high percentage (24%) were Glu69 homozygotes. Most of the CD4 + responders on the Immuno-LPT (10/14) carried rare, non-*0201 Glu69 DPB1 alleles; while most of the non-CD4 + responders (9/11) were common Glu69 carriers (*0201 or *0202) or non-Glu69 individuals (non-Glu69/non-Glu69). This is the first direct evidence that HLA-DP genotype is linked to a phenotypic response that occurs in beryllium sensitization in the absence of clinical CBD. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Beryllium; Chronic beryllium disease; Immune response; Genetic susceptibility; Lymphocyte proliferation test; HLA-DP alleles www.elsevier.com/locate/toxicol 1. Introduction Beryllium, due to its unique chemical and phys- ical properties, is being used increasingly in al- most every modern industry. However, inhalation of Be-containing vapor mist or dust can cause two types of toxicity; an acute inflammation response and a chronic immune response (Sterner and Eisenbud, 1951). The latter is the basis for chronic beryllium disease (CBD), which was first de- scribed in 1946 (Hardy and Tabershaw, 1946). CBD is a lung granulomatous disease character- ized by a Type IV, delayed hypersensitivity, cell- mediated immunity (Newman, 1995). Some * Corresponding author. Tel.: +1-505-667-3279; fax: +1- 505-665-6894. E-mail address: blm@lanl.gov (B.L. Marrone). 0300-483X/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0300-483X(01)00410-3