The bioinorganic chemistry and associated immunology of chronic beryllium disease

Abstract

Chronic beryllium disease (CBD) is a debilitating, incurable, and often fatal disease that is caused by the inhalation of beryllium particulates. The growing use of beryllium in the modern world, in products ranging from computers to dental prosthetics (390 tons of beryllium in the US in the year 2000) necessitates a molecular based understanding of the disease in order to prevent and cure CBD. We have investigated the molecular basis of CBD at Los Alamos National Laboratory during the past six years, employing a multidisciplinary approach of bioinorganic chemistry and immunology. The results of this work, including speciation, inhalation and dissolution, and immunology will be discussed.

Fig 1

Immunopathogenesis of CBD. Upon inhalation of beryllium, antigen presenting cells such as macrophages present beryllium to CD4⁺ T cells resulting in T cell activation. Cytokine release (arrows) by both APC and T cells marks the immune response to beryllium.

Fig 2

Homology model of an HLA-DP antibody indicated in CBD (*0201; Table 1). The antigen binding groove resides between the two yellow α-helices. The residues listed in Table 1, glutamic acid (E), aspartic acid (D), tyrosine (Y), and serine (S), are shown as ball and stick representations (carbon as gray; oxygen as red). The far left residue is 55, and the far right residue is 82.

Fig 3

Drawings of beryllium clusters bridged by carboxylate, carbonate, hydroxo, oxo, alkoxide, and phenoxide ligands. In c, the ligand is glycolate, and the carbon backbone for only one glycolate is shown.

Fig 4

Biologically relevant ligands chosen to support the formation of five- and six-membered rings containing beryllium.

Fig 5

Thermal ellipsoid plot (70%) of the [Be₂Al₂(CA)₄]⁶⁻ anion. Blue is aluminium, green is beryllium, red is oxygen, and gray is carbon.

Fig. 6

Plot of pK_a versus beryllium binding, log K, for 11 different ligands based on literature values.^,

Fig 7

Relative LPT response of Be ligands Be₂DHBA (Be–DHBA), BeFeDHBA (Be–Fe–DHBA) BeAlCA (Be–Al–CA), BeAlCA in phosphate buffer (Be–Al–CA-p) and BeFeCA (Be–Fe–CA) as compared to the BeSO₄ response for the same Be concentration at day 5 and day 7.

Scheme 1