Brian Scott and colleagues at Los Alamos National Laboratory, US, examine the molecular basis of chronic beryllium disease

Beryllium pervades today's technologies, from cars and computers through to dental prosthetics. Its popularity is related to its unique properties: it is lightweight, six times stiffer than steel, has a high melting point (1285 ºC) and heat absorption capacity, and is non-magnetic and corrosion resistant. Beryllium also reflects neutrons and is used for nuclear power and weapons applications. In the year 2000 the US used 390 tons of beryllium, with an estimated value of $140 million. 

But, the metal has negative health effects: in susceptible individuals, beryllium exposure causes a lung disorder called chronic beryllium disease (CBD) - a debilitating, incurable and often fatal condition. Given beryllium's widespread use, this toxicity makes it imperative to better understand beryllium's chemistry under biological conditions and how this leads to disease and potential cures and therapeutics.

A beryllium antigen (centre) binds to an HLA molecule on an antigen presenting cell and is presented to a T cell, triggering an immune response

It is thought that the immune response to beryllium is triggered when the unwittingly-inhaled element is detected by antigen presenting cells (APC, see figure). An unknown beryllium species serves as the antigen which binds to a human leukocyte antigen (HLA) molecule on an APC's surface. The beryllium antigen is then presented to a T cell - a white blood cell with a key role in immune response. Research over the past six years at Los Alamos has resulted in a more complete picture of beryllium's speciation under biological conditions, including its interactions with proteins and the subsequent immunological consequences.

Through the study of several biologically relevant small molecule complexes of beryllium, it was discovered that beryllium has a high propensity to displace hydrogen atoms in strong hydrogen bonds. These bonds, often formed between amino acids containing carboxylate and alcohol groups, help provide the framework supporting protein structure and function. Extending this model to real biological systems, it was shown that beryllium displaced all 12 strong hydrogen bond atoms in transferrin, an iron transport protein found in blood plasma. This presents a potential pathway for beryllium to enter cells with transferrin receptors. These binding studies represent a new paradigm for beryllium binding in biological systems. 

Related to its propensity to displace hydrogen bond atoms, beryllium is known to form polymetallic clusters with carboxylate groups. So it has been predicted that beryllium will also form clusters in proteins with many adjacent carboxylate residues. A striking discovery was that the HLA molecules of CBD patients contain a larger number of carboxylate residues than the HLA molecules of people without CBD. And ⁹Be NMR binding studies point to a carboxylate bridged cluster of beryllium atoms as an integral structural feature of the antigen (see figure). 

Microarray studies have led to other insights into the mechanisms governing beryllium immune response. Cell adhesion genes and chemokines (small proteins that mediate cell migration) are upregulated in cells treated with beryllium. This suggests a mechanism involving chemokine gradients to attract immune cells to sites of inflammation. Additionally, immune cells treated with beryllium show altered intracellular signalling and cytokine release in response to lipopolysaccharide - a toxin found in bacterial outer cell membranes. This suggests that prior exposure to beryllium may alter the host immune response to subsequent bacterial infections. The implication that cell adhesion molecules and chemokines are linked to CBD potentially opens the door to using molecules that downregulate these immune molecules to inhibit progression of disease symptoms.

A multidisciplinary, molecular based approach to studying CBD has identified relevant beryllium species, their interactions with proteins and the potential roles they play in disease. This may not only lead to potential cures and therapeutics for CBD, but also lend insight into mechanisms of other metal and autoimmune diseases. 
 
Read more in the feature article 'The bioinorganic chemistry and associated immunology of chronic beryllium disease' in ChemComm