Berylliosis: X-ray clues to lung disease

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  • Published: Jul 15, 2014
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Berylliosis: X-ray clues to lung disease

Allergic-autoimmune response

New clues as to why inhalation of dust containing the group II metal, beryllium, causes a deadly immune response in the lungs of some people have emerged from X-ray diffraction, genetic, molecular binding and electrostatic studies. The research shows that a single amino acid change present in one lung protein, HLA-DP2, creates a pocket able to bind beryllium and sodium ions simultaneously and trigger the often lethal allergic disease berylliosis.

New clues as to why inhalation of dust or fumes containing the group II metal, beryllium, causes a deadly immune response in the lungs of some people have emerged from X-ray diffraction, genetic, molecular binding and electrostatic studies. The research shows that a single amino acid change present in one lung protein, HLA-DP2, creates a pocket able to bind beryllium and sodium ions simultaneously and trigger the often lethal allergic disease berylliosis.

John Kappler and colleagues at National Jewish Health have discovered how beryllium triggers a deadly immune response in the lungs. "The immune system does not actually 'see' beryllium," explains Kappler. "The beryllium changes the shape of otherwise innocuous self-peptides so that [immune system] T cells recognize them as foreign and dangerous.

Beryllium is a relatively rare metal whose unique combination of strength and lightness makes it invaluable for various industrial applications in satellite components, computers and mobile phones. It was discovered in the 1930s and 1940s that workers inhaling dust containing the metal can become lodged in the lungs leading to the debilitating and ultimately lethal chronic beryllium disease, berylliosis. While acute problems with beryllium have been eradicated by improved industrial hygiene the chronic disease, which resembles other granulomatous diseases such as sarcoidosis still occurs in industries where beryllium is manufactured and processed.

Protein paradox

Paradoxically, not everyone exposed to inhaled beryllium dust will develop this condition. Kappler and his colleagues describe the molecular biology that gives rise to a genetic susceptibility in about 85 percent of people who develop the condition. The findings, bolstered at the molecular rather than genetic level by X-ray studies reveal for the first time an immune condition that is a hybrid of classical known allergic hypersensitivity and an autoimmune disorder.

Kappler explains that about 85 percent of people with berylliosis have an immune system protein known as HLA-DP2, histocompatibility antigen DP2. This protein flags up protein fragments from within the cell on to the cell surface informing the immune system's sentinels, the T cells, which attack the cell if the protein fragment being displayed is not derived from one of the body's own proteins. If the flag is foreign, from a pathogen that has invaded the cell, then the T cell triggers the immune response.

HLA-DP2 differs from most other peptide-presenting proteins by a single amino acid and Kappler and his colleagues have now used X-ray diffraction, molecular binding and electrostatic studies to show how this single amino acid can combine with other amino acids from HLA-DP2 and some of its bound self-peptides to create a unique molecular pocket that captures a single beryllium ion along with a sodium ion.

Peptide flags

The peptides that bind to HLA-DP2 come from the body’s own tissues and normally elicit no immune response. With the beryllium and sodium firmly lodged in the molecular pocket, however, those peptides are distorted and so T cell sentinels fail to recognize them as self, triggering the immune response, which damages otherwise healthy cells in the lungs causing chronic inflammation and scarring.

"This response resembles allergic hypersensitivity in that a metal ion causes an allergic reaction," Kappler explains. "But it also resembles autoimmunity in that the immune system is mounting an attack against a self-peptide. It is a new form of immune response, and may lead to new therapeutic strategies to treat and prevent the disease."

Kappler has worked long-term Shaodong Dai at National Jewish Health and Andrew Fontenot of the University of Colorado School of Medicine on this lung condition.

Related Links

Cell, 2014, 158, 132-142: "Structural Basis of Chronic Beryllium Disease: Linking Allergic Hypersensitivity and Autoimmunity"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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