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Understanding Autoimmune Lung Involvement

Investigators at Cedars-Sinai have uncovered important insights into the pathophysiology of diffuse alveolar hemorrhage (DAH), a rare but dangerous complication that can occur in people with autoimmune diseases, such as vasculitis or systemic lupus erythematosus (SLE).

Autoimmune diseases are ones in which the immune system mistakenly attacks the body's own organs and tissues. When a haywire immune system damages the lungs' small blood vessels, it causes blood to pool in the alveoli—the tiny air sacs at the end of the lungs that allow for oxygen and carbon dioxide exchange. The result is DAH, which can be life threatening if not diagnosed promptly.

The biologic mechanisms that drive bleeding in DAH, however, are not well understood. A new study by Cedars-Sinai investigators, published in Frontiers in Immunology, offers some new clues as to why the bleeding happens.

"We found that immune cells called neutrophils cause a damaging inflammatory response in the cells lining the lungs," said principal investigator and corresponding author Caroline Jefferies, PhD, associate professor within the Division of Rheumatology and the Kao Autoimmunity Institute and Scleroderma Program in the Cedars-Sinai Department of Medicine.

Investigators analyzed lung tissue from laboratory mice in which they had induced DAH. The lung samples showed an accumulation of neutrophils—white blood cells that act as the immune system's first defense. When activated, neutrophils release DNA and proteins as neutrophil extracellular traps (NETs), which trigger inflammation and are known to be involved in the pathophysiology of SLE and vasculitis.

Caroline Jefferies, PhD

Caroline Jefferies, PhD

They also found the lung tissue samples showed increased expression of genes associated with harmful inflammation in the body. Specifically, they observed increased expression of genes involved in a phenomenon called endoplasmic reticulum stress. Normally proteins are folded in an area found in cells called the endoplasmic reticulum (ER). But when cells are stressed, unfolded proteins accumulate in the ER. This activates an ER stress response, which then tries to restore normal function to the ER. If the stress to the cells is too severe, ER stress can drive cell death.

But neutrophils and NETs, the investigators discovered, may drive ER stress in the epithelial cells lining the lung. By deleting an enzyme in neutrophils that is required for the release of NETs, the investigators reduced ER stress and prevented DAH in the lung.

"Our findings suggest that the activated neutrophils in the lung may cause the development of DAH by driving ER stress," Jefferies said.

The investigators also looked at samples of human lung epithelial cells, or the cells that line the lungs. When these samples were cultured with neutrophils from people with SLE, they showed more ER stress than when they were cultured with neutrophils from healthy people.

The findings shed light on what is driving autoimmune lung involvement and may contribute to the development of new drugs to treat DAH and autoimmune lung inflammation.

"Drugs that inhibit neutrophils and the release of NETs may reduce ER stress and lung damage," Jefferies said.