Abnormal Immune Response May Underlie Severe Brain Inflammation in Cerebral ALD, Study Suggests

Abnormal Immune Response May Underlie Severe Brain Inflammation in Cerebral ALD, Study Suggests

The abnormal behavior of immune cells called macrophages may be behind the development of cerebral adrenoleukodystrophy (CALD), a violent form of brain inflammation that affects many patients with X-linked adrenoleukodystrophy (X-ALD), a study reports.

In X-ALD patients, macrophages, which are prominent at tissue injury sites, are predisposed to induce inflammation, and unable to revert to an anti-inflammatory state to prevent brain damage, the data suggests.

The study, “Impaired plasticity of macrophages in X-linked adrenoleukodystrophy,” was published in the journal Brain.

X-ALD, the most common type of adrenoleukodystrophy, is a hereditary condition caused by mutations in the ABCD1 gene. These mutations prevent cells from breaking down a type of fat molecule called very long chain fatty acids, causing them to build up inside the patient’s body. This accumulation may damage the adrenal glands (hormone-producing glands above the kidneys), and destroy the myelin sheath that protects and insulates nerve fibers in the brain and spinal cord.

Myelin is a substance made of fat and proteins that wraps around nerve fibers, allowing neurons to send electric signals faster and more efficiently.

About 60 percent of males with X-ALD develop CALD, a violent form of brain inflammation and myelin loss, or demyelination. This condition often starts early in childhood, rapidly progressing, and is marked by the infiltration of the brain by certain types of white blood cells including monocytes, macrophages, and T-cells. The only available treatment is a blood stem cell transplant or gene therapy at its early stages.

Recently, a team led by researchers at the Medical University of Vienna in Austria found that monocytes and macrophages had a strongly altered metabolism in X-ALD patients.

Monocytes are cells circulating in the blood that, in the presence of injury stimuli, can enter the brain and reach the damaged areas. There, they convert to macrophages, which, together with immune cells in the brain called microglia, begin the healing process of the injury by producing immune messengers and clearing the myelin debris by ingesting it, a process referred to as phagocytosis.

Given the researchers’ observation that the metabolism of X-ALD monocytes and macrophages worked abnormally, they sought to explore more in depth if these defects would play a role in X-ALD development, particularly in the severe brain inflammation of those with CALD.

They performed experiments to compare the biological status of monocytes and macrophages collected from 19 healthy individuals with those of seven patients with adrenomyeloneuropathy (AMN, a milder manifestation of X-ALD) and no signs of brain inflammation.

A gene expression analysis suggested that monocytes of patients are still able to convert to macrophages and clear degraded myelin, i.e., perform phagocytosis, but are more prone to induce inflammation than monocytes from healthy people.

Experiments with macrophages cultured in the laboratory supported these observations. Normally, the uptake of myelin debris by macrophages makes them switch to an anti-inflammatory state to limit the inflammation-associated damage and promote tissue regeneration and remyelination in the brain. However, macrophages from X-ALD patients were unable to completely reverse their pro-inflammatory status, in contrast to those from non-ALD subjects.

Researchers then looked at the status of macrophages in brain lesions of post-mortem samples from patients with CALD, comparing them with samples from people with multiple sclerosis — an inflammatory disease also marked by the loss of myelin.

Comparing both types of lesions, the team found a similar extent of pro-inflammatory activation in the macrophages present; however, in CALD injury sites, the macrophages lacked anti-inflammatory markers.

Researchers have interpreted these results as X-ALD, caused by the ABCD1 deficiency, leading to an aberrant response of macrophages, skewed toward inflammation and incapable of switching to an anti-inflammatory state that limits brain damage. This defect could contribute “to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy that only in rare cases arrests spontaneously,” they wrote.

They concluded that the “findings emphasize monocytes/macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy.”

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