Tuberculosis vaccine screening links T-cell response to ALS risk

Lower risk with weaker response supports 'role for immune regulation' in disease

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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People with negative responses to a tuberculin skin test a few years after being vaccinated against tuberculosis had a significant, 25% lower risk of developing amyotrophic lateral sclerosis (ALS) in their lifetime, according to a study in Norway.

Because a positive reaction is linked to the recruitment of T cells — a type of immune cell involved in memory immunity and responses to vaccines — these findings may support the role of T-cell responses in the development of ALS, its researchers said.

The study, “Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk,” was published in the journal Brain, Behavior, & Immunity – Health.

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Immune system response to motor neuron damage known in ALS

In people with ALS, inflammatory cells such as T-cells and microglia are known to locate in brain and spinal cord regions where motor neurons are damaged. However, it remains unknown if this immune cell infiltration is an actual contributor to disease onset and progression, or if it is a consequence of other disease processes.

“If T cells play a primary role, one would expect to find evidence of altered regulation of T cell responses before ALS development,” the researchers wrote.

To better understand T-cells’ role in ALS, researchers at the University of Oslo and Akershus University Hospital used data from a compulsory screening program of people in a Bacillus Calmette–Guerin (BCG) vaccine drive to prevent tuberculosis. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis bacteria that mainly affects the lungs.

Individuals were monitored regularly to determine if they had a positive immunological response to the vaccination and remained protected from tuberculosis, which was widespread in Norway in the early 20th century.

Monitoring was done using the tuberculin skin test, or TST, in which a small amount of tuberculin — a protein from the bacteria that causes tuberculosis — is injected into the skin. The skin reaction was evaluated for size, hard area, or swelling after a few days.

Usually, BCG vaccination results in a positive TST test, but some vaccinated people fail to develop an immune response against tuberculin, meaning their immune system is not equipped to fight the tuberculosis bacteria in case of an infection.

While seemingly unrelated, immune mechanisms involved in a TST response are relevant to ALS because both involve the recruitment of T-cells, enabling researchers to compare T-cell responses in people who later ended up developing ALS with those who didn’t.

From the screening program data, the scientists identified nearly 325,000 people, born between 1910 and 1955, who received a BCG vaccination and had a TST examination one to 15 years afterwards.

Over a median of 40 years of follow-up, 496 of them developed ALS.

Negative skin test results indicate a weaker adaptive immune response

People with a negative TST result had a 25% lower risk of ALS, compared with those with a positive TST reaction, results showed. This association was observed throughout the follow-up, and it was still present four decades later.

Notably, the association between a negative TST test result and reduced ALS risk was even greater as the time between vaccination and TST decreased. For example, patients with a negative TST result within 10 years of vaccination were 33% less likely to develop the disease, and those with a negative test within five years of getting the vaccine were 43% less likely.

In a subgroup of 228,900 people who were vaccinated during adolescence (ages 12 to 17), researchers identified 275 cases of ALS over a median follow-up of 43 years. Regardless of the interval between vaccination and screening, patients in this group with a negative TST reaction had a 33% lower risk of developing ALS.

“We conclude that on population level, a weak secondary adaptive immune response, as measured by TST following BCG vaccination, is associated with low ALS risk several decades later. These results support a primary role for immune regulation in ALS development,” the researchers wrote.

The inability to exclude possible confounding factors that could impact the risk for ALS was noted as a study limitation.