Amyotrophic lateral sclerosis (ALS) is a somewhat age-related disease in that it tends to show up in later life, with fewer than 10% of cases occurring under the age of 40. The relationship between age and risk of ALS is not a clear progression of increasing risk after age 40, however. Most patients with ALS start to exhibit the condition in their 40s or 50s, and the risk declines at older ages. The reasons for this remain obscure, as the research community has struggled to identify the cause of the condition, or even why it progresses very rapidly in some patients versus more slowly in others.
There has long been a strong suspicion than ALS is an autoimmune disease, based on the relationship with age and other aspects of its epidemiology, even lacking firm mechanistic proof of that suspicion. Today's research materials offer a first step towards that firm proof. Researchers provide a mechanism by which the immune system malfunctions to attack motor neurons, and aspects of this mechanism can explain the difference between patients whose disease proves fatal within a couple of years and those who live on for a decade or more.
As this and the relatively recent discovery of type 4 diabetes indicates, we might suspect that a great deal of poorly characterized, quite varied, and poorly understood autoimmunity occurs in later life as the immune system finds ways to malfunction in response to the damage and dysfunction of aging. Only when the onset of a form of autoimmunity occurs relatively early in later life and the outcome is quite characteristic across much of the patient population do we see a lot of attention given to the problem. And even there, as ALS demonstrates, it can take a long time to make progress. Meanwhile the suspected autoimmunities of later old age are obscured by other health issues, and receive comparatively little attention from the research community.
ALS appears to be an autoimmune disease
Around 5,000 Americans are diagnosed with amyotrophic lateral sclerosis (ALS) each year. About half of patients die within 14 to 18 months of being diagnosed, usually due to breathing failure. The exact cause of ALS has long been unknown. Now, scientists have uncovered evidence that ALS may be an autoimmune disease. The researchers discovered that inflammatory immune cells, called CD4+ T cells, mistakenly target a specific protein (called C9orf72), which is expressed in neurons. This kind of "self-attack" is the defining feature of autoimmune disease.
By examining T cell responses in ALS patients, the researchers were surprised to find two distinct patient groups. One group had shorter predicted survival times. Their inflammatory CD4+ T cells were quick to release inflammatory mediators when they recognized C9orf72 proteins. The second patient group also had harmful inflammatory CD4+ T cells, but they also had higher numbers of different T cells, anti-inflammatory CD4+ T cells. This second group also had significantly longer projected survival times. This suggests that the anti-inflammatory CD4+ T cells may reduce harmful autoimmune responses and slow the progression of ALS.
Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Neuroinflammation is apparent in affected tissues, including increased T cell infiltration and activation of microglia, particularly in the spinal cord. Autoimmune responses are thought to have a key role in ALS pathology, and it is hypothesized that T cells contribute to the rapid loss of neurons during disease progression. However, until now there has been no reported target for such an autoimmune response.
Here we show that ALS is associated with recognition of the C9orf72 antigen, and we map the specific epitopes that are recognized. We show that these responses are mediated by CD4+ T cells that preferentially release IL-5 and IL-10, and that IL-10-mediated T cell responses are significantly greater in donors who have a longer predicted survival time. Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T cell responses. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells, and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.
View the full article at FightAging
