Scientists at La Jolla Institute for Immunology (LJI) have made progress toward understanding the origins of ALS. Their work also offers new directions for treating the disease.

Autoimmunity and ALS

In a recent study, LJI Professor Alessandro Sette, Dr.Biol.Sci., and collaborators at Columbia University Irving Medical Center uncovered evidence that ALS may be an autoimmune disease. The researchers discovered that inflammatory immune cells, called CD4+ T cells, mistakenly target certain proteins that are part of the nervous system in people with ALS.

This was the first study to clearly demonstrate an autoimmune reaction that targets specific proteins associated with the disease in people with ALS. The researchers found that people with ALS produce high numbers of CD4+ T cells that target a specific protein (called C9orf72), which is expressed in neurons. This kind of “self-attack” is the defining feature of autoimmune disease.

The new study gives researchers clues to why ALS progresses so rapidly, and the work presents a possible direction for new ALS treatments that could block this autoimmune activity.

Shedding light on survival times

Although ALS usually progresses quickly, around ten percent of patients live with the disease for ten years or longer. Baseball player Lou Gehrig passed away just two years after his ALS diagnosis. In contrast, physicist Stephen Hawking, Ph.D., lived for 55 years following his diagnosis.

New research from the Sette Lab suggests the immune system plays a big role in patient survival times. 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.

Anti-inflammatory CD4+ T cells are important because they can regulate disease. When the immune system fights a viral infection, for example, it churns out inflammatory T cells to eliminate the infected cells. Once the immune system clears the virus, anti-inflammatory CD4+ T cells step in to prevent overzealous T cells from damaging healthy tissues.

The scientists weren’t expecting to observe this same process in ALS patients. The new research suggests that CD4+ T cells may reduce harmful autoimmune responses and slow the progression of ALS. Now the researchers are interested in exploring whether future ALS therapies might boost protective CD4+ T cell responses and dial back harmful inflammation

Rethinking neurological diseases

Researchers at LJI are leaders in the growing field of neuroimmunology. Recent findings from the Sette Lab have also shown connections between autoimmunity and Parkinson’s disease, another disease marked by the death of neurons.