A new publication indicates that amyotrophic lateral sclerosis, a chronic and progressive neurodegenerative disease of the upper and lower motor neurons, is associated with an inflammatory attack of the brain and spinal cord.
This is certainly not a common view among scientists, although some related views have long been held for example by Dr. Stanley Appel. On contrary this view, that in some patients the disease begins as a result of trauma or severe infection, has long been advocated by patients on Internet forums.
For dr Appel, initially, motor neurons sustain injuries causing disruptions of critical intracellular pathways. But as injuries add up, motor neurons release distress signals, which induce inflammatory processes produced by surrounding glial cells in the CNS as well as peripheral innate and adaptive immune cells. In addition there are infiltrating peripheral monocytes and lymphocytes
In a rare perspective, the authors, led by Milan Fiala of UCLA's David Geffen School of Medicine, report that while the cause of ALS is unknown, epidemiological data show an association of ALS with trauma antecedents and microbial infections.
For example, the role of microbial infection was noted by the lead author in a study of a genetically identical pair of twins with both twins possessing common ALS mutations, but only the twin suffering from a cat bite and from a severe systemic Pasteurella infection later developed ALS, while the other twin remains healthy 11 years later. The ALS twin exhibited spontaneous production of the cytokines IL-6 and TNFα and epigenetic modification through differential methylation of immune-related regions near the EGFR and TNFRSF11A genes.
For the authors, TDP-43, a nuclear DNA/RNA binding protein present in 95% of ALS patients in an aggregated, poorly localized and unfolded form, induces inflammation. It is not clear from the publication why TDP-43 should have this deleterious behavior. TDP-43 is an essential protein for correcting DNA errors, such as those induced by HIV infections. Interestingly, leading scientists believe it's the opposite: inflammation promotes TDP-43 aggregation.
Scientists studied the peripheral blood mononuclear cell (PBMC) transcriptome of eight patients with sporadic ALS (sALS) over the course of the disease. They also analyzed the relationship between inflammation and autoimmunity in PBMC and NK cells from a pair of ALS-discordant identical twins. But they only followed 2 patients for a year and the results they claim came mostly from one patient (#10). So take all of this with a pinch of salt.
The authors initially hypothesized that activation of the inhibitory co-receptor PD-1 by recombinant PD-L1 would be anti-inflammatory. However, recombinant PD-L1 ligand and recombinant PD-1 receptor were strongly pro-inflammatory.
Then they abandoned the PD-L1 strategy and chose a strategy with dimethyl fumarate (DMF), a drug approved against two autoimmune diseases, multiple sclerosis and psoriasis, and the cGAS- STING H-151 involved in autoimmunity.
While DMF and H-151 have been shown to inhibit inflammatory and autoimmune signaling in the immune cells of some ALS patients, the results are really inconclusive. Scientists suggest that due to the heterogeneity of inflammatory mechanisms in ALS, various immunotherapeutic strategies may be needed.