Immunological Phenotypes Associated with Neurodegenerative Disease

Abstract

The etiology of most neurodegenerative diseases remains a mystery. Environmental factors seemingly play an important role in neurodegenerative diseases, as does the immune system. Here, we describe immunological phenotypes associated with the neurodegenerative diseases AOA2 and ALS. During CSR, B-cells and neurons share a preferred pathway for DNA repair, NHEJ. SETX, the gene implicated in AOA2, has been implicated in the DDR. In SETX-deficient conditions, B-cells exhibit a defect in IgA class-switching as a result of impaired NHEJ and enhanced alternate-end joining, a slower process with higher mutational burden. These results suggest that neurons in SETX-deficient patients may also demonstrate defects in DNA repair, leaving them more susceptible to death. Further, IgA plays an important role in both protection from infections and as an anti-inflammatory mediator at mucosal surfaces. Defects in IgA class switching might lead to immune dysregulation in AOA2, similar to that observed in other neurodegenerative diseases. Viral infections have been associated with several neurodegenerative diseases, including ALS. However, a causal role for viruses in the etiology of ALS has never been established. Common viral infections can impact immune cell phenotypes within the CNS. Microglia are the primary immune cell of the CNS and are able to respond to subtle changes in the microenvironment. Microglia have neurotoxic properties upon hyper-activation. Influenza infection of SOD1G93A mice accelerated ALS disease progression and reduced overall survival. Exacerbated microgliosis was evident within the spinal cords of infected mice. Thus, the immune response stimulated by viral infections may result in toxic microgliosis that accelerates the progression of ALS. Together, this body of work describes a series of novel immunological abnormalities associated with AOA2 and ALS4. A deeper understanding of the role played by the immune system in patients with neurodegenerative disorders may unveil new targets for future therapies.