The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.

Amyotrophic Lateral Sclerosis (ALS) is a poorly understood and fatal disease. It has a low prevalence and a 2-4 year survival period. Various theories and hypotheses relating to its development process have been proposed, albeit with no breakthrough in its treatment. Recently, the role of the adaptive immune system in ALS, particularly CD4+ T cells, has begun to be investigated. CD4+ T cells are a heterogeneous group of immune cells. They include highly pro-inflammatory types such as Th1 and Th17, as well as highly anti-inflammatory cells such as Tregs. However, the landscape of the role of CD4+ T cells in ALS is still not clearly understood. This review covers current hypotheses that elucidate how various CD4+ T cells can contribute to ALS development. These hypotheses include the SWITCH model, which suggests that, in the early stages of the disease, Tregs are highly capable of regulating the immune response. However, in the later stages of the disease, it seems that pro-inflammatory cells such as Th1 and Th17 are capable of overwhelming Treg function. The reason why this occurs is not known. Several research groups have proposed that CD4+ T cells as a whole might experience aging. Others have proposed that gamma delta T cells might directly target Tregs. Additionally, other research groups have argued that less well-known CD4+ T cells, such as Emoes+ CD4+ T cells, may be directly responsible for neuron death by producing granzyme B. We propose that the ALS landscape is highly complicated and that there is more than one feasible hypothesis. However, it is critical to take into consideration the differences in the ability of different populations of CD4+ T cells to infiltrate the blood-brain barrier, taking into account the brain region and the time of infiltration. Shedding more light on these still obscure factors can help to create a personalized therapy capable of regaining the balance of power in the battle between the anti-inflammatory and pro-inflammatory cells in the central nervous system of ALS patients.