Intron retention dysregulation in Aicardi-Goutières syndrome

Aicardi Goutières syndrome is an autosomal recessive, severe and progressive inflammatory disorder, characterized by defects in the central nervous system and chronic cerebrospinal fluid lymphocytosis with elevated expression of interferon responsive gene representing the strong autoimmune component of the disease. Nowadays the precise mechanism at the basis of the onset and progression of Aicardi Goutières syndrome is still partly unknown and more efforts are needed to shed light on the different altered pathways Intron retention is an alternative splicing mechanism where an intron, instead of being removed by the splicing machinery, is maintained in the mature transcript. Intron retention has been overlooked so far but it is now gaining attention due to its newly recognized involvement in immune response and neuronal development. In fact, many recent findings have identified an unappreciated relation between intron retention dysregulation and the onset of neurodegenerative and autoimmune diseases. In this scenario I have decided to investigate the possible involvement of intron retention in Aicardi Goutières syndrome. Moreover, I have extended this study to another relevant autoimmune disease, systemic lupus erythematosus, which share a certain degree of similarity with Aicardi Goutières syndrome. I have discovered that Aicardi Goutières syndrome whole blood samples are characterized by increased intron retention and this can be further associated with the aberrant activation of immune system cells, in particular B-cells. The results obtained have been further extended to FACS isolated systemic lupus erythematosus B-cells subtypes thus confirming the possible involvement of intron retention in the onset and progression of Aicardi Goutières syndrome related autoimmune diseases. Generally, intron retention has been associated with a reduced cell proliferation at the expense of a more differentiated and activated cell state. Intron retention can thus act as a mechanims capable of sustaining the aberrant immune system response observed in Aicardi Goutières syndrome and systemic lupus erythematosus. Finally, the analysis of Aicardi Goutières syndrome neuronal samples have revealed that aberrant intron retention can be also observed in other cell types. This evidence further extend the possibility that 1disregulation of intron retention can be involved in neural cell differentiation in Aicardi Goutières syndrome. This study identifies a novel and yet undescribed phenomenon in Aicardi Goutières syndrome and systemic lupus erythematosus. Although more in-depth investigation are needed, I propose that intron retention could be used as a marker for disease identification and a target that can lead to the development of new treatments for reducing the symptom of these diseases.