Studies on the Innate and Humoral Immune Responses in Neurological Diseases

Abstract

Neurological diseases affect millions of people worldwide, and their etiology is not fully understood. Recent studies suggest that viral and bacterial infections can contribute to the onset of neurological disorders, leading to neuroinflammatory responses and pathological signs. In recent years, increasing evidence has supported the role of the immune system in the pathogenesis of these disorders. Specifically, immune dysregulation and inflammation have been identified as key players in the development and progression of these disorders. Therefore, it is crucial to understand the underlying immunological mechanisms and identify related biomarkers for the development of accurate diagnoses and effective treatments for these complex disease. In this study, I investigated the innate and humoral immune responses underlying neurological disorders using in vitro infection systems of Mycoplasma fermentans and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus, as well as the antibody profiles of Alzheimer’s disease (AD) patients. In Part I, I investigated the potential of M. fermentans as a risk factor for neurological diseases. I found that M. fermentans can infect and replicate in human neuronal cells, leading to necrotic cell death accompanied by Aβ1-42 deposition. I discovered that interferon-induced transmembrane protein 3 (IFITM3) plays a crucial role in both Aβ1-42 deposition and necrotic cell death induced by M. fermentans infection. Furthermore, I showed that M. fermentans infection can cause necrotic neuronal cell death in brain organoids. These results suggest that M. fermentans may contribute to neurological disease development and progression through IFITM3-mediated Aβ1-42 deposition and necrotic neuronal cell death. In Part II, I used random peptide microarrays to identify antibodies in the blood of AD patients. I found that specific combinations of these antibodies can be used to diagnose AD and that some of the identified target proteins are involved in AD-related signaling pathways. These findings could be used to develop biomarkers for AD diagnosis and further understanding of AD progression. In Part III, I examined the functional roles of pre-pandemic elderly individuals' antibodies for SARS-CoV-2 infection, considering its potential risk factor for neurological diseases. The presence of SARS-CoV-2 receptor-binding domain (RBD)-reactive cross antibodies in these individuals was found, which exhibited either neutralizing or enhancing activity towards the virus. Although, no correlation was observed between the neutralizing activity and the antibody levels, opposing functions were detected among different plasma groups with high levels of SARS-CoV-2 RBD-reactive antibodies. These findings highlight the importance of cross-reactive antibodies in pre-pandemic individuals, which may have opposing roles for viral infection.