Identification of autoantibodies against neuronal and glial targets in CNS and PNS disorders.

In recent decades, research has significantly advanced the understanding of autoimmunity's role in neurological disorders affecting the central and peripheral nervous systems. While several autoantibody targets have been identified, the pathogenic mechanisms remain to be elucidated, or their pathogenicity has yet to be confirmed. Several lines of evidence suggest a possible autoimmune aetiology in neuropathies. Autoantibodies to neuronal surface antigens have been discovered to be involved in the development of pain, with CASPR2 antibodies being particularly relevant, as 50% of CASPR2 Ab-positive patients manifest pain. In vitro and in vivo studies further support the pathogenicity of some autoantibodies, and some patients have shown the benefit of immunotherapy. In particular, small fiber neuropathy (SFN) is a peripheral neuropathy characterized by pain and autonomic dysfunction. Although various causes are associated with this disease, over 50% of cases are idiopathic. For instance, FGFR3 antibodies have been detected in 17% of iSFN patients and TS-HDS antibodies in 20%, though their clinical significance is debated. Recently, new potential autoantibody targets, including MX1, DBNL, and KRT8, have been identified, along with PlexinD1 antibodies, which in vivo and in vitro studies supported their pathogenic role. This thesis explores autoimmunity’s role in neurological diseases by developing assays to detect autoantibodies in patient serum and cerebrospinal fluid. Cell-based assays (CBAs) were developed to identify antibodies against mGluR1, mGluR5, and AK5. A cohort of SFN patients was screened using CBAs and ELISAs for known pain-associated antibodies and potential novel targets, identifying and characterizing positive cases. Additionally, serum reactivity on murine dorsal root ganglia neurons and human sensory neurons derived from iPSCs was evaluated to detect unknown antigens. Our findings highlight a potential role for autoimmunity in SFN and pain development, emphasizing the need to identify novel antibody targets and clarify their possible pathogenic role in neurological diseases.