Autoantibodies in autoimmune disease : pathogenicity and production.

Autoantibody titers and disease severity do not always have a direct relationship. Various factors, such as antigen specificity, binding site, and subclass, can influence an autoantibody's pathogenicity and effector function. To better understand how autoantibodies mediate pathology and why they are produced, we investigated two autoimmune diseases: myasthenia gravis (MG) and neurofascin-155 (NF155) mediated chronic inflammatory demyelinating polyneuropathy (CIDP). MG is a debilitating autoimmune disorder that affects the neuromuscular junction, leading to muscle weakness. Autoantibodies against the acetylcholine receptor (AChR) play a critical role in MG, where autoantibody-mediated complement activation has been implicated in neuromuscular junction damage. Chapters one to four of this thesis focus on AChR autoantibody-mediated complement activation, where we established a novel immunofluorescent cytometric assay to measure it in MG patients. We found that while complement deposition was correlated with autoantibody binding and disease severity, heterogeneity amongst patients was observed. For example, some patients had high AChR autoantibody-mediated complement activity but low AChR autoantibody binding and vice versa. These results indicate the complexity underlying complement activity in MG patients and the need for further investigation. Chapters five and six focus on NF155-mediated CIDP, a disabling IgG4-mediated autoimmune disease affecting the peripheral nervous system. In another IgG4-mediated disease, muscle-specific tyrosine kinase (MUSK) MG, patients showed higher dysfunction in their B cell tolerance mechanisms compared to AChR MG (which is predominantly IgG1). Furthermore, germline encoded and affinity mature MuSK recombinant autoantibodies showed reactivity to MuSK antigen. This suggests that MuSK autoreactive B cell clones may have escaped B cell tolerance mechanisms and are then driven to maturation via interactions with MuSK. Accordingly, we examined the fidelity of early B cell tolerance checkpoints by utilizing a well-established approach that quantifies the frequency of polyreactive B cells that escape tolerance mechanisms at central and peripheral B cell tolerance checkpoints. We found that NF155 CIDP patients had compromised early B cell tolerance checkpoints; however, further studies are needed to explore whether the interaction between escaped B cell clones and self-antigens drives the disease.