Kevin C O'Connor, PhD

Immunomechanisms of AChR myasthenia gravis (MG).

My team and I have developed a comprehensive, multidisciplinary program to investigate the immunopathology of the AChR subtype of MG. Our research has yielded several key findings:

1. We discovered that MG patients exhibit defects in B cell tolerance checkpoints, which correlate with abnormalities in the naive B cell repertoire, setting the stage for the development of autoantibody-producing B cells.
2. We explored B cell trafficking in MG and found that the MG thymus can act as a reservoir for B cells that produce autoantibodies against acetylcholine receptors (AChR). While thymectomy is offered as a treatment, many patients do not show improvement. Our research revealed that disease-associated B cell clones mature in the thymus before entering circulation, persist in the bloodstream after thymectomy, and their persistence correlates with less favorable clinical outcomes post-thymectomy.
3. To better understand the molecular pathology of AChR autoantibodies, we developed a novel assay to evaluate their ability to mediate complement activity. We found that a subset of patients lacks an association between complement activity and autoantibody binding, which improves our understanding of the heterogeneous autoantibody molecular pathology and may help identify patients likely to benefit from complement inhibitor therapy.
4. In the subsequent phase, to gain a deeper understanding at the molecular level, we generated recombinant AChR-specific autoantibodies from MG patient samples and investigated their pathogenic mechanisms. Our findings revealed that these autoantibodies possess a broad range of pathological capabilities:
• Some autoantibodies execute a single pathogenic mechanism from the three known processes: blocking acetylcholine binding, reducing AChR quantity, or activating complement.
• Others are versatile, capable of mediating two of these mechanisms.
• Notably, we identified several highly pathogenic autoantibodies that can simultaneously execute all three disease mechanisms.
• Current therapeutic approaches targeting only one autoantibody-mediated pathogenic mechanism may be evaded by AChR autoantibodies with multifaceted capacity.

These findings have significant implications for our understanding and treatment of AChR myasthenia gravis. The discovery of autoantibodies with multifaceted pathogenic capabilities challenges the current therapeutic paradigm. While existing treatments often target a single autoantibody-mediated mechanism, our research suggests that this approach may be insufficient for patients with versatile autoantibodies. This insight calls for the development of more comprehensive treatment strategies that can simultaneously address multiple pathogenic mechanisms. Furthermore, our work on B cell tolerance defects, thymic B cell reservoirs, and complement activity provides new avenues for targeted therapies and personalized medicine approaches. By deepening our understanding of the complex immunomechanisms underlying MG, we pave the way for more effective diagnostics, prognostic tools, and tailored treatment options that could significantly improve outcomes for patients with this challenging autoimmune disorder.

Immunomechanisms of MuSK myasthenia gravis (MG).

Our research focusing on the MuSK subtype of MG has concentrated on isolating and identifying the specific cells that produce MuSK autoantibodies. This challenging endeavor, despite requiring significant time and resources, has yielded valuable results. We can now identify and isolate these rare cells from which we have produced a series of human MG monoclonal autoantibodies (mAbs). These mAbs have provided unprecedented insight into the details of autoimmune mechanisms. Our findings reveal that MuSK autoantibodies possess exceptionally high affinity, due to extensive somatic mutation, and recognize diverse MuSK epitopes. Both are key elements in their ability to inhibit AChR clustering, the fundamental aspect of MuSK MG pathology. We also showed that CD20-expressing plasmablasts are key producers of pathogenic autoantibodies. This finding explains the effectiveness of B cell depletion therapy (through rituximab) in patients with MuSK MG. We then established that patients who experience relapse following successful treatment with rituximab harbor identical clones of MuSK-specific B cells that were present prior to treatment. This key finding demonstrated that rituximab is not fully effective at eliminating autoantibody-producing B cells, providing a mechanistic understanding of post-rituximab relapse. Collectively, this research has significantly advanced our understanding of MuSK MG pathogenesis and treatment responses, paving the way for more targeted and effective therapies in the future.

Defining pathogenic roles for human MOG autoantibodies.

Our innovative approaches to studying MOG autoantibodies, particularly the development of antigen tetramers and live cell-based assays, played a crucial role in distinguishing MOG antibody disease MOGAD as a separate clinical entity from MS. By accurately representing the biological presentation of MOG, these techniques allowed us to demonstrate that MOG autoantibodies were more characteristic of encephalomyelitis rather than MS. This discovery led to the recognition of MOGAD as a distinct disease, with its own diagnostic criteria and clinical profile. Our work showed that self-antigen tetramers could discriminate between autoantibodies binding to native or denatured MOG protein, providing a more nuanced understanding of the autoimmune response. Furthermore, our recent studies on the pathogenic mechanisms of MOGAD patient autoantibodies, including their ability to induce complement activation, phagocytosis, and cellular cytotoxicity, have further solidified MOGAD as a separate condition with unique pathological features. These findings have not only improved diagnostic accuracy but also opened new avenues for targeted therapeutic approaches specific to MOGAD, distinct from those used in MS treatment.