Translational Neuroimmunology
Our group has a special interest in autoimmune disorders of the neuromuscular synapse and the unique role of IgG4 (auto)antibodies.
Research focus and aim
Our lab investigates the aetiology and pathophysiology of neuromuscular autoimmune diseases and IgG4-predominated autoimmune diseases using 2D and 3D cell cultures, genetic and passive transfer animal models and a variety of immunological methods. The goal of our lab is to get a fundamental understanding of the processes that contribute to the development and chronification of these diseases and use this knowledge to develop novel treatments for them.
Our ambitious objectives are explored in close collaboration with the clinical research group Clinical Neuroimmunology of Prof. Dr. Jan Verschuuren and Dr. Martijn Tannemaat and electrophysiology expert Dr. Jaap Plomp at the department of Neurology, which is part of the center of expertise for Neuromuscular diseases in the LUMC. This is one of the Health Care Providers of the EURO-NMD European Reference Network and part of NL-NMD (Dutch society for neuromuscular diseases).
Our research involves the following three main objectives:
1. Understanding the pathophysiology of myasthenia gravis
2. Deciphering and targeting (pathogenic) IgG4 (auto)immune responses.
3. Therapeutic application of MuSK antibodies in neuromuscular diseases.
Our projects
1. Understanding the pathophysiology of myasthenia gravis.
Myasthenia gravis is the name of a group of autoimmune diseases hallmarked by fluctuating and fatigable skeletal muscle weakness. These diseases are caused by autoantibodies that block the function of proteins that are essential for neuromuscular synaptic transmission. Myasthenia gravis is further classified based on the type of autoantibody involved. 80% of patients have autoantibodies against the AChR which are predominantly of the IgG1-3 subclass and cause disease through complement-mediated or cell-mediated cytotoxicity. MuSK myasthenia gravis is the second most common form of myasthenia gravis and is characterized by predominant IgG4 autoantibodies against MuSK. IgG4 is a unique antibody molecule as it is largely unable to activate complement or immune cells. We’re investigating how the unique features of IgG4 cause disease. We’re furthermore developing several cell-based models and animal models to study the pathophysiology of myasthenia gravis and perform preclinical tests with novel therapeutics for these diseases.
Vergoossen et al. Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis. Proc Natl Acad Sci USA. 2021.
2. Deciphering and targeting (pathogenic) IgG4 (auto)immune responses.
Why certain autoimmune diseases are predominated by a specific antibody subclass is not known. We are studying why IgG4 autoimmune disease are predominated by IgG4 autoantibodies and aim to identify (potentially targetable) unique regulators of IgG4 production.
Paardekooper et al. Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development. Clin Immunol. 2023.
3. Therapeutic application of MuSK antibodies in neuromuscular diseases.
MuSK acts as a critical orchestrator of synaptic stability. We hypothesize that manipulation of MuSK signalling, using MuSK monoclonal antibodies, has therapeutic potential for a range of neuromuscular disorders hallmarked by impaired neuromuscular junctions.
Lim et al. Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK. Sci Rep. 2023.
FAQ
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In myasthenia gravis and Lambert-Eaton myasthenic syndrome muscle weakness is a direct consequence of autoantibodies binding to, and interfering with, the function of key neuromuscular junction proteins. A subgroup of patients have antibodies against muscle-specific kinase (MuSK). MuSK is essential for the formation and maintenance of neuromuscular synapses as it propagates a trophic signal to induce acetylcholine receptor clustering and supports presynaptic motor nerve terminal differentiation. We confirmed that MuSK autoantibodies are predominantly of the IgG4 subclass and can induce myasthenia gravis in immune-incompetent mice through blocking the signal of MuSK to maintain the synapse (Klooster & Plomp et al. 2012 Brain, Huijbers et al. 2013 PNAS).
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IgG4 antibodies are a subclass of antibodies. In contrast to the other IgG subclass antibodies (IgG1-3), these antibodies are considered anti-inflammatory as they are generally bad at activating the immune system (e.g. via complement, or antibody-dependent cellular cytotoxicity (ADCC). IgG4s therefore mostly acts through antigen binding and blocking. IgG4 furthermore undergoes a unique process called Fab-arm exchange (Figure 1). When IgG4 is produced by plasma cells this molecule looks like other antibodies and has two antigen-binding sites specific for one antigen. When IgG4 reaches the circulation IgG4 molecules undergo Fab-arm exchange and switch with other IgG4 molecules half-antibodies. Due to the large heterogeneity of circulating IgG4 molecules IgG4 rapidly becomes bispecific and functionally monovalent. This only occurs in humans and primates and the role for this in evolution has yet to be elucidated. In MuSK myasthenia gravis Fab-arm exchange turns out to be important as monovalent antibodies are more pathogenic then their bivalent parental equivalents (Vergoossen et al. 2021 PNAS, Huijbers et al. 2019 Neurol, Neuroimmunol & Neuroinflamm).
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Interestingly, a niche of other autoimmune diseases has been identified that are associated with predominating IgG4 autoantibodies (Huijbers et al. 2018 Ann N Y Acad Sci, Huijbers et al. 2015 Eur J Neurol.). These include diseases affecting the skin, brain, muscle, peripheral nerve, blood clothing and kidneys. These diseases share many of the disease mechanism characteristics observed in MuSK myasthenia gravis. Why these diseases are hallmarked by IgG4 autoantibodies is not known.