Translational NeuroImmunology

Principal investigators
 Dr. Maartje G. Huijbers

Our group has a special interest in autoimmune disorders of the neuromuscular synapse and the unique role of IgG4 (auto)antibodies. 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 (Klooster & Plomp et al. 2012 Brain). From monoclonal antibodies isolated from these patients we learned that MuSK antibodies binding with one-arm (monovalent) are more pathogenic than MuSK antibodies that bind with both arms to MuSK (bivalent) (Figure 1). Monovalent MuSK antibodies inhibit MuSK signalling and obstruct neuromuscular junction functioning, while bivalent MuSK antibodies activate MuSK signalling (Huijbers & Zhang et al. 2013 PNAS, Vergoossen et al. 2021 bioRxiv, Huijbers et al. 2019 Neurol, Neuroimmunol & Neuroinflamm). IgG4 is the only antibody subclass that binds with one arm to a specific target, thus class switching to IgG4 is likely a critical step in development of MuSK myasthenia gravis.

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 diseases share many of the disease mechanism characteristics observed in MuSK MG. Why these diseases are hallmarked by IgG4 autoantibodies is not known.

Our research focuses on the following objectives:

1. Deciphering and targeting (pathogenic) IgG4 (auto)immune responses
We are studying why IgG4-mediated autoimmune disease are predominated by IgG4 autoantibodies and aim to identify (potentially targetable) unique regulators of IgG4 production.

2. 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.

3. Understanding NMJ homeostasis and pathophysiology of myasthenia gravis
Basic knowledge on neuromuscular transmission and synaptic homeostasis is not only valuable for understanding normal physiology, but can also shed light on important aspects of development and progression of myasthenic muscle weakness. It may furthermore identify druggable targets that can strengthen neuromuscular synapses. We therefore use our in vitro and in vivo models to test novel therapeutics and study neuromuscular synapse physiology.

Anti-MuSK IgG4 plasma cell

Figure 1: Disease mechanism of MuSK myasthenia gravis Biorxvs 2020

These ambitious objectives are explored in close collaboration with the clinical research group Clinical Neuroimmunology of Prof. Dr. Jan Verschuuren 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 ambition
Together with our broad network of collaborators, we aim to advance knowledge on healthy and diseased neuromuscular junction physiology, understand the aetiology of IgG4-mediated autoimmunity and develop new therapeutics for these disorders. We welcome all students and scientists interested in our work to contact us for any questions regarding positions or collaborations.

M.G.M.Huijbers@lumc.nl or HG_NEURIMM@lumc.nl


Relevant websites
https://www.spierziektencentrum.nl/
https://mgexpertisecentrum.nl/
https://www.lumc.nl/org/neurologie/research/myasthenie-register/
https://www.bcellnetwork.nl/target-to-b-2/