2026 ECNP Congress

PS04-4056

α9 Nicotinic acetylcholine receptor autoantibodies characterization in schizophrenic and bipolar disorder patients

Jose Fernando Garcia Rodrigo — A. Velázquez de Castro Esteve, S. Pons, M. Leboyer, A. Blondel, M. Zouridakis, U. Maskos, F. Jönsson · Institut Pasteur, Neuroscience, Paris, France

2026 ECNP Congress

Psychiatric disorders are a leading cause of disability and economic burden in developed countries, affecting close to 30% of the global population [1]. Due to their heterogeneity and the absence of reliable biomarkers for patient stratification, there is an urgent unmet need for a deeper understanding of their underlying causes. The immune system has gained growing recognition as a potentially critical component in their pathophysiology [2], and a series of neuronal antigens has been identified as targets of autoimmune antibodies (AAbs) that can cause psychotic symptoms [3]. Among the various possible targets implicated in psychiatric conditions, nicotinic acetylcholine receptors (nAChRs) have emerged as particularly compelling candidates due to their fundamental roles in neurotransmission, cognitive function, and immune regulation [4]. nAChRs were among the first autoimmune targets identified in the context of Myasthenia gravis, however, the role of neural nAChR AAbs has not yet been thoroughly addressed. Compelling evidence for their involvement in neuropsychiatric disease is provided by an augmented nAChR antibody seroreactivity in patients with psychotic disorders compared to healthy controls [2]. Here we focus in particular on the α9 nAChR receptor. While traditionally associated with non-neural tissues, α9-containing nAChRs are present in immune cells, where they influence the secretion of pro- and anti-inflammatory cytokines. Dysfunctional α9 signaling may therefore contribute to chronic inflammation present in subgroups of schizophrenic (SZ) and bipolar disorder (BP) patients. Additionally, nAChR α9 AAbs have been suggested to play a role in pemphigus vulgaris, an autoimmune bullous skin disease, which has a strong co-morbidity with SZ [5]. Our project aims to characterize the role of anti-a9 nAChR AAbs present in psychotic patients. We used an extracellular domain (ECD) of human a9 nAChR to sort specific memory B cells from the blood of psychotic patients, characterize the a9 nAChR AAb repertoires, and produce recombinant patient- derived AAbs for structural and functional analysis. Cytokine profiling, AAbs features, and clinical data will be used for network analysis to identify patients that could benefit from immunomodulatory treatments. We identified a significantly increased seroreactivity against the α9 nAChR ECD in a cohort of 559 patients with psychiatric disorders compared to 182 healthy controls. We sequenced, cloned, and recombinantly produced eight anti-a9 monoclonal antibodies from the blood of psychiatric patients with high α9 nAChR AAb titers. Recombinant AAbs display affinities in the tens of nM range. In silico docking analysis using the monomeric ECD or the pentameric receptor structure demonstrated the potential interaction of the patient’s antibodies with different epitopes found in the a9 nAChR. These results demonstrate the presence of a9 nAChR AAbs in psychiatric patients. Further validation of the function and mechanism of these AAbs on in vitro and in vivo models will generate mechanistic insights into how the cholinergic system is implicated in the modulation of psychiatric disorders.

References

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  2. Darrau E, Jacquemet E, Pons S, Schlick L, Zouridakis M, Wu CL, et al. Serum autoantibodies against α7-nicotinic receptors in subgroups of patients with bipolar disorder or schizophrenia: clinical features and link with peripheral inflammation. Transl Psychiatry. 2024 Mar 14;14(1):146.
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