N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Wenke, Nina K.; Kreye, Jakob; Andrzejak, Ewa; Casteren, Adriana van; Leubner, Jonas; Murgueitio, Manuela S.; Reincke, S. Momsen; Secker, Christopher; Schmidl, Lars; Geis, Christian; Ackermann, Frauke; Nikolaus, Marc; Garner, Craig C.; Wardemann, Hedda; Wolber, Gerhard; Prüß, Harald

doi:10.1002/ana.25460

Cited by 47 publications

(39 citation statements)

References 28 publications

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“…25 The NMDA receptor encephalitis repertoire contained antibodies lacking any mutation as compared to the germline sequence. 25,30 Our findings in LGI1 encephalitis are in striking contrast. First, in LGI1 encephalitis, the fraction of ASCs expressing LGI1 antibodies was high.…”

Section: Discussioncontrasting

confidence: 63%

“…Furthermore, the number of somatic hypermutations in the V genes of NMDA receptor autoantibodies among all patients was significantly lower compared to CSF antibodies not targeting the NMDA receptor of the same patients . The NMDA receptor encephalitis repertoire contained antibodies lacking any mutation as compared to the germline sequence . Our findings in LGI1 encephalitis are in striking contrast.…”

Section: Discussionmentioning

confidence: 49%

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Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Kornau

Kreye

Stumpf

et al. 2020

Annals of Neurology

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Objective Leucine‐rich glioma‐inactivated 1 (LGI1) encephalitis is the second most common antibody‐mediated encephalopathy, but insight into the intrathecal B‐cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. Methods We cloned, expressed, and tested antibodies from 90 antibody‐secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Results Eighty‐four percent of the ASCs and 21% of the memory B cells encoded LGI1‐reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non–ADAM22‐competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation Our data show that the patients’ intrathecal B‐cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N‐methyl‐D‐aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405–418

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 49%

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Kornau

Kreye

Stumpf

et al. 2020

Annals of Neurology

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“…Examples includes viral infections [30][31][32][33] and responses to influenza hemagglutinin, wherein unmutated revertants of virus antigen-specific monoclonal antibodies retain binding activity. These scenarios, however, must be carefully considered, as there are some exceptions of autoantibody germline binding [34,35]. The collective findings may point toward limitation of the approaches available to measure antibody-antigen interactions,…”

Section: Autoreactivity In the Naïve Repertoirementioning

confidence: 99%

“…MuSK appears to both initiate and propagate the B cell response, which is a rare finding in human autoimmunity [35]. The generation of pathogenic autoantibodies may be the result of an aberrant immune response to self-antigen that is both initiated and driven by the same selfantigen.…”

Section: Autoreactivity In the Naïve Repertoirementioning

confidence: 99%

Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

Fichtner

Vieni

et al. 2020

Preprint

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Pathogenic IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The origin and development of these unique autoantibodies are not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCA) and monovalent antigen-binding fragments (Fabs) to investigate how antigen-driven affinity maturation contributes to both binding and immunopathology. Mature mAbs, their UCA counterparts and mature monovalent Fabs bound to the autoantigen and retained their pathogenic capacity. However, monovalent UCA Fabs still bound the autoantigen but lost their pathogenic capacity. The mature Fabs were characterized by very high affinity (sub-nanomolar) driven by a rapid on-rate and slow off-rate. However, the UCA affinity was approximately 100fold less than that of the mature Fabs, which was driven by a rapid off-rate. Crystal structures of two Fabs shed light on how mutations acquired during affinity maturation may contribute to increased MuSK binding affinity. These collective findings indicate that the autoantigen initiates the autoimmune response in MuSK MG and drives autoimmunity through the accumulation of somatic hypermutation such that monovalent IgG4 Fab-arm exchanged MG autoantibodies reach a high affinity threshold required for pathogenic capacity.

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“…The increasing knowledge on these antibodies showed differences to other autoimmune diseases. For example, NR1 antibodies in patients' CSF had only few somatic hypermutations or were even unmutated, suggesting that T cell help might not be required for antibody development (Wenke, Kreye et al 2019). Such germline antibodies were nonetheless pathogenic in established in vitro assays.…”

Section: Introductionmentioning

confidence: 99%

Decreased inflammatory cytokine production of antigen-specific CD4⁺T cells in NMDA receptor encephalitis

Dao

Machule

Bächer

et al. 2020

Preprint

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Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is the most common autoimmune encephalitis with psychosis, amnesia, seizures and dyskinesias. The disease is mediated by pathogenic autoantibodies against the NR1 subunit that disrupt NMDAR function. Antibody infusion into mouse brains can recapitulate encephalitis symptoms, while active immunization resulted also in strong T cell infiltration into the hippocampus. However, whether T cells react against NMDAR and their specific contribution to disease development are poorly understood. Here we characterized the ex vivo frequency and phenotype of circulating CD4+ T helper (TH) cells reactive to NR1 protein using antigen-reactive T cell enrichment (ARTE) in 24 patients with NMDAR encephalitis, 13 patients with LGI1 encephalitis and 51 matched controls. Unexpectedly, patients with NMDAR encephalitis had lower frequencies of CD154-expressing NR1-reactive TH cells than healthy controls and produced significantly less inflammatory cytokines. No difference was seen in T cells reactive to the synaptic target LGI1 (Leucine-rich glioma-inactivated 1), ubiquitous Candida antigens or neoantigens, suggesting that the findings are disease-specific and not related to therapeutic immunosuppression. Also, patients with LGI1 encephalitis showed unaltered numbers of LGI1 antigen-reactive T cells. The data reveal disease-specific functional alterations of circulating NMDAR-reactive TH cells in patients with NMDAR encephalitis and challenge the idea that increased pro-inflammatory NMDAR-reactive T cells contribute to disease pathogenesis.

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N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Cited by 47 publications

References 28 publications

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

Decreased inflammatory cytokine production of antigen-specific CD4⁺T cells in NMDA receptor encephalitis

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N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Cited by 47 publications

References 28 publications

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

Decreased inflammatory cytokine production of antigen-specific CD4+T cells in NMDA receptor encephalitis

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Decreased inflammatory cytokine production of antigen-specific CD4⁺T cells in NMDA receptor encephalitis