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000257584 041__ $$aEnglish
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000257584 1001_ $$0P:(DE-HGF)0$$aRahman, Kazi Atikur$$b0
000257584 245__ $$aMicroglia actively remove NR1 autoantibody-bound NMDA receptors and associated post-synaptic proteins in neuron microglia co-cultures.
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000257584 520__ $$aAutoantibodies against the NR1 subunit of NMDA receptors (NMDARs) have been shown to promote crosslinking and internalization of bound receptors in NMDAR encephalitis (NMDARE). This internalization-mediated loss of NMDARs is thought to be the major mechanism leading to pathogenic outcomes in patients. However, the role of bound autoantibody in engaging the resident immune cells, microglia, remains poorly understood. Here, using a patient-derived monoclonal NR1 autoantibody (hNR1-mAb) and a co-culture system of microglia and neurons, we could show that hNR1-mAb bound to hippocampal neurons led to microglia-mediated removal of hNR1-mAb bound NMDARs. These complexes were found to accumulate inside endo-lysosomal compartments of microglia. Utilizing another patient isolated monoclonal autoantibody, against the α1-subunit of GABAA receptors (α1-GABAA -mAb), such removal of receptors was found to be specific to the antibody-bound receptor targets. Interestingly, along with receptor removal, we also observed a reduction in synapse number, more specifically in the numbers of post-synaptic proteins like PSD95 and Homer 1, when microglia were present in the culture. Importantly, mutations in the Fc region of hNR1-mAb, blocking its Fcγ receptor (FcγR) and complement binding, attenuated hNR1-mAb driven loss of NMDARs and synapses, indicating that microglia engagement by bound hNR1-mAb is critical for receptor and synapse loss. Our data argues for an active involvement of microglia in removal of NMDARs and other receptors in individuals with autoimmune encephalitis, thereby contributing to the etiology of these diseases.
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000257584 650_2 $$2MeSH$$aHumans
000257584 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: genetics
000257584 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: metabolism
000257584 650_2 $$2MeSH$$aAutoantibodies: metabolism
000257584 650_2 $$2MeSH$$aCoculture Techniques
000257584 650_2 $$2MeSH$$aMicroglia: metabolism
000257584 650_2 $$2MeSH$$aNeurons: metabolism
000257584 650_2 $$2MeSH$$agamma-Aminobutyric Acid: metabolism
000257584 650_7 $$2Other$$aco-culture
000257584 650_7 $$2Other$$aNMDAR
000257584 650_7 $$2Other$$aantibody mediated autoimmune encephalitis
000257584 650_7 $$2Other$$aautoantibodies
000257584 650_7 $$2Other$$amicroglia, hippocampal neurons, co-culture, pre-labeling
000257584 650_7 $$2Other$$ahippocampal neurons
000257584 650_7 $$2Other$$amicroglia
000257584 650_7 $$2Other$$apre-labeling
000257584 650_7 $$2NLM Chemicals$$aReceptors, N-Methyl-D-Aspartate
000257584 650_7 $$2NLM Chemicals$$aAutoantibodies
000257584 650_7 $$056-12-2$$2NLM Chemicals$$agamma-Aminobutyric Acid
000257584 7001_ $$aOrlando, Marta$$b1
000257584 7001_ $$aBoulos, Ayub$$b2
000257584 7001_ $$0P:(DE-2719)2811708$$aAndrzejak, Ewa$$b3$$udzne
000257584 7001_ $$0P:(DE-2719)2810725$$aSchmitz, Dietmar$$b4$$udzne
000257584 7001_ $$aZiv, Noam E$$b5
000257584 7001_ $$0P:(DE-2719)2810931$$aPrüss, Harald$$b6$$udzne
000257584 7001_ $$0P:(DE-2719)2810922$$aGarner, Craig C$$b7$$udzne
000257584 7001_ $$0P:(DE-2719)9000590$$aIchkova, Aleksandra$$b8$$eLast author$$udzne
000257584 773__ $$0PERI:(DE-600)1474828-9$$a10.1002/glia.24369$$gp. glia.24369$$n8$$p1804-1829$$tGlia$$v71$$x0894-1491$$y2023
000257584 8564_ $$uhttps://onlinelibrary.wiley.com/doi/10.1002/glia.24369
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