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@ARTICLE{Rahman:257584,
      author       = {Rahman, Kazi Atikur and Orlando, Marta and Boulos, Ayub and
                      Andrzejak, Ewa and Schmitz, Dietmar and Ziv, Noam E and
                      Prüss, Harald and Garner, Craig C and Ichkova, Aleksandra},
      title        = {{M}icroglia actively remove {NR}1 autoantibody-bound {NMDA}
                      receptors and associated post-synaptic proteins in neuron
                      microglia co-cultures.},
      journal      = {Glia},
      volume       = {71},
      number       = {8},
      issn         = {0894-1491},
      address      = {Bognor Regis [u.a.]},
      publisher    = {Wiley-Liss},
      reportid     = {DZNE-2023-00460},
      pages        = {1804-1829},
      year         = {2023},
      abstract     = {Autoantibodies 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.},
      keywords     = {Humans / Receptors, N-Methyl-D-Aspartate: genetics /
                      Receptors, N-Methyl-D-Aspartate: metabolism /
                      Autoantibodies: metabolism / Coculture Techniques /
                      Microglia: metabolism / Neurons: metabolism /
                      gamma-Aminobutyric Acid: metabolism / co-culture (Other) /
                      NMDAR (Other) / antibody mediated autoimmune encephalitis
                      (Other) / autoantibodies (Other) / microglia, hippocampal
                      neurons, co-culture, pre-labeling (Other) / hippocampal
                      neurons (Other) / microglia (Other) / pre-labeling (Other) /
                      Receptors, N-Methyl-D-Aspartate (NLM Chemicals) /
                      Autoantibodies (NLM Chemicals) / gamma-Aminobutyric Acid
                      (NLM Chemicals)},
      cin          = {AG Garner / AG Schmitz 1 ; AG Schmitz / AG Prüß},
      ddc          = {610},
      cid          = {I:(DE-2719)1810001 / I:(DE-2719)1810004 /
                      I:(DE-2719)1810003},
      pnm          = {351 - Brain Function (POF4-351) / 353 - Clinical and Health
                      Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37026600},
      doi          = {10.1002/glia.24369},
      url          = {https://pub.dzne.de/record/257584},
}