Project description
Interplay between adaptive and innate immunity in autoimmune encephalitides
Antibodies recognise foreign substances and neutralise their threat. In autoimmune encephalitides, the body’s immune system erroneously attacks natural substances in the brain, causing inflammation. Antibody-depleting therapies have been effective, but recovery is incomplete in many patients. Funded by the European Research Council, the ImmuBRAIN project aims to investigate the interplay between the adaptive immune system – which responds to specific antigens and is responsible for the autoantibodies – and the innate immune system, which mounts a general response to any antigen. The team will leverage human studies and experimental models together with cutting-edge antibody engineering to investigate the unexplored contribution of antibody glycosylation, which modulates innate immunity, to neuropathology.
Objective
Autoimmune encephalitides (AE) are severe brain disorders mediated by antibodies against neuronal proteins, such as the N-Methyl-D-Aspartate receptor (NMDAR). The antibody effects are reversible, explaining recovery after antibody-depleting therapies. However, it is unknown why many patients have incomplete recovery and persistent deficits. In these cases, additional immune mechanisms might be at play.
The objective of ImmuBRAIN is to define how the adaptive immune response (autoantibodies) cross-talks with innate immune-mechanisms, resulting in neuronal dysfunction or death, by using NMDAR encephalitis as a disease model. Cutting-edge antibody engineering will define the unexplored contribution of antibody glycosylation (which modulates innate functions) to neuropathology.
ImmuBRAIN combines human studies with experimental models. Human studies will extensively profile patients NMDAR antibodies using a novel antibodyomics platform; characterize the compartmentalized antibody responses between brain and periphery using B-cell receptor repertoire analyses; define the distribution of brain innate infiltrates and quantify neuronal death using advanced microscopy. In vitro models will determine the effects of patients and glycan-modified antibodies on neurons using confocal microscopy and electrophysiology; explore the neuron-microglia interactions during trogocytosis using super-resolution and live cell imaging. Finally, a new mouse model of NMDAR encephalitis will serve to define the dynamics of antibody and innate responses over time and at different disease stages, and explore the therapeutic role of in vivo antibody glycan modifications in reversing the observed behavioural and molecular alterations.
These findings will revolutionize the current understanding of innate immune mechanisms in AE and other inflammatory brain disorders, and will provide novel antibody-modulating therapies (e.g. glycan modifications) that will ultimately improve patients outcomes.
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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08036 Barcelona
Spain
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