Unravelling the role of neuronal antibodies and innate immunity partnership in human autoimmune encephalitis

Introduction

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.

Objective

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.

Methodology

ImmuBRAIN combines human studies with experimental models.

Human Studies

Human studies will:

1. Extensively profile patients’ NMDAR antibodies using a novel antibodyomics platform.
2. Characterize the compartmentalized antibody responses between brain and periphery using B-cell receptor repertoire analyses.
3. Define the distribution of brain innate infiltrates and quantify neuronal death using advanced microscopy.

In Vitro Models

In vitro models will:

1. Determine the effects of patients’ and glycan-modified antibodies on neurons using confocal microscopy and electrophysiology.
2. Explore the neuron-microglia interactions during trogocytosis using super-resolution and live cell imaging.

Mouse Model

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.
• Explore the therapeutic role of in vivo antibody glycan modifications in reversing the observed behavioral and molecular alterations.

Impact

These findings will revolutionize the current understanding of innate immune mechanisms in AE and other inflammatory brain disorders. They will also provide novel antibody-modulating therapies (e.g., glycan modifications) that will ultimately improve patients’ outcomes.