Diversity of anti-NMDA receptor autoantibodies in lupus patients
Lupus patients suffer from many symptoms, including brain disorders ranging from memory loss to more severe problems such as epilepsy and psychosis. These symptoms negatively impact quality of life, and treatments are limited. This grant awarded to Dr. Wollmuth will be used to develop strategies targeting the N-methyl-D-aspartate (NMDA) receptor on nerve cells to prevent or reduce brain disorders in lupus patients. The NMDA receptor is a critical molecule that controls the signals that the brain uses for communication. NMDA receptors are involved in the higher order processes like learning and memory. In some lupus patients, antibodies are produced that attack the NMDA receptor, which damage the receptor and may be linked to brain disorders. Dr. Wollmuth will collaborate with Dr. Betty Diamond to obtain antibodies against the NMDA receptor from lupus patients who have lupus-related brain disorders. The researchers will investigate how these antibodies impair or affect NMDA receptors. Using mouse models, the research team will first look at the damage caused by individual antibodies targeting the NMDA receptor, and then see if the damage can be blocked by various agents.
What this study means for people with lupus
This study will lay the foundation for personalized medicine for lupus patients experiencing brain disorders by showing how the NMDA receptor is affected, and by identifying potential therapeutic agents.
Systemic Lupus Erythematosus (SLE) or lupus is an autoimmune disorder characterized by peripheral tissue pathologies and brain dysfunctions ranging from subtle spatial memory deficits to more severe manifestations that encompass cognitive fatigue, epilepsy, depression, and acute psychosis. Cognitive dysfunctions have a negative impact on quality of life, leading to what lupus patients often refer to as ‘brain fog’. The goal of the present proposal is to study the interactions and the outcomes of these interactions of a subset of lupus autoantibodies with the NMDA receptor, a glutamate-gated ion channel central to brain function. We are particularly interested in the patient-to-patient diversity of these anti-NMDA receptor autoantibodies and how these variations contribute to the clinical diversity of brain dysfunction. Our proposed experiments will provide novel insights into the etiology and diversity of brain dysfunctions in lupus patients and potentially will lead to personalized medicine to specifically treat and attenuate this dysfunction.
A subset of SLE autoantibodies, referred to as DNRAbs, target the NMDA receptor. The DNRAb-NMDA receptor interaction is associated with cognitive dysfunctions in lupus, but patients expressing DNRAbs show a wide range of neuropsychological symptoms. The central hypothesis of this proposal is that DNRAbs, while targeting the NMDA receptor, show patient-specific or clonal variations that result in subtle variations in the DNRAb-NMDA receptor interaction and in turn how they alter NMDA receptor function and lead to brain dysfunction. In a collaboration with Dr. Betty Diamond, we will address this hypothesis by obtaining polyclonal autoantibodies from lupus patients, who have undergone a rigorous screen for neuropsychiatric disorders. We will characterize how these diverse polyclonals affect NMDA receptor function using patch clamp electrophysiology (Aim#1). For subsets of these polyclonals, we will generate monoclonal DNRAbs which are a unique strength of our proposal since they allow a more rigorous and extensive testing of the effects of DNRAbs and avoid the complications of other Abs and other molecules commonly present in human bodily tissue. We will rigorously test these monoclonals for their effects on NMDA receptor function and cell biology (Aim#2) and, in a mouse model, for inducing acute (cell death) and chronic (microglia activation, changes in neuron morphology, spatial memory deficits) effects, which are associated with the clinical pathology (Aim#3). As a template for potential neuroprotection, we will also assay how inhibitors of NMDA receptors may prevent the DNRAb-induced pathophysiology. Our experiments will begin to generate a matrix of how diverse DNRAbs alter NMDA receptor function and induce different degrees of pathophysiology and how these variations are correlated to the neuropsychological symptoms found in lupus patients.