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Published on: April 9, 2012
LP-BM5 virus-infected mice produce activating autoantibodies to the AMPA receptor
1Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases/NIH, Bethesda, Maryland 20892-0008, USA.
Abstract:
Autoantibodies to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors may contribute to chronic hyperexcitability syndromes and neurodegeneration, but their origin is unclear. We examined LP-BM5 murine leukemia virus-infected mice, which manifest excitotoxic brain lesions and hypergammaglobulinemia, for the presence of AMPA-receptor Ab's. Endogenous IgG accumulated upon neurons in the neocortex and caudate/putamen of infected mice and interacted with native and recombinant AMPA-receptor subunits with the following relative abundance: GluR3 > or = GluR1 > GluR2 = GluR4, as determined by immunoprecipitation. In a radioligand assay, IgG preparations from infected mice specifically inhibited [(3)H]AMPA binding to receptors in brain homogenates, an activity that was lost after preadsorbing the IgG preparation to immobilized LP-BM5 virus. These IgGs also evoked currents when applied to hippocampal pyramidal neurons or to damaged cerebellar granule neurons. These currents could be blocked using any of several AMPA receptor antagonists. Thus, anti-AMPA-receptor Ab's can be produced as the result of a virus infection, in part through molecular mimicry. These Ab's may alter neuronal signaling and contribute to the neurodegeneration observed in these mice, actions that may be curtailed by the use of AMPA-receptor antagonists.
Insights
Viral infections can trigger autoantibodies against alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. These autoantibodies may contribute to neurodegeneration and neuronal signaling alterations, potentially mitigated by AMPA receptor antagonists.
Area of Science:
- Neuroimmunology
- Viral Pathogenesis
- Neurodegeneration
Background:
- Autoantibodies targeting alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors are implicated in neurological disorders.
- The origin of these autoantibodies, particularly in the context of viral infections, remains largely unknown.
Purpose of the Study:
- To investigate the presence and characteristics of AMPA receptor autoantibodies in mice infected with the LP-BM5 murine leukemia virus.
- To explore the potential role of molecular mimicry in the generation of these autoantibodies following viral infection.
Main Methods:
- Analysis of endogenous IgG accumulation in neurons of infected mice.
- Immunoprecipitation assays to determine the binding affinity of IgG to different AMPA receptor subunits.
- Radioligand binding assays to assess the functional impact of IgG on AMPA receptor activity.
- Electrophysiological recordings on neurons treated with IgG preparations.
Main Results:
- Accumulation of endogenous IgG in the neocortex and caudate/putamen of infected mice.
- IgG preferentially bound to GluR3 and GluR1 subunits of AMPA receptors.
- IgG from infected mice inhibited [(3)H]AMPA binding and evoked currents in neurons, effects blocked by AMPA receptor antagonists.
- Antibody activity was linked to the LP-BM5 virus, suggesting molecular mimicry.
Conclusions:
- Viral infections can induce the production of autoantibodies against AMPA receptors.
- These autoantibodies may contribute to altered neuronal signaling and neurodegeneration observed in viral infections.
- AMPA receptor antagonists show potential for mitigating the effects of these virus-induced autoantibodies.
