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Arthritis Rheumatol. 2015 Jun;67(6):1598-610. doi: 10.1002/art.39081.

Pathogenicity of lupus anti-ribosomal P antibodies: role of cross-reacting neuronal surface P antigen in glutamatergic transmission and plasticity in a mouse model.

Author information

1
Pontificia Universidad Católica de Chile, Santiago, Chile.
2
Universidad Andrés Bello, Santiago, Chile.
3
Universidad Católica de Temuco, Temuco, Chile.
4
Regeneron Pharmaceuticals, New York, New York.
5
Pontificia Universidad Católica de Chile, Santiago, Chile, and Universidad de Magallanes, Punta Arenas, Chile.

Abstract

OBJECTIVE:

To assess whether autoantibodies against ribosomal P (anti-P), which are possibly pathogenic in neuropsychiatric systemic lupus erythematosus (NPSLE), alter glutamatergic synaptic transmission and to what extent the cross-reacting neuronal surface P antigen (NSPA) is involved.

METHODS:

We analyzed glutamatergic transmission and long-term potentiation (LTP) mediated by AMPA receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) by field excitatory postsynaptic potential (EPSP) at the CA3-CA1 synapse. AMPAR activation by patch-clamp recordings in primary ventral spinal cord neurons was analyzed. In primary hippocampal neurons, NSPA distribution was assessed by double immunofluorescence, and intracellular calcium changes were evaluated using Fura-2 AM. NSPA-LacZ reporter-knockin mice expressing a truncated NSPA were used to assess NSPA expression pattern and function in the brain using β-galactosidase staining and comparative electrophysiology, calcium responses, and water maze memory tests.

RESULTS:

NSPA was expressed in the brain in hippocampal CA1, dentate gyrus and ventral, but not dorsal, CA3 regions, encompassing postsynaptic regions and partial colocalization with NMDAR. Notably, NSPA-LacZ reporter-knockin mice showed impaired memory, and decreased NMDAR activity and LTP, with neurons insensitive to anti-P autoantibodies. Anti-P autoantibodies enhanced CA1 postsynaptic transmission, increasing AMPAR and NMDAR activity and leading to LTP abrogation after prolonged (20-minute) incubation.

CONCLUSION:

Our findings indicate that the neuronal cell surface target of anti-P, NSPA, is involved in glutamatergic synaptic transmission and plasticity related to memory in the hippocampus, and mediates the deleterious effects of anti-P on these processes. Cognitive impairment, as well as other diffuse NPSLE manifestations, may develop when anti-P autoantibodies have access to brain regions coexpressing NSPA, AMPAR, and NMDAR.

PMID:
25709106
DOI:
10.1002/art.39081
[Indexed for MEDLINE]
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