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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, Surface
  • Autoantibodies / immunology*
  • CA1 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / metabolism
  • Dentate Gyrus / metabolism
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials
  • Female
  • Gene Knock-In Techniques
  • Glutamic Acid / metabolism
  • Hippocampus / metabolism*
  • Humans
  • Long-Term Potentiation*
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Memory
  • Mice
  • Neuronal Plasticity
  • Neurons / immunology
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Ribosomal Proteins / immunology*
  • Ribosomal Proteins / metabolism
  • Spinal Cord / cytology
  • Synaptic Transmission*
  • Young Adult


  • Antigens, Surface
  • Autoantibodies
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Ribosomal Proteins
  • Glutamic Acid