Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo.

  • Ezeoke A
  • Mellor A
  • Buckley P
 et al. 
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Abstract

In this paper we demonstrate that, circulating antibodies from schizophrenic patients interacting with cerebral M1 muscarinic acetylcholine receptors (M1 mAChRs), can act as an inducer of m 1 mAChR-mRNA, and neuronal nitric oxide synthase (nNOS) mRNA gene expression of rat frontal cortex. The different signaling pathways involved in the autoantibody's actions, were characterized. As previously reported serum autoantibodies from schizophrenic patients reacted against neural cells surface inhibiting the binding of the specific mAChR radioligand to rat cerebral frontal cortex membrane. Moreover, by ELISA using M1 synthetic peptide (with identical aminoacid sequence to human M1 mAChR) as coating antigen we demonstrated the reactivity against the second extracellular loop of human cerebral M1 mAChR. The corresponding affinity-purified anti M 1 peptide IgG (anti M1 peptide IgG) from schizophrenic patients by stimulation of M1 mAChR exerted an increase in m 1 mAChR-mRNA and nNOS-mRNA levels, that significantly correlated with the accumulation of phosphoinositides (IPs) and activation of NOS (α = 0.05). All these effects were blunted by pirenzepine and mimicked the action of the authentic agonist. Concurrent analysis of the effects of nNOS, phospholipase C (PLC) and calcium/calmodulin (CaM) inhibition on both, m1 mAChR-mRNA and nNOS-mRNA levels, showing that antibody up-regulation mRNA level is under the control of endogenous nitric oxide (NO) signaling system. On the basis of our results, the activation of M1 mAChR by schizophrenic autoantibody appears to induce nNOS-mRNA expression and reciprocally, the activation of NOS up-regulates m1 mAChR gene expression. These results gave support to the participation of an autoimmune process in a particular group of chronic schizophrenic patients.

Author-supplied keywords

  • 10.1002/rcm.7753 and Schizophrenia
  • Adult
  • Animals
  • Antibody
  • Antipsychotic Agents/pharmacology
  • Autoantibodies
  • Autoantibodies/*pharmacology
  • Autoantibody
  • Autoantigen
  • Autoimmune
  • Autoimmune encephalitis
  • Biological
  • Brain
  • Calcium/calmodulin
  • Case-Control Studies
  • Cell Fates
  • Cell Line
  • Cell surface antigen
  • Cell-nucleus penetration
  • Cell-penetrating antibodies
  • Central nervous system
  • Cerebral Cortex/*drug effects
  • Cerebral frontal cortex
  • Cholinoceptors
  • Combinatorial Libraries
  • Conformational modification
  • Cyclooxygenase 1/*genetics
  • DNA binding
  • Dinoprostone/*metabolism
  • Dose-Response Relationship
  • Drug
  • ELISA procedure
  • Elution
  • Epidemiology
  • Female
  • First-episode psychosis
  • Gene Expression Regulation/drug effects
  • Heat shock protein
  • Humans
  • IgG
  • IgG concentration
  • IgG size
  • Immunoglobulin Fab Fragments
  • Immunoglobulin Fab Fragments: immunology
  • Immunoglobulin G
  • Immunoglobulin G: immunology
  • Immunoglobulin G: therapeutic use
  • Immunological
  • Immunology
  • Ion channel
  • Lupus-prone mice
  • MALDI-TOF MS
  • Male
  • Matrix Metalloproteinase 3/*metabolism
  • Membrane Proteins/*genetics
  • Mental disorder
  • Messenger/metabolism
  • Meta-analysis
  • Mice
  • Middle Aged
  • Models
  • Muscarinic M1/immunology
  • Neurotransmitter receptor
  • Nitric Oxide Synthase Type II/*genetics
  • Nitric Oxide/*metabolism
  • Nuclear molecules
  • Peptides/pharmacology
  • Phospholipase C
  • Pleiotropism
  • Polyreactive anti-DNA antibodies
  • Protein A
  • Protein associated with MYC (PAM)
  • RNA
  • RT-PCR
  • Rats
  • Receptor
  • Schizophrenia
  • Schizophrenia/blood/immunology
  • Wistar
  • aberrant immune response associated
  • abs
  • acid hydrolysis
  • acute phase protein
  • ampa-r
  • anti-DNA
  • anti-dna antibodies
  • antibody
  • are part of the
  • autoantibody
  • autoimmune
  • barrier
  • blood
  • blood brain barrier
  • brain
  • cytokine
  • dna-binding proteins
  • dr
  • effector mechanisms
  • erythematosus
  • gaba-r
  • hemihedral twinning
  • immunocompetent cell
  • immunoglobulin
  • immunology
  • immunopathology
  • m1 mAChR-mRNA
  • nNOS-mRNA
  • neuronal surface antigens
  • neuropsychiatric disorders
  • nmda-r
  • postmo
  • postmortem
  • risperidone
  • schizophrenia
  • structure
  • systemic lupus
  • vgkc complex
  • with sys-
  • x-ray crystallography

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Authors

  • Amaka Ezeoke

  • Andrew Mellor

  • Peter Buckley

  • Brian Miller

  • David S. Pisetsky

  • Sabrina Ganzinelli

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