Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide.

Abstract

Mice with a heterozygous null mutation in myelin protein zero (P0(+/-)) develop late-onset clinical paralysis associated with inflammatory pathology in the peripheral nerves. Although the development of this illness is known to require T cells and macrophages, little is understood regarding the immunological defect in the mice. Here we report that young P0(+/-) mice, free from clinical manifestations, have a defect in central tolerance to P0, and are more prone to induction of experimental autoimmune neuritis (EAN) by sensitization against P0(180-199 )peptide. Notably, we found that the P0 gene is transcribed in the thymus of wild-type and the P0(+/-) mice in an amount proportional to the gene dosage. We then replaced the thymus of wild-type mice with that of the P0-deficient mice and vice versa. Immunization of these mice with P0(180-199 )revealed that a lower thymic P0 transcript would be associated with the higher recall T cell response to P0(180-199), thus accounting for the higher susceptibility of the P0(+/-) mice to P0-induced EAN. These results imply that a heterozygous mutation in an autoantigen could cause defective central tolerance to the autoantigen. As such, autoimmune T cells may play some role in "genetic" diseases caused by a heterozygous gene defect.

• Authors: Katsuichi Miyamoto, Sachiko Miyake, Melitta Schachner, Takashi Yamamura
• Journal: European journal of immunology (Eur J Immunol) Vol. 33 Issue 3 Pg. 656-65 (Mar 2003) ISSN: 0014-2980 [Print] Germany
• PMID: 12616486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myelin P0 Protein
• Peptide Fragments

Topics

• Amino Acid Sequence
• Animals
• Genetic Predisposition to Disease
• Heterozygote
• Immune Tolerance
• Mice
• Molecular Sequence Data
• Mutation
• Myelin P0 Protein (genetics, immunology)
• Neuritis, Autoimmune, Experimental (etiology, genetics)
• Peptide Fragments (immunology)
• T-Lymphocytes (immunology)
• Transcription, Genetic