Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide.
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.
Miyamoto
Katsuichi
K
Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
Miyake
Sachiko
S
Schachner
Melitta
M
Yamamura
Takashi
T
D000595:Amino Acid Sequence; D000818:Animals; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D007108:Immune Tolerance; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics* / Q000276:immunology*; D009444:Neuritis, Autoimmune, Experimental / Q000209:etiology* / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic
D018993:Myelin P0 Protein; D010446:Peptide Fragments