HMSN (CMT) myelin protein zero research from Germany

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(FYI HMSN is another term for CMT: Hereditary Motor and Sensory

Neuropathy) ~ G

Abstract from J Immunol. 2004 Feb 1; 172(3): 1364-70.

Tolerance induction by intrathymic expression of p0.

Visan L, Visan IA, Weishaupt A, Hofstetter HH, Toyka KV, Hunig T, Gold

R.

Department of Neurology, Clinical Research Group for Multiple Sclerosis

and Neuroimmunology, Department of Internal Medicine, and Institute for

Virology and Immunobiology, University of Wurzburg, Wurzburg, Germany.

Genetic deficiency or instability of myelin protein zero (P0) results in

hereditary motor sensory neuropathy. In view of recent advances in gene

therapy, substitution of the molecular defect may become realistic in

the near future. Here we investigate the impact of genetic deficiency of

P0 on selection of the autoreactive T cell repertoire in the

corresponding mouse model. We show that P0 mRNA transcripts are

expressed in thymic stroma, similar to other myelin proteins and that

expression of intact P0 protein can be detected by Western blot. Using a

library of overlapping 20mer peptides spanning the entire length of P0

and applying the ELISPOT technique, we detected a strong immune response

toward P0 extracellular domain peptide aa 41-60 in P0(-/-) knockout

mice, but not in heterozygous P0(+/-) or wild-type (wt) mice. In

addition, one cryptic epitope and two subdominant epitopes of P0 were

identified. Using P0(-/-) into wt bone marrow (BM) chimeras we found

that P0 expression in the host suffices for full tolerance induction,

which is in line with its presence in thymic stroma. However,

repopulation of P0(-/-) mice with wt BM led to partial induction of

tolerance, suggesting that BM derived cells can also express this

protein. Our findings may have implications for secondary autoimmunity

developing after gene therapy in hereditary neuropathies and other

diseases with genetically determined protein deficiency, because the

repaired protein will then represent a foreign, nontolerized Ag.