Autoimmunity and tumor immunity induced by immune responses to mutations in self

Nat Med. 2006 Feb;12(2):198-206. doi: 10.1038/nm1363. Epub 2006 Jan 29.


Little is known about the consequences of immune recognition of mutated gene products, despite their potential relevance to autoimmunity and tumor immunity. To identify mutations that induce immunity, here we have developed a systematic approach in which combinatorial DNA libraries encoding large numbers of random mutations in two syngeneic tyrosinase-related proteins are used to immunize black mice. We show that the libraries of mutated DNA induce autoimmune hypopigmentation and tumor immunity through cross-recognition of nonmutated gene products. Truncations are present in all immunogenic clones and are sufficient to elicit immunity to self, triggering recognition of normally silent epitopes. Immunity is further enhanced by specific amino acid substitutions that promote T helper cell responses. Thus, presentation of a vast repertoire of antigen variants to the immune system can enhance the generation of adaptive immune responses to self.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm / genetics
  • Autoantigens / genetics*
  • Autoimmunity / genetics*
  • Base Sequence
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • COS Cells
  • Chlorocebus aethiops
  • Cross Reactions
  • DNA, Complementary / genetics
  • Gene Library
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / immunology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutation*
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / immunology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Self Tolerance / genetics
  • Transfection


  • Antigens, Neoplasm
  • Autoantigens
  • DNA, Complementary
  • Recombinant Proteins
  • Intramolecular Oxidoreductases
  • dopachrome isomerase