Autoimmunity and tumor immunity induced by immune responses to mutations in self.
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.
Engelhorn
Manuel E
ME
Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. engelho1@mskcc.org
Guevara-Patiño
José A
JA
Noffz
Gabriele
G
Hooper
Andrea T
AT
Lou
Olivia
O
Gold
Jason S
JS
Kappel
Barry J
BJ
Houghton
Alan N
AN
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D001324:Autoantigens / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003429:Cross Reactions; D018076:DNA, Complementary / Q000235:genetics; D015723:Gene Library; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics; D014162:Transfection
D000951:Antigens, Neoplasm; D001324:Autoantigens; D018076:DNA, Complementary; D011994:Recombinant Proteins; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase