Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice.
Insulin-dependent diabetes mellitus is characterized by the infiltration of lymphocytes into the islets of Langerhans of the pancreas (insulitis) followed by destruction of insulin-secreting beta-cells leading to overt diabetes. The best model for the disease is the non-obese diabetic (NOD) mouse. Two unusual features of the class II major histocompatibility complex (MHC) of the NOD mouse are the absence of I-E and the presence of unique I-A molecules (I-ANOD), in which aspartic acid at position 57 of the beta-chain is replaced by serine. This feature is also found in the HLA-DQ chain of many Caucasians with insulin-dependent diabetes mellitus. We have previously reported that the expression of I-E prevents the development of insulitis in NOD mouse. Here we report that the expression of I-Ak (A alpha kA beta k) in transgenic NOD mice can also prevent insulitis, and that this protection is seen not only when the I-A beta-chain has aspartic acid as residue 57, but also when this residue is serine. These results show that the single amino-acid substitution at position 57 of the I-A beta-chain from aspartic acid to serine is not sufficient for the development of the disease.
Miyazaki
T
T
Institute for Medical Genetics, Kumamoto University Medical School, Japan.
Uno
M
M
Uehira
M
M
Kikutani
H
H
Kishimoto
T
T
Kimoto
M
M
Nishimoto
H
H
Miyazaki
J
J
Yamamura
K
K
D000818:Animals; D001224:Aspartic Acid; D001483:Base Sequence; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D011487:Protein Conformation; D012694:Serine
D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D015345:Oligonucleotide Probes; D001224:Aspartic Acid; D012694:Serine