Journal ArticleDOI
Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice
Toru Miyazaki,Masashi Uno,Masahiro Uehira,Hitoshi Kikutani,Tadamitsu Kishimoto,Masao Kimoto,Hirofumi Nishimoto,Junichi Miyazaki,Ken Ichi Yamamura +8 more
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TLDR
The results show that the single amino-acid substitution at position 57 of the I-A β-chain from aspartic acid to serine is not sufficient for the development of the disease.Abstract:
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.read more
Citations
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Journal ArticleDOI
Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1
Jerry H. Brown,Theodore S. Jardetzky,Joan C. Gorga,Joan C. Gorga,Lawrence J. Stern,Lawrence J. Stern,Robert G. Urban,Jack L. Strominger,Don C. Wiley,Don C. Wiley +9 more
TL;DR: A dimer of the class II αβ heterodimers is seen in the crystal forms of HLA-DR1, suggesting class II HLA dimerization as a mechanism for initiating the cytoplasmic signalling events in T-cell activation.
Journal ArticleDOI
Finding Genes That Underlie Complex Traits
TL;DR: This work proposes standards for proof of gene discovery in complex traits and evaluates the nature of the genes identified to date, and demonstrates the insights that can be expected from the accelerating pace of geneiscovery in this field.
Journal ArticleDOI
MHC Class-II Molecules and Autoimmunity
Gerald T. Nepom,H Erlich +1 more
TL;DR: Molecular and genetic studies of HLA class-II genes provide new insights into the basis for MHC associations with autoimmunity and suggest a number of possible mechanisms critical for autoimmune triggering events involving class- II molecules.
Book ChapterDOI
The Murine Autoimmune Diabetes Model: NOD and Related Strains
Hitoshi Kikutani,Susumu Makino +1 more
TL;DR: This chapter summarizes the experimental findings and observations based on the nonobese diabetic (NOD) mouse model and discusses the pathogenesis and the etiology of autoimmune diabetes.
Journal ArticleDOI
Genetic analysis of autoimmune type 1 diabetes mellitus in mice.
John A. Todd,T J Aitman,Richard J. Cornall,S Ghosh,Jennifer Ruth Sadler Hall,C M Hearne,Andrew M. Knight,Jennifer M. Love,M A McAleer,Jan-Bas Prins +9 more
TL;DR: In this article, a genetic map of the mouse genome, analysed using the polymerase chain reaction, has been assembled specifically for the study of autoimmune type 1 diabetes in the nonobese diabetic mouse.
References
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Journal ArticleDOI
HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.
TL;DR: Analysis of DNA sequences from diabetics indicates that alleles ofHLA-DQβ determine both disease susceptibility and resistance, and that the structure of the DQ molecule, in particular residue 57 of the β-chain, specifies the autoimmune response against the insulin-producing islet cells.
Journal ArticleDOI
Breeding of a non-obese, diabetic strain of mice.
Susumu Makino,Kikuko Kunimoto,Yoshihiro Muraoka,Yukio Mizushima,Ken Katagiri,Yoshihiro Tochino +5 more
TL;DR: The nod mouse may be a useful animal model for investigating the human juvenile type diabetes because of the high frequency of lymphocyte infiltration around and/or into the Langerhans' islet.
Journal ArticleDOI
A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules.
Jerry H. Brown,Theodore S. Jardetzky,Mark A. Saper,Boudjéma Samraoui,Pamela J. Bjorkman,Pamela J. Bjorkman,Don C. Wiley +6 more
TL;DR: The hypothetical class II foreign-antigen binding site presented is consistent with mutation experiments1828 and provides a structural framework for proposing peptide binding models to help understand recent peptidebinding data11,2933.
Journal ArticleDOI
In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis.
TL;DR: After the death of a 12-year old girl with newly discovered insulin-dependent diabetes mellitus, monoclonal antibodies were used in an effort to identify the cells invading the pancreas and may contribute to an understanding of the sequence of events leading to the destruction of beta cells in classic Type I diabetes mell Titus.
Journal ArticleDOI
A molecular basis for MHC class II--associated autoimmunity
John A. Todd,Hans Acha-Orbea,John I. Bell,Nelson J. Chao,Zdenka Fronek,Chaim O. Jacob,M McDermott,Animesh A. Sinha,Luika A. Timmerman,Lawrence Steinman +9 more
TL;DR: This study identifies certain class II polymorphic amino acid residues that are strongly associated with susceptibility to insulin-dependent diabetes mellitus, rheumatoid arthritis, and pemphigus vulgaris.