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Autoimmunity associated genes encode exceptionally unstable proteins

A new clue for the mechanistic basis of autoimmunity

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Graduate School of Medicine / Faculty of Medicine
2014/12/19

Autoimmune diseases, such as type 1 diabetes, are elicited through undesired immunological reactions against healthy tissues or organs, which occur through misrecognition of healthy tissues or organs as in infected states or as foreign matters by immune molecules. Genes encoding human leukocyte antigens (HLA) play a central role in the recognition of the immunological self and non-self, and HLA gene polymorphism (variation between individuals) is strongly associated with a variety of autoimmune diseases including type 1 diabetes, but the underlying mechanism remained elusive.


The graph shows protein stability of HLA (HLA-DQ) measured for the major HLA alleles  in Japanese and European populations. HLA proteins are displayed in order of increasing protein stability (x-axis) with estimated protein stability of HLA plotted on the y-axis. This study revealed that HLA alleles that are associated with type 1 diabetes mostly encoded unstable proteins, whereas HLA alleles that are associated with protection against type 1 diabetes generated extremely stable proteins.

The graph shows protein stability of HLA (HLA-DQ) measured for the major HLA alleles in Japanese and European populations. HLA proteins are displayed in order of increasing protein stability (x-axis) with estimated protein stability of HLA plotted on the y-axis. This study revealed that HLA alleles that are associated with type 1 diabetes mostly encoded unstable proteins, whereas HLA alleles that are associated with protection against type 1 diabetes generated extremely stable proteins.
© 2014 Hiroko Miyadera.

In this study, the research group of then-Assistant Professor Hiroko Miyadera and Professor Katsushi Tokunaga at the Graduate School of Medicine, the University of Tokyo, profiled protein stability of diverse HLA allele products and found that HLA alleles (variations in a gene) that are associated with susceptibility to type 1 diabetes encoded extremely unstable HLA proteins.

In previous studies, the relation between HLA gene polymorphism and autoimmune disease has been attributed to the allelic differences of the HLA in the recognition of peptides, but the actual mechanism of pathogenesis remained unknown. The current study suggests that a fundamentally different process may operate in the development of autoimmune diseases. This finding provides a new clue to explore the mechanistic basis of autoimmunity.

Press release [PDF] (Japanese)

Paper

Hiroko Miyadera, Jun Ohashi, Ake Lernmark, Toshio Kitamura, Katsushi Tokunaga,
“Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA,”
The Journal of Clinical Investigation Online Edition: 2014/12/9 (Japan time), doi: 10.1172/JCI74961.
Article link (Publication, UTokyo Repository)

Links

Graduate School of Medicine

School of International Health, Graduate School of Medicine

Department of Human Genetics, School of International Health, Graduate School of Medicine (Japanese)

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