complicated article about ype 1 diabetes

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This article originally posted 29 April, 2010 and appeared in

Issue 519

Past five issues:

Issue 520 |

Issue 519 |

Issue 518 |

Issue 517 |

Issue 516 |

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" People have been looking for the mechanism linking HLA and autoimmunity for

40 years, " said Scripps Research Professor Luc Teyton, who led the study

with

Scripps Research Professor Ian . " This study provides a big leap

forward in understanding and suggests a critical new target to intervene in

Type

1 diabetes. "

Teyton notes that his lab has been trying to solve the mystery of autoimmune

mechanisms and related conditions like celiac disease for some 25 years.

This new study focuses on Type 1, or insulin-dependent diabetes, a rapidly

progressive disease of the young that leads to high blood sugar, coma, and

death

if not treated with replacement insulin.

While genes predispose people to many different types of diseases in many

different ways, specific genetic variations are an especially strong

predictor

of the development of Type 1 diabetes. Three genetic variations in

particular (HLA-DQ2, HLA-DQ8, and HLA-DR0405) all located in the region of

the genome

called HLA for " human leukocyte antigen " are known to dramatically increase

the risk of coming down with the condition.

These three genes encode molecules that present peptides (protein fragments)

to the body's T cells. T cells then determine whether the peptide being

presented

is dangerous and needs to be eliminated from the body as in the case of

foreign invaders such as bacteria or viruses or whether the peptide is

" self, "

part of the host and something the immune system needs to leave alone.

However, in the context of Type 1 diabetes, T cells aggressively attack the

body's

own cells.

The scientists wanted to know on a molecular level how mutations in the

immune surveillance machinery could lead to Type 1 diabetes.

" We were interested in trying to understand why certain MHC molecules (which

are molecules in mice analogous to HLA molecules in humans) are linked to

autoimmune

disease, particularly Type 1 diabetes, " said Research Associate Adam Corper

of the lab, who was first author of the paper. " In particular, we

wanted

to know why a single residue at position 57 on the â chain of HLA molecules

seems to be linked to the disease. "

In the new research, the team used a series of structural and biophysical

studies to answer that question.

Previously, Teyton and labs had determined the structure of a

" diabetogenic " MHC molecule and found that mutations to position 57 caused

only subtle

changes. It did not, as some had speculated, cause the molecule to become

unstable and non-functional.

Now, in the new study the researchers found that diabetes-causing mutations

changed the charge at one end of the MHC peptide-binding groove. In

individuals

not predisposed to Type 1diabetes, MHC molecules usually have a negatively

charged residue at position 57. In contrast, disease-causing MHC molecules

have

a neutral residue at position 57 and consequently the surrounding region is

more positively charged.

The result of this molecular change was that the mutated MHC molecules

selected a unique subset of T cells that bound to it strongly, with " higher

affinity. "

These T cells may overreact and potentially misidentify " self " peptides as

dangerous rather than harmless.

" We found that the MHC region around position 57 can be seen by the T cell

receptor, " said Teyton. " That's the big novelty of the paper: for the first

time,

we show that it is not only essential for peptide binding, but also critical

for the selection of T cells. Finally, we have an idea of why those

particular

MHC molecules are associated with disease. "

Corper added, " What we have here is potentially a way of breaking

'tolerance,' the mechanism where the immune system doesn't respond to self.

Obviously,

if that breaks down you get autoimmune disease. "

The team is now investigating potential antibody or small molecule therapies

that could target and correct mutated MHC.

Journal of Clinical Investigation

May 2010

Diabetes In Control Advertisers

CME/CE of the Week Lilly Submits Reply to FDA Complete Response Letter

for BYDUREONT

Bookmark and Share

|

Print |

Category |

Home

This article originally posted 29 April, 2010 and appeared in

Issue 519

Past five issues:

Issue 520 |

Issue 519 |

Issue 518 |

Issue 517 |

Issue 516 |

Diabetes In Control Advertisers

Click here to find out more! frame

Flash movie start

Flash movie end

Click here to find out more! frame end

Flash movie start

Advertisement

" People have been looking for the mechanism linking HLA and autoimmunity for

40 years, " said Scripps Research Professor Luc Teyton, who led the study

with

Scripps Research Professor Ian . " This study provides a big leap

forward in understanding and suggests a critical new target to intervene in

Type

1 diabetes. "

Teyton notes that his lab has been trying to solve the mystery of autoimmune

mechanisms and related conditions like celiac disease for some 25 years.

This new study focuses on Type 1, or insulin-dependent diabetes, a rapidly

progressive disease of the young that leads to high blood sugar, coma, and

death

if not treated with replacement insulin.

While genes predispose people to many different types of diseases in many

different ways, specific genetic variations are an especially strong

predictor

of the development of Type 1 diabetes. Three genetic variations in

particular (HLA-DQ2, HLA-DQ8, and HLA-DR0405) all located in the region of

the genome

called HLA for " human leukocyte antigen " are known to dramatically increase

the risk of coming down with the condition.

These three genes encode molecules that present peptides (protein fragments)

to the body's T cells. T cells then determine whether the peptide being

presented

is dangerous and needs to be eliminated from the body as in the case of

foreign invaders such as bacteria or viruses or whether the peptide is

" self, "

part of the host and something the immune system needs to leave alone.

However, in the context of Type 1 diabetes, T cells aggressively attack the

body's

own cells.

The scientists wanted to know on a molecular level how mutations in the

immune surveillance machinery could lead to Type 1 diabetes.

" We were interested in trying to understand why certain MHC molecules (which

are molecules in mice analogous to HLA molecules in humans) are linked to

autoimmune

disease, particularly Type 1 diabetes, " said Research Associate Adam Corper

of the lab, who was first author of the paper. " In particular, we

wanted

to know why a single residue at position 57 on the â chain of HLA molecules

seems to be linked to the disease. "

In the new research, the team used a series of structural and biophysical

studies to answer that question.

Previously, Teyton and labs had determined the structure of a

" diabetogenic " MHC molecule and found that mutations to position 57 caused

only subtle

changes. It did not, as some had speculated, cause the molecule to become

unstable and non-functional.

Now, in the new study the researchers found that diabetes-causing mutations

changed the charge at one end of the MHC peptide-binding groove. In

individuals

not predisposed to Type 1diabetes, MHC molecules usually have a negatively

charged residue at position 57. In contrast, disease-causing MHC molecules

have

a neutral residue at position 57 and consequently the surrounding region is

more positively charged.

The result of this molecular change was that the mutated MHC molecules

selected a unique subset of T cells that bound to it strongly, with " higher

affinity. "

These T cells may overreact and potentially misidentify " self " peptides as

dangerous rather than harmless.

" We found that the MHC region around position 57 can be seen by the T cell

receptor, " said Teyton. " That's the big novelty of the paper: for the first

time,

we show that it is not only essential for peptide binding, but also critical

for the selection of T cells. Finally, we have an idea of why those

particular

MHC molecules are associated with disease. "

Corper added, " What we have here is potentially a way of breaking

'tolerance,' the mechanism where the immune system doesn't respond to self.

Obviously,

if that breaks down you get autoimmune disease. "

The team is now investigating potential antibody or small molecule therapies

that could target and correct mutated MHC.

Journal of Clinical Investigation

May 2010

Diabetes In Control Advertisers

CME/CE of the Week