[acb-diabetics] complicated article about ype 1 diabetes

[Patricia LaFrance-Wolf]

Lilly Submits Reply to FDA Complete Response Letter for BYDUREONT 

 

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

to know why a single residue at position 57 on the β 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 Wilson 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 Wilson. "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 Wilson lab, who was first author of the paper. "In particular, we
wanted

to know why a single residue at position 57 on the β 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 Wilson 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

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