Genetic signature helps distinguish latent autoimmune diabetes in adults from pediatric-onset T1D

A multi-center team of researchers led by Children's Hospital of Philadelphia (CHOP) has discovered a genetic signature that could help distinguish an adult-onset form of diabetes sharing many type 1 diabetes (T1D) characteristics from pediatric-onset T1D, opening the door to potentially more straightforward diagnostic tests for the adult condition and improving responses by ensuring patients receive the most appropriate treatment.

This is our first insight into genetic differences between latent autoimmune diabetes in adults and T1D in children that may be diagnostically useful. We have found a genetic means of discriminating between the two conditions without expensive and cumbersome anti-autobody screening."Struan Grant, PhD, study leader, Co-Director of the Center for Spatial and Functional Genomics at CHOP and the Daniel B. Burke Endowed Chair for Diabetes Research

The study was published online December 16, 2019 in Diabetes Care.

Latent autoimmune diabetes in adults (LADA) is sometimes referred to as "type 1.5 diabetes" because it shares characteristics of both T1D and type 2 diabetes (T2D). Like T1D, LADA produces autoantibodies that attack the body's insulin-producing beta cells in the pancreas. However, like those with T2D, patients with LADA are diagnosed in adulthood and do not require insulin at the time of diagnosis. For this reason, LADA is often misdiagnosed as T2D; studies have shown that up to 10% of T2D diagnoses are, in fact, LADA, and as a result patients do not respond to the commonly inappropriate treatments prescribed to them.

An earlier genome-wide association study led by CHOP found that, from a genetic perspective, LADA has more in common with T1D than with T2D. Researchers wanted to take a deeper dive and look for genetic differences that could help discriminate between LADA and T1D, meaning the diagnosis of LADA could potentially begin with a simple genotype array, rather than with a more complex and expensive auto-antibody screening.

To do so, the team decided to look at the major histocompatibility complex (MHC), a highly variable region of the genome that helps drive the immune system and is implicated in T1D. Earlier studies have shown that when researchers control for T1D genetic variants in one part of the MHC, other variants associated with T1D appear in another part of the MHC.

The study team applied that methodology to both a set of T1D data as well as a cohort of LADA patients. They found that when it came to the T1D group, the results from the earlier studies held: controlling for genetic variants in one part of the MHC revealed variants in another part of the MHC.
However, researchers did not find the same effect with LADA patients. When controlling for genetic variants in the MHC in those patients, the additional association was not observed within this key region - an important genetic distinction between the two conditions. When a sensitivity test was applied to the two cohorts, researchers still saw the effect only in T1D patients, not in those with LADA.

"This suggests that these MHC class associations may be a genetic discriminator between LADA and childhood-onset T1D," said Diana Cousminer, PhD, a geneticist at CHOP and a joint-first author of the study. "The next step is to look at this association in different ethnicities, particularly African ancestry, where the prevalence of adult-onset diabetes can be significantly higher in certain parts of the world."

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Researchers Have Identified Why Our Bodies Reject Transplanted Organs

Researchers have identified a previously hidden link between our immune system and the activation of cells that lead to organ rejection.

The discovery opens the way for scientists to develop new forms of treatment that could prevent immune responses from attacking life-saving tissue transplants without leaving the body so open to infection or cancer.

A type of receptor on bone marrow cells called signal regulatory protein alpha  (SIRPα) has been identified by scientists, as the body's watchdog responsible for dispatching the lymphocytes that target and destroy foreign cells.

In simple terms, whenever we take cells from another person's body and put them into our own, white blood cells see them as foreign and attempt to break them apart.

Not only is this bad news for the transplanted tissues, the swelling and fever that comes with the immune response isn't exactly a picnic either.

The mechanisms behind the white blood cell assault are fairly well understood – molecules on the outside of the cells belonging to what's called the major histocompatibility complex (MHC) identify them as different.

A type of white blood cell called a T lymphocyte has receptors on its surface capable of recognising unknown MHC proteins and responds by attempting to break up the foreign material they're attached to.

Lymphocytes aren't born knowing what's foreign and what's not; they need to be taught. Which is the job of another part of the immune system called a dendritic cell. 

Dendritic cells chew up foreign proteins and weave them into their own MHC before displaying them on their surface like a microscopic 'wanted' poster. They then migrate into the body's lymph nodes where they interact with the gun-slinging T lymphocytes.

Exactly how dendritic cells identify foreign materials, however, has been something of a mystery.

To learn more, the researchers studied the transplanted tissues in mice engineered to lack certain white blood cells such as their T lymphocytes.

They found that differences between the mice donor's and recipient's SIRPα gene correlated with the recipient's immune responses.

SIRPα isn't an unknown protein, already understood to bind to another protein called CD47 that triggers a range of immune responses in different white blood cells.

Joining the dots, the researchers believe CD47 on monocytes – the white blood cells that grow into dendritic cells – interact with SIRPα receptors on foreign tissues, setting off the entire ID check process.

"Once these cells are activated, then they turn around and activate the rest of the immune system, and that leads to the full-blown rejection of the organ," lead researcher.

"What we would like to do is sequence the SIRP-alpha gene in many humans who are donors and recipients of organ or bone marrow, and then ask whether a mismatch affects the outcome after transplantation."

A better match between the donor's and recipient's SIRPα genes could help reduce the risk of the immune response being sparked in the first place.



Even when organs are chosen to have closely matching MHC proteins, subtle differences can still produce immune responses. For example, one in 10 hearts and nearly one in 20 kidneys will show signs of being rejected by the body within the first year in spite of being declared compatible.

To avoid rejection, organ recipients need to be on treatments that suppress the immune system, not only making them prone to infection and cancer but often raising the risk of heart attacks and strokes by increasing blood pressure.

New treatments focusing on SIRPα might help reduce the doses or types of medications, and possibly help prolong the organ's life.

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