autoimmune conditions

Posted on autoimmune conditions, Diabetes, Multiple Sclerosis

‘Boot camp’ enzyme prevents autoimmune conditions

Thymus cells making AIRE (green) that educate the surrounding developing T cells (red).


Thymus cells making AIRE (green) that educate the surrounding developing T cells (red).CREDIT WEHI

WEHI researchers have identified an enzyme in the thymus that is essential for immune T cells to correctly identify threats, safeguarding them from going rogue and attacking healthy tissue in the body.

The thymus is an important organ where immune T cells learn to fight infection. The new findings revealed that the enzyme KAT7 is necessary to activate thousands of genes required for ‘training’ immune T cells not to attack healthy tissue. Without proper training, immune T cells are at risk of sabotaging the immune system which could lead to autoimmune conditions such as Type 1 diabetes, or multiple sclerosis. 

Published in Science Immunology, the research paves the way for potential treatments to target KAT7, which could modify the training of immune T cells as needed. Such treatments could be used to either restrain immune T cells from drivingautoimmune conditions, or to supercharge immune T cells to better fight diseases such as cancer.

The research was led by former WEHI PhD student Dr Melanie Heinlein, along with Associate Professor Tim Thomas and Associate Professor Daniel Gray from WEHI, in collaboration with researchers at Monash University and the Weizmann Institute of Science in Israel.

At a glance

  • Researchers have discovered that the enzyme KAT7 is crucial for ‘training’ immune T cells to correctly identify and fight threats in the body.
  • They showed that blocking the function of KAT7 in pre-clinical models sent the immune system into overdrive, leading to a range of autoimmune conditions.
  • These findings show that KAT7 could be targeted therapeutically to either dampen or boost the immune system as required.

A ‘preview’ of threats

The thymus is like a ‘boot camp’ where immune T cells are trained to identify and fight pathogens, and taught not to attack healthy organs. As part of this preparation, immune T cells are shown a ‘preview’ of all the various components of healthy tissues they could encounter once they exit the thymus.

While it was previously known that the Autoimmune Regulator (AIRE) protein activated the thousands of genes needed for this preview, it was unclear how AIRE knew which genes it needed to ‘switch on’, until now. 

Dr Melanie Heinlein said the new findings revealed that the enzyme KAT7 was crucial for determining which genes AIRE needed to activate for immune T cells to be properly trained. 

“Like a training coordinator, KAT7 directs AIRE to the thousands of genes that must be activated for the ‘boot camp’ to run smoothly. KAT7 does this by tagging the genes that AIRE needs to ‘switch on’ for the preview of the body’s proteins to work. When all goes to plan, immune T cells are trained not to fight any normal tissues they could encounter in the body, ensuring they do not cause autoimmune disease,” she said.

Importance of KAT7

Associate Professor Tim Thomas said KAT7’s crucial role in keeping immune T cells to task was made clear when the researchers used a new drug to block its function. 

“We showed how a KAT7 inhibitor, developed in collaboration with Jonathan Baell at Monash University, was able to stop AIRE from switching on the genes needed to properly train immune T cells. Stopping this process sent the immune system into overdrive, leading to immune T cells going rogue and causing a range of autoimmune conditions in pre-clinical models. This shows a clear link between KAT7 and AIRE in maintaining immune tolerance,” he said.

“This has been a wonderful team effort. The highly collaborative study was made possible with expertise from across WEHI’s Flow Cytometry Laboratory, Genomics Facility, and the Centre for Dynamic Imaging, along with colleagues from Monash University and the Weizmann Institute of Science in Israel.”

Exciting treatment potential

Associate Professor Daniel Gray said the discovery could lead to new treatments for restraining immune T cells in order to prevent autoimmune conditions, or for supercharging immune T cells to fight disease.

“Our research shows KAT7 could be targeted to modify the training of immune T cells so they can either be stopped from causing autoimmunity, or boosted to fight disease.

“Potential applications of this knowledge include organ-specific autoimmune diseases such as Type 1 diabetes and multiple sclerosis, as well as cancer immunotherapy. In the latter scenario, the immune system could be supercharged to combat cancer by blocking KAT7 in the thymus,” he said.

Posted on autoimmune conditions

The protein that stands between us and autoimmunity

Tet-Mediated B Cell Tolerance


Tet2/3-deficient B cells are activated by self-antigen and express exaggerated amount of CD86. Then those B cells stimulate autoreactive CD4<sup>+</sup> T cells, resulting in autoimmune response. CREDIT Osaka University

 Our immune system is supposed to protect us from external microbial invaders, but sometimes it turns its efforts inward, potentially resulting in autoimmune diseases. In a new study, researchers from Osaka University discovered how reversible modifications to our DNA by certain proteins protect us from autoimmune diseases and, conversely, how the absence of these proteins paves the way to autoimmunity.

DNA contains all information that cells in our body need to function by providing specific codes to produce specific proteins. Nonetheless, not all parts of DNA are accessible in all cells at all times. The regulated production of proteins ensures that different cells and organs can be developed from the same DNA code. An important regulatory mechanism is the reversible addition (methylation) or removal (demethylation) of chemical bonds, so-called methyl groups, to segments of DNA. This modifies the readout of said DNA segment. Proteins of the ten-eleven translocation (Tet) family are known DNA demethylases that decrease the production of certain proteins in immune cells. How Tet proteins play into the development of autoimmune diseases has remained unknown—until now.

“Epigenetics deals with how reversible changes in DNA affect gene activity and protein expression,” says corresponding author of the study Tomohiro Kurosaki. “Disrupting this machinery can have dramatic effects on cellular function. The goal of our study was to understand how epigenetic control in a specific type of immune cells, called B cells, affects the development of autoimmune diseases.”

To achieve their goal, the researchers developed a novel mouse line in which B cells did not produce the epigenetic regulator proteins Tet2 and Tet3. They found that these mice developed a mild form of systemic lupus erythematosus, an autoimmune disease that can affect the joints, skin, kidneys and other organs, and for which there is currently no curative treatment. Similar to human patients, the mice showed increased serum levels of autoantibodies and damage to their kidneys, lungs and liver.

“These findings suggest that Tet2 and Tet3, as well as proteins whose expression is regulated by Tet2 and Tet3, might play a fundamental role in the development of systemic lupus erythematosus,” says lead author of the study Shinya Tanaka. “We wanted to gain a deeper molecular understanding of the mechanism behind the effects of Tet2 and Tet3 on the immune system.”

The researchers next investigated a different type of immune cell, called T cells, which often interact with B cells, and found that T cells were excessively activated in the Tet2/Tet3 knockout mice. By examining the molecular interaction between B and T cells closer, the researchers found that the protein CD86 was produced at higher levels in B cells of Tet2/Tet3 knockout mice, leading to aberrant T cell activation and autoimmunity.

“These are striking results that show how Tet proteins suppress autoimmune diseases by inactivating B cells and thus ultimately preventing them from attacking our bodies,” says Kurosaki. “Our findings provide new insights into the contribution of epigenetics to the development of autoimmune disease. Regulating Tet proteins and their downstream effectors could be a novel treatment for autoimmune diseases.”

Posted on autoimmune conditions

How to deal with autoimmune disease flares- A Rheumatologist POV

How to deal with autoimmune disease flares- A Rheumatologist POV - YouTube


Flares happen. We do everything we can to prevent them and to understand why they occur. But sometimes they just happen. This is true regardless of the inflammatory or autoimmune disease: lupus, arthritis, fibromyalgia, vasculitis and all the others. As frustrating as they can be, there are things you can do to maneuver your way through them with care and grace.

Posted on autoimmune conditions

Research pinpoints rogue cells at root of autoimmune disease

Research Pinpoints Rogue Cells at Root of Autoimmune Disease


Researchers discovered that in patients with cryoglobulinemic vasculitis, antibodies in the blood aggregate at colder temperatures closer to the skin and also in the kidneys, nerves, and other organs, damaging blood vessels. CREDIT Dr Ofir Shein-Lumbroso

There are more than 100 different autoimmune diseases. But what unites them all is that they arise from an individual’s own cells – rare and mysterious immune cells that target not external viruses and bacteria but the body’s own healthy organs and tissues.

For the first time, a team led by researchers at the Garvan Institute of Medical Research have pinpointed individual cells that cause autoimmune disease from patient samples. They also uncovered how these cells ‘go rogue’ by evading checkpoints that normally stop immune cells from targeting the body’s own tissues.

The findings could have significant implications for the diagnosis and treatment of autoimmune disease, which affects one in eight individuals in Australia.

“Current treatments for autoimmune disease address only the symptoms, but not the cause. To make more targeted treatments that address disease development and progression, we first need to understand the cause,” says Professor Chris Goodnow, co-senior author of the published work, Executive Director of the Garvan Institute and Director of the UNSW Sydney Cellular Genomics Futures Institute.

“We have developed a technique that allows us to look directly at the cells that cause autoimmune disease – it’s as though we’re looking through a new microscope lens for the first time, learning more about autoimmune disease than was ever possible before.”

The findings, published in the journal Cell today, are part of the visionary Hope Research program.

Research Pinpoints Rogue Cells at Root of Autoimmune Disease

(L-R) Dr Mandeep Singh, Professor Chris Goodnow, Dr Joanne Reed CREDIT Garvan Institute

Tracing autoimmune disease to its origins

Because ‘rogue’ immune cells are so rare in a blood sample – less than one in 400 cells – studying them has been a challenge. Analysis to date has at best revealed ‘averages’ of the vast mix of cells in a patient’s sample, says Dr Mandeep Singh, first author of the published paper.

“Using cellular genomics, we developed a method to ‘zoom in’ on these disease-causing immune cells in the blood samples of four patients with cryoglobulinemic vasculitis – a severe inflammation of the blood vessels,” says Dr Singh.

By first separating individual cells, and then separating their genetic material, the researchers isolated immune cells that produced ‘rheumatoid factors’ – antibody proteins that target healthy tissues in the body and are associated with the most common autoimmune diseases, including rheumatoid arthritis.

Once isolated, the researchers then analysed the DNA and messenger RNA of each of these ‘rogue’ cells, scanning more than a million positions in the genome to identify DNA variants that may be at the root of disease.

The evolution of autoimmune disease

Through their analysis, the researchers discovered that the disease-causing immune cells of the vasculitis patients had accumulated a number of mutations before they produced the damaging rheumatoid factors.

“We identified step-wise genetic changes in the cells at the root of an autoimmune disease for the first time, tracing an ‘evolutionary tree’ of how normal immune cells develop into disease-causing cells,” says co-senior author Dr Joanne Reed, who heads the Rheumatology and Autoimmunity Group at the Garvan Institute.

Remarkably, the researchers found that some of the first gene mutations that occurred in these rogue cells were known to drive lymphomas (cancerous immune cells).

“We uncovered ‘lymphoma driver mutations’, including a variant of the CARD11 gene, which allowed the rogue immune cells to evade immune tolerance checkpoints and multiply unchecked,” explains Professor Goodnow, who first hypothesised that disease-causing autoimmune cells employ this cancer tactic in 2007.

Further, the researchers found that cells with the lymphoma driver mutations accumulated further mutations that caused the rheumatoid factors they produced to aggregate, or ‘clump together’, at lower temperatures.

“This explains the patients’ cryoglobulinemic vasculitis, a severe condition that develops in some people with Sjögren’s syndrome, systemic lupus, rheumatoid arthritis, or hepatitis C virus infection. In these individuals, rheumatoid factors in the blood aggregate at colder temperatures closer to the skin and also in the kidneys, nerves, and other organs, which damages blood vessels and often proves very difficult to treat,” says Dr Reed.

New hope for personalised diagnosis and treatments

Not only have the research findings uncovered the root cause of an autoimmune disease – the ability to identify and investigate specific immune cells at such resolution has vast potential for future treatments to target the cause of all autoimmune diseases.

“In our study, we uncovered specific mutations that mark early stages of autoimmune disease. If we can diagnose a patient at these stages, it may be possible to combine our knowledge of these mutations with new targeted treatments for lymphoma to intervene in disease progression or to track how well a patient is responding to treatments,” says Dr Reed.

The researchers are now planning follow-up studies to investigate mutations of autoimmune cells in a range of other diseases, including lupus, celiac disease and type 1 diabetes.

“Identifying these rogue immune cells is a significant step forward for how we study autoimmune disease – and crucially the first step to finding ways to eliminate them from the body entirely,” says Professor Goodnow.

Posted on autoimmune conditions

But you don’t look sick? How broad categories like autoimmune impact patient experience

When your disease is hard to name and doesn’t have visible symptoms, it can be hard for others to understand that you are sick

"But You Don't Look Sick" || How to Respond to People Who Don't Understand Chronic Illness
“But You Don’t Look Sick” || How to Respond to People Who Don’t Understand Chronic Illness



When your disease is hard to name and doesn’t have visible symptoms, it can be hard for others to understand that you are sick. And, when people don’t know much about your disease, it can be hard to explain it to family and friends.


This sentiment is particularly true for the some 50 million people in the United States living with autoimmune diseases, like lupus or multiple sclerosis (MS) — where the condition is chronic but achieving a specific diagnosis may take time, the diagnosis may change, symptoms may not be overtly apparent, and, in many cases, both a cause and a “cure” are unknown.
Patients with autoimmune diseases often have an illness experience riddled with symptom ambiguities and shifting diagnoses. A new Drexel University study found that one way patients and physicians can work through the difficulty and frustration of communicating about these conditions is to use both broad diagnostic terms, like “autoimmune disease,” as well as narrow ones, such as “lupus or MS.”
Kelly Joyce, PhD, a professor in Drexel’s College of Arts and Sciences and a member of the Center for Science, Technology & Society, studies the cultural dimensions of medicine. Her research investigates the experiences of people diagnosed with autoimmune illnesses. In analyzing how people live with autoimmune illnesses, Joyce and former Drexel graduate student Melanie Jeske found that the use of a broad category – like autoimmune – provides continuity, certainty and even community for patients who struggle to convey their often-inconsistent illness experiences with clinicians, family and friends.
Drawing on 45 in-depth interviews with people who live with autoimmune illnesses, Joyce’s research showed that both broad diagnostic classifications and narrow diagnostic classifications are integral to diagnostic work and illness experiences.


Talking About Illness:
Researchers found that participants, regardless of gender, age or specific disease diagnosis, tended to use the broad category “autoimmune” in addition to a specific diagnosis, like Celiac disease or Rheumatoid arthritis, to talk about their health.
Some of the reasons they used the terminology were to describe what’s happening in their bodies, and to make it easier to provide continuity, even when there was a change in their specific diagnosis.
“Although friends and families may not understand the precise mechanisms of Lupus or Rheumatoid arthritis, for example, they could understand the general autoimmune process in which the body’s immune systems attacks healthy tissue and cells,” Joyce said.


The broad term also simplified the process of talking about the disease to friends and family, even as the specific diagnosis might change over time.
“Use of the category ‘autoimmune’ meant participants did not have to put their lives on hold even as aspects of their specific diagnosis changed from ulcerative colitis to Crohn’s disease, from lupus to mixed connective tissue disease (MCT), from one type of MS or lupus to another type of MS or lupus, and from having MS to not having MS to having MS,” said Joyce. “Autoimmune, although an umbrella or broad category, is productive for those experiencing illness, lending legitimacy to the symptoms that a person will experience.”
It can also help to distinguish their affliction from others that are more stigmatized. One specific example of this was that participants who live with type 1 diabetes — which is an autoimmune disease — who use the broad terminology to distinguish their illness from type 2 diabetes — a chronic condition caused by the body’s inability to metabolize sugar — as a way avoiding the stigma and blame often associated with the latter.
Finding Community:
Because people can experience the same autoimmune disease differently, participants noted that using “autoimmune” allows them to see similarities between themselves and others– creating a sense of community and shared experience.
“Many participants in our study stressed the heterogeneity of autoimmune illnesses, often saying things like ‘My MS is not like her MS,’ or ‘No two people are alike,'” Joyce said. “While most participants knew others, who shared their specific diagnosis, it did not mean that their experience of symptoms, their triggers for symptoms, or their responses to particular treatments were similar.”
Raising Awareness:
Research has shown that people who are ill can benefit from social support when their disease is widely recognized. For example, there is often an outpouring of support during the various cancer and disease awareness months and efforts – both broadly in society and at an individual level. This unifying support can be difficult for illnesses like autoimmune disease that is not as well understood in society.
The researchers suggest that recognizing that autoimmune can be a range of diseases and disorders — similar to the way we think about the autism spectrum — could aid our collective understanding of these diseases and support for those who are suffering from it.
Why Broad Categories are Important:
More than 80 illnesses are considered to be autoimmune or autoimmune-related. Though the illnesses under the umbrella vary widely, the common thread is an immune response that attacks healthy cells, tissue and/or organs. The study suggests that the label autoimmune provides, at minimum, some understanding and a scientific explanation as to what is happening to patients, though an exact diagnosis may be a moving target.
While this research focuses specifically on autoimmune illnesses, it does signal that broad and narrow categories may be important to medicine more generally.
“Within medicine, clinicians and researchers use the language of lumping and splitting to distinguish between two valuable diagnostic classification practices,” said Joyce. “The process of lumping creates broad categories and emphasizes connections. In contrast, splitting emphasizes the differences between illnesses – creating categories that tend to be narrow and more specialized, prioritizing difference rather than similarity.”
Sociologists study how clinical encounters and medical practice are social practices, that is, practices imbued with values, beliefs, and institutional and policy incentives. Yet, many sociologists who study diagnostic practices have yet to acknowledge the importance of broad categories in diagnostic work, according to Joyce.
“They focus on how clinicians and patients use narrow diagnostic labels, missing the importance of broad categories,” she said. “Sociologists who study how people live with illnesses tend to focus on life after a specific diagnosis, so they have also paid little attention to the importance of broad categories in medical practice.”
Now That We Know:
In light of her findings, Joyce suggests clinicians should consider presenting patients with both broad and narrow disease classifications when discussing autoimmune diagnoses initially and over time.
The use of the broad category may provide continuity and certainty in doctor-patient communications even as narrow disease diagnoses change or when symptoms do not map neatly into diagnostic tests or markers.
Some health care organizations are taking the lead and reorganizing the delivery of services in recognition of the changing diagnoses and, at times, unknowable, dimensions of autoimmune illnesses. As an example of this reorganization, West Penn Hospital in Pittsburgh, Pennsylvania opened the first institute dedicated to autoimmune illnesses in February 2018.
In the excitement over precision medicine, Joyce notes this study shows the importance of maintaining the use of broad categories in the experience and treatment of illness as well as using narrow diagnostic labels.