Potential new ways to treat lupus

Lupus, including systemic lupus erythematosus, occurs when the immune system attacks the body's own healthy tissues, causing pain, inflammation, and tissue damage
.
Lupus most often affects the skin, joints, brain, lungs, kidneys, and blood vessels
.
According to the American Lupus Foundation, about 1.
5 million Americans and 5 million people worldwide suffer from some form of lupus
.
Only one targeted biologic is approved for the treatment of SLE, and that is belimab
.

Treatment of lupus is aimed at controlling symptoms, reducing the attack of the immune system on tissues, protecting organs from damage
.
Targeting iron metabolism in immune system cells may provide a new approach to treating systemic lupus erythematosus (SLE), the most common form of
the chronic autoimmune disease lupus.

A multidisciplinary team of Vanderbilt University Medical Center found that blocking iron uptake receptors in a mouse model of SLE reduces disease pathology and promotes the activity
of anti-inflammatory regulatory T cells.
The findings were published Jan.
13 in Science Immunology
.

Dr Jeffrey Rathmell, Professor of Pathology, Microbiology and Immunology and Chair of Immunobiology at Cornelius Vanderbilt, said: "Coming up with new treatments for lupus has been a real challenge
.
Patient populations and diseases are heterogeneous, which makes it difficult
to design and conduct clinical trials.
”

Rathmell's research group has long been interested in lupus as part of
a broader effort to understand autoimmune mechanisms.

When Dr.
Kelsey Voss, a postdoc, began studying T cell metabolism in lupus, she noticed that iron seemed to be "the common denominator of many problems in T cells," she said
.
She was also interested in the discovery that T cells in lupus erythematosus patients had high iron levels, even though patients were usually anemic.

"It's unclear why T cells are high in iron, or what that means," said
Voss, the study's lead author.

To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other researchers at VUMC:

• Dr.
  Eric Skaar and his team are experienced in the study of iron and other metals;

• Dr.
  Amy Major and her team provided a mouse model of SLE;

• Michelle Ormseth and her team recruited SLE patients to provide blood samples
  .
  

First, Voss used the CRISPR genome editing screen to assess iron-processing genes
in T cells.
She found that transferrin receptors are essential for inflammatory T cells and also have inhibitory effects
on anti-inflammatory regulatory T cells.

The researchers found that transferrin receptors were expressed higher on T cells in SLE-prone mice and T cells in SLE patients, which led to the cells accumulating too much iron
.

"We're seeing a lot of complications that come with that — mitochondria don't work properly and other signaling pathways are altered
," Voss said.

An antibody that blocks the transferrin receptor reduces intracellular iron levels, inhibits inflammatory T cell activity, and enhances regulatory T cell activity
.
Treatment of mice with SLE-prone tendencies with this antibody can reduce kidney and liver pathologies and increase the production
of anti-inflammatory factor IL-10.

Voss said: "It was really surprising and exciting
to find different effects of transferrin receptors in different types of T cells.
If you're trying to target an autoimmune disease by affecting T cell function, you want to suppress inflammatory T cells but not harm regulatory T cells
.
This is exactly what targeting transferrin receptors does
.
”

In T cells of lupus patients, the expression of transferrin receptor correlates with disease severity, and blocking this receptor in vitro promotes IL-10 production
.

The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells to avoid any potential off-target effects (transferrin receptor mediates iron uptake in many cell types).

They were also interested in investigating the details they unexpectedly discovered that blocking transferrin receptors could enhance regulatory T cell activity
.

Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus