Infiltrating self-defense cells provoke kidney failure in a chronic autoimmune disease

August 24, 2016, Agency for Science, Technology and Research (A*STAR), Singapore
Infiltrating self-defense cells provoke kidney failure in a chronic autoimmune disease
Some of the A*STAR team involved in the project: (left to right) HuiYin Lee, Anna-Marie Fairhurst, Susannah Thornhill, Teja Celhar from SIgN; and Richard Hopkins and Leigh Jones from the Connolly lab at IMCB. Credit: A*STAR Institute of Molecular and Cell Biology and A*STAR Singapore Immunology Network

The crucial role of dendritic cells in a fatal renal condition of systemic lupus erythematosus (SLE) has been exposed by A*STAR researchers. "Our studies show that these cells switch mild autoimmune phenotypes to severe kidney disease," says Anna-Marie Fairhurst at the A*STAR Singapore Immunology Network, who led the study.

SLE is a complex autoimmune disorder that predominantly affects women of child-bearing age. The disease is characterized by a range of gradually worsening symptoms, including joint pain, heart inflammation, and a butterfly-shaped rash across the nose and cheeks. A third of patients will develop life-threatening kidney disease, which Fairhurst has been trying to trace back to its pathological origins.

The of healthy individuals express a protein, called Toll-like receptor 7 (TLR7), that helps them recognize foreign pathogens. When hyper expressed in mouse models of SLE, however, TLR7 directs kidneys to their death. Fairhurst wondered which specific immune cells helped precipitate this decline. In an earlier study, she had eliminated the role of B cells, so her next suspect was the antigen-presenting dendritic cells.

Fairhurst and her colleagues doubled TLR7 expression levels in a mouse model of SLE and then selectively eliminated the surplus receptors from individual cell populations. When they deleted TLR7 in B cells, the disease continued to progress. But, this time, when they deleted TLR7 in dendritic cells, the disease stopped and they observed no inflammation in the kidneys (see image).

Further analysis revealed that a specific type of dendritic cell, known as conventional CD11b+, was primarily responsible for infiltrating the kidneys and causing the disease.

The problem with these findings was that the same dendritic cells in humans typically do not express TLR7. This raised a troubling question for Fairhurst about their role in human disease.

To test their relevance, she isolated dendritic from blood samples of healthy individuals and prodded them into expressing TLR7 using heat inactivated or live flu viruses, and a protein known to stimulate an immune response called interferon-alpha. Surprisingly, live influenza and interferon-alpha increased TLR7 expression in the .

Fairhurst plans to analyse blood samples from human patients of SLE to chart TLR7 expression levels for different manifestations of autoimmunity. Doctors recommend annual flu vaccines for SLE patients, but Fairhurst wants to investigate different vaccination strategies to determine which are the most beneficial.

"More than two-thirds of SLE patients 'in remission' still suffer and take daily medication," says Fairhurst. "We hope to make some changes in this process."

Explore further: Protein implicated in lupus promotes disease progression by distinct mechanisms in different immune cells

More information: Teja Celhar et al. RNA sensing by conventional dendritic cells is central to the development of lupus nephritis, Proceedings of the National Academy of Sciences (2015). DOI: 10.1073/pnas.1507052112

S.-H. Hwang et al. B Cell TLR7 Expression Drives Anti-RNA Autoantibody Production and Exacerbates Disease in Systemic Lupus Erythematosus-Prone Mice, The Journal of Immunology (2012). DOI: 10.4049/jimmunol.1202195

Related Stories

Protein implicated in lupus promotes disease progression by distinct mechanisms in different immune cells

March 13, 2013
Patients with systemic lupus erythematosus (SLE) come under attack by their immune system, producing 'autoantibodies' that inflict damage throughout the body. Antibodies normally target foreign proteins, but SLE autoantibodies ...

African-American lupus patient immune cell characteristics may increase disease severity

June 16, 2016
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs. SLE severity is highly variable, and this variability is known to be partially dependent on ancestral background. Notably, African ...

Antibody targets and destroys cells implicated in systemic lupus erythmatosis

May 5, 2016
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organ systems. Autoantibodies, which are produced by B cells, contribute to development of SLE. Recent studies have also shown that ...

Study reveals role for oxidized mitochondrial DNA in lupus

April 18, 2016
Researchers at the Baylor Institute for Immunology Research have discovered that the neutrophils of systemic lupus erythematosus (SLE) patients release oxidized DNA from their mitochondria that can stimulate an unwanted immune ...

Study identifies protein that triggers lupus-associated immune system activation

April 6, 2015
Massachusetts General Hospital (MGH) investigators have identified an inflammatory molecule that appears to play an essential role in the autoimmune disorder systemic lupus erythematosus, commonly known as lupus. In their ...

How rotavirus infection accelerates autoimmune diabetes in a mouse model

March 27, 2014
A combination of genetic predisposition and environmental factors is believed to cause autoimmune (type 1) diabetes. A study published on March 27th in PLOS Pathogens gets at the mechanisms by which rotavirus infection contributes ...

Recommended for you

Thymic tuft cells play key role in preventing autoimmunity, mouse experiments show

July 18, 2018
UC San Francisco researchers were recently surprised to discover fully formed gut and skin cells in the thymus, a lemon-sized organ that sits in front of the heart and is responsible for training the T cells of the immune ...

Autism risk determined by health of mom's gut, research reveals

July 18, 2018
The risk of developing autism-spectrum disorders is determined by the mother's microbiome—the collection of microorganisms that naturally live inside us—during pregnancy, new research from the University of Virginia School ...

New findings suggest allergic responses may protect against skin cancer

July 17, 2018
The components of the immune system that trigger allergic reactions may also help protect the skin against cancer, suggest new findings.

The immune system: T cells are built for speed

July 17, 2018
Without T cells, we could not survive. They are a key component of the immune system and have highly sensitive receptors on their surface that can detect pathogens. The exact way that these receptors are distributed over ...

Broadly acting antibodies found in plasma of Ebola survivors

July 17, 2018
Recent Ebola virus disease (EVD) outbreaks, including the 2013-2016 epidemic that ravaged West Africa and the 2018 outbreak in the Democratic Republic of the Congo, highlight the need for licensed treatments for this often-deadly ...

How protein fragments could help to tackle the cause of hay fever

July 16, 2018
Imperial researchers are looking to protein fragments to help people build up resistance to grass pollen.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.