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

March 13, 2013
Mice with extra copies of the Tlr7 gene showed no signs of SLE (above), but mice with extra copies of Tlr7 and Sle1 were symptomatic. Credit: iStockphoto/Thinkstock

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 attack targets contained within the nuclei of host cells, and immunologists have struggled to untangle how this happens.

Research led by Anna-Marie Fairhurst of the A*STAR Singapore Immunology Network has now uncovered valuable insights into early SLE onset. Part of SLE's complexity arises from the intersecting involvement of multiple genetic factors. Accordingly, one of the primary SLE mouse models that Fairhurst uses contains two clusters of genomic variants, Sle1 and Yaa. Each cluster contains numerous SLE-.

One of the most interesting genes contained within Yaa is Tlr7, which encodes the TLR7 protein. Fairhurst's team revealed previously that increased Tlr7 expression is an essential contributor to in Sle1Yaa mice. TLR7 is a cell-surface receptor that recognizes , so it is important for the immune response to infection. However, since TLR7 performs different functions in different immune cell types, its potential contributions to disease are ambiguous. One possibility is that TLR7 hyperactivity establishes a 'feedback loop' that drives autoantibody-secreting to overreact to host proteins.

To discern TLR7's role, Fairhurst and co-workers engineered mice whose cells each contain extra copies of its gene. These mice were asymptomatic. When the researchers crossed these mice with Sle1 mice, their offspring produced antinuclear autoantibodies and exhibited severe abnormalities of the kidney and spleen that are typically seen in Sle1Yaa mice.

Fairhurst and her co-workers designed their mouse strain so that the extra Tlr7 copies could be selectively deleted in certain cells via a targeted mechanism (see image). They anticipated that by normalizing TLR7 levels in B cells, they could largely prevent disease onset in animals that still overexpress this receptor elsewhere. Although the researchers observed the expected strong reduction in anti-RNA autoantibodies in these mice, they were surprised to see only partial mitigation of other SLE symptoms.

This suggests a more complex role for TLR7 in SLE. "TLR7 is required for the initial steps of autoimmunity, meaning autoantibody production," says Fairhurst, "but the [increased expression] of TLR7 in other cells drives the inflammation that leads to tissue destruction and severe disease." Accordingly, she and her co-workers are now actively investigating both how TLR7 drives B cells to attack inappropriate targets in early SLE onset and the cell populations in which it acts to accelerate progression.

Explore further: Scientists show lack of single protein results in persistent viral infection

More information: Hwang, S.-H., Lee, H., Yamamoto, M., Jones, L. A., Dayalan, J. et al. B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus–prone mice. The Journal of Immunology 189, 5786–5796 (2012). www.jimmunol.org/content/189/12/5786.abstract

Related Stories

Scientists show lack of single protein results in persistent viral infection

June 13, 2012
Scientists from The Scripps Research Institute have shown a single protein can make the difference between an infection clearing out of the body or persisting for life. The results also show where the defects occur in the ...

B-cell discovery suggests why women suffer more autoimmune disease

August 4, 2011
Researchers at National Jewish Health have discovered a type of cell that may contribute to autoimmune disease and suggests why diseases such as lupus, multiple sclerosis and rheumatoid arthritis strike women more frequently ...

Why do women suffer autoimmune diseases more often?

July 4, 2011
Researchers at National Jewish Health have discovered a type of cell that may contribute to autoimmune disease. The findings also suggest why diseases such as lupus, multiple sclerosis and rheumatoid arthritis strike women ...

Appetite suppressant for scavenger cells: Influenza curbs part of the immune system and abets bacterial infections

November 15, 2012
When infected with influenza, the body becomes an easy target for bacteria. The flu virus alters the host's immune system and compromises its capacity to effectively fight off bacterial infections. Now, a team of immunologists ...

Recommended for you

Team finds link between backup immune defense, mutation seen in Crohn's disease

July 27, 2017
Genes that regulate a cellular recycling system called autophagy are commonly mutated in Crohn's disease patients, though the link between biological housekeeping and inflammatory bowel disease remained a mystery. Now, researchers ...

Co-infection with two common gut pathogens worsens malnutrition in mice

July 27, 2017
Two gut pathogens commonly found in malnourished children combine to worsen malnutrition and impair growth in laboratory mice, according to new research published in PLOS Pathogens.

Study sheds light on how body may detect early signs of cancer

July 26, 2017
Fresh insights into how cells detect damage to their DNA - a hallmark of cancer - could help explain how the body keeps disease in check.

How genetically engineered viruses develop into effective vaccines

July 26, 2017
Lentiviral vectors are virus particles that can be used as a vaccine to stimulate the immune system to fight against specific pathogens. The vectors are derived from HIV, rendered non-pathogenic, and then engineered to carry ...

Accounting for human immune diversity increases clinical relevance of fundamental immunological research

July 26, 2017
Mouse models have advanced our understanding of immune function and disease in many ways but they have failed to account for the natural diversity in human immune responses. As a result, insights gained in the lab may be ...

Does your child really have a food allergy?

July 24, 2017
(HealthDay)—Many people misunderstand what food allergies are, and even doctors can be confused about how to best diagnose them, suggests a new report from the American Academy of Pediatrics.

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.