Anti-dsDNA, surface-expressed TLR4 and endosomal TLR9 cooperate to exacerbate lupus

June 12, 2014, Society for Experimental Biology and Medicine

Systemic lupus erythematosus (SLE) is a complicated multifactorial autoimmune disease influenced by many genetic and environmental factors. The hallmark of systemic lupus erythematosus (SLE) is the presence of high levels of anti-double-stranded DNA autoantibody (anti-dsDNA) in sera. In addition, greater infection rates are found in SLE patients and higher morbidity and mortality usually come from bacterial infections. Deciphering interactions between the susceptibility genes and the environmental factors for lupus complex traits is challenging and has resulted in only limited success.

In the June issue of Experimental Biology and Medicine Lee et al, from National Yang-Ming University in Taiwan, studied the role of anti-double stranded DNA (anti-dsDNA) and the Toll-like receptors (TLRs), TLR4 and TLR9, in the pathogenesis of lupus. They prepared transgenic mice carrying the anti-dsDNA transgene and challenged these mice with TLR4 and TLR9 agonists. They demonstrate that in the anti-dsDNA transgenic mice TLR4 and TLR9 are cooperatively linked to Lupus progression.

''Since simultaneous activation of extracellular and intracellular pattern-recognition receptors (PRR) is able to trigger more intense host immune responses, it is really crucial to determine whether co-engagement of extracellular and intracellular PRRs may increase disease severity in lupus,'' said Dr. Kuang-Hui Sun, corresponding author. However, only individual conditional knockout models were used in previous studies to study the roles of TLR4 or TLR9. In addition, intracellular nucleic acid-sensing TLR9 plays either stimulatory or protective roles in different murine lupus models. Therefore, Sun and colleagues injected the ligands of TLR4 and TLR9 into the anti-dsDNA transgenic mice as a new model to investigate whether anti-dsDNA and co-activation of extracellular TLR4 and endosomal TLR9 impacts the pathogenesis of in normal background mice. Their data suggest that, in addition to anti-dsDNA, signaling pathways triggered by simultaneous activation of surface-expressed TLR4 and endosomal TLR9 can promote the progression of SLE. These results suggest that simultaneous targeting of anti-dsDNA, TLR4 and 9 may be a potential therapy for SLE.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said "These studies in offer new concepts for affecting immune tolerance and reducing SLE disease progression as future therapeutics are developed."

Explore further: Kidney involvement, high anti-dsDNA predict lupus flares

Related Stories

Kidney involvement, high anti-dsDNA predict lupus flares

July 2, 2013
(HealthDay)—Kidney involvement and high anti-double stranded (ds) DNA are independent predictors of moderate-severe lupus flare, according to research published online June 10 in Arthritis & Rheumatism.

Genetic mutation causes lupus in mice

January 3, 2014
Yale researchers have identified a genetic mutation that leads to lupus in mice. The discovery could open the way for development of therapies that target the mutation. The study appears in Cell Reports.

Unique individual demonstrates desired immune response to HIV virus

March 10, 2014
One person's unique ability to fight HIV has provided key insights into an immune response that researchers now hope to trigger with a vaccine, according to findings reported by a team that includes Duke Medicine scientists.

A nanogel-based treatment for lupus

March 1, 2013
Systemic lupus erythematosus (SLE) is disease in which the immune system mistakenly attacks healthy tissues, resulting in inflammation and tissue damage. Current treatments are focused on suppression of the immune system, ...

Predictors of organ damage identified in patients with SLE

December 16, 2012
(HealthDay)—Patient age, hypertension, and corticosteroid use are the most important predictors of the cumulative organ damage that occurs in patients with systemic lupus erythematosus (SLE), according to research published ...

Commonly used drugs may not be effective against autoimmune illness

March 17, 2014
(Medical Xpress)—Drugs for autoimmune diseases like lupus that block only one of the two principal signaling pathways can activate an overabundance of one potentially disease-causing type of immune cell population over ...

Recommended for you

Creation of synthetic horsepox virus could lead to more effective smallpox vaccine

January 19, 2018
UAlberta researchers created a new synthetic virus that could lead to the development of a more effective vaccine against smallpox. The discovery demonstrates how techniques based on the use of synthetic DNA can be used to ...

Study ends debate over role of steroids in treating septic shock

January 19, 2018
The results from the largest ever study of septic shock could improve treatment for critically ill patients and save health systems worldwide hundreds of millions of dollars each year.

New approach could help curtail hospitalizations due to influenza infection

January 18, 2018
More than 700,000 Americans were hospitalized due to illnesses associated with the seasonal flu during the 2014-15 flu season, according to federal estimates. A radical new approach to vaccine development at UCLA may help ...

Zika virus damages placenta, which may explain malformed babies

January 18, 2018
Though the Zika virus is widely known for a recent outbreak that caused children to be born with microencephaly, or having a small head, and other malformations, scientists have struggled to explain how the virus affects ...

Certain flu virus mutations may compensate for fitness costs of other mutations

January 18, 2018
Seasonal flu viruses continually undergo mutations that help them evade the human immune system, but some of these mutations can reduce a virus's potency. According to new research published in PLOS Pathogens, certain mutations ...

Study reveals how MRSA infection compromises lymphatic function

January 17, 2018
Infections of the skin or other soft tissues with the hard-to-treat MRSA (methicillin-resistant Staphylococcus aureus) bacteria appear to permanently compromise the lymphatic system, which is crucial to immune system function. ...

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.