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

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."

add to favorites email to friend print save as pdf

Related Stories

Genetic mutation causes lupus in mice

Jan 03, 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.

A nanogel-based treatment for lupus

Mar 01, 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, ...

Recommended for you

Ebola-hit Liberia delays school reopening

2 hours ago

Liberia's education ministry said on Sunday it had postponed by two weeks the reopening of the country's schools, which were closed six months ago to limit the spread of the Ebola virus.

Ebola: timeline of a ruthless killer

11 hours ago

Here are key dates in the current Ebola epidemic, the worst ever outbreak of the haemorrhagic fever which first surfaced in 1976 in the Democratic Republic of Congo (DRC).

Ebola reveals shortcomings of African solidarity

Jan 31, 2015

As Africa's leaders meet in Ethiopia to discuss the Ebola crisis, expectations of firm action will be tempered by criticism over the continent's poor record in the early stages of the epidemic.

Second bird flu case confirmed in Canada

Jan 30, 2015

The husband of a Canadian who was diagnosed earlier this week with bird flu after returning from a trip to China has also tested positive for the virus, health officials said Friday.

User 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.