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

Africa's uneven health care becomes easy prey for Ebola

4 hours ago

Threatened by the possible spread of an Ebola epidemic which respects no borders, Africa is divided between a handful of countries equipped to withstand an outbreak and many more which would be devastated, experts say.

Ebola case stokes concerns for Liberians in Texas

5 hours ago

The first case of Ebola diagnosed in the U.S. has been confirmed in a man who recently traveled from Liberia to Dallas, sending chills through the area's West African community whose leaders urged caution ...

Is Australia prepared for Ebola?

8 hours ago

Australia needs to be proactive about potential disease outbreaks like Ebola and establish a national centre for disease control.

Dallas hospital confirms first Ebola case in US

14 hours ago

A patient at a Dallas hospital has tested positive for Ebola, the first case of the disease to be diagnosed in the United States, federal health officials announced Tuesday.

User comments