Endolysosomal TLRs and Lupus

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Lupus erythmatosusLupus erythematosus is a chronic autoimmune disease that, worldwide, is more common than leukaemia, multiple sclerosis, and muscular dystrophy. There are three recognised forms of lupus: discoid (cutaneous) lupus which affects the skin, systemic lupus (SLE) which attacks multiple organ systems, and drug-induced lupus which generally resolves once the drug is discontinued. The symptoms of lupus, which can flare and subside, vary from patient to patient but include severe fatigue, joint pain, muscle aches, anaemia, and general malaise. Approximately 10% of discoid lupus cases develop into systemic lupus which can result in the destruction of vital organs.

The causes of lupus are poorly understood, but researchers at the Scripps institute have now shown that specific Toll-like receptors (TLRs) play a key role in the development of this disease. One of the principal diagnostic indicators of lupus is a high level of self-recognising antinuclear antibodies. Antinuclear antibodies normally form part of the immune response and are produced when bacteria or viruses are degraded in the endolysosome. TLRs inside this compartment specifically detect viral RNA and viral and bacterial DNA and stimulate immune cells to produce antibodies against these molecules.

Writing in the Proceedings of the National Academy of Sciences, the Scripps team have shown that three TLRs in the endolysosome are necessary for the generation of antinuclear antibodies in mice. Previous studies had pointed to endolysosomal TLRs – TLR3, TLR7, TLR8 (in humans but not mice) and TLR9 – as important for the production of antinuclear antibodies but, in mouse models of lupus, knocking out only TLR 7 or TLR9 had not dramatically reduced symptoms. The Scripps team wanted to eliminate all three TLRs in mice and achieved this by knocking out a transmembrane endoplasmic reticulum protein, UNC-93B, which is necessary for correct functioning of the endolysosomal TLRs. Knocking out UNC-93B in strains of laboratory mice that spontaneously develop many of the same symptoms as human lupus sufferers produced animals with fewer antinuclear antibodies and fewer and less severe symptoms of lupus. Even lipid A stimulation of TLR4 – which is known to promote production of autoantibodies – did not produce symptoms of lupus in the knockout animals. Nucleic acid-sensing TLRs may thus provide a critical pathway in the development of systemic autoimmunity by reducing tolerance to nucleic acid-containing antigens.


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