Although all the endosomal TLRs are trafficked by UNC93B1, notable differences exist, he said. TLR 7 seems to be more pathogenic than the others, possibly due to increased signaling, and evidence shows that TLR 8 and 9 may be protective.
“How do we avoid recognition of self-nucleic acids? Is it really complete avoidance of recognition by a normal individual, or perhaps there is some recognition of a low grade that may be important for the priming of the immune system. We do not know,” he said. “But the absence of disease-promoting recognition is thought to be due to the intracellular sequestration of these nucleic acid sensors, effects of nucleases, and other processes.”
“In autoimmunity, there may be an oversupply of self-nucleic acids due to increased apoptosis, necrosis or NETosis. There may be defective clearance, such as defects in scavenger receptors that remove apoptotic or necrotic materials, as well. If these processes don’t work properly, autoimmunity could be the result,” he said.
“So there are processes whereby we may avoid recognition, and there are circumstances where these barriers are broken, and then autoimmune disease might be the consequence,” he said. Cytosolic sensors may play a role too, because specific mutations of RIG-I or MDA-5 (IFIH1), and defects in nucleases like TREX-1 and RNASEH2, and certain signaling molecules (STING) promote development of syndromes called interferonopathies.
“These diseases are very peculiar. They’re not necessarily lupus, although occasionally, but very rarely, classical lupus patients may have mutations in the genes that induce these interferonopathies,” he said. “Only about 500 families in the world have been identified that have the TREX1 mutation for Aicardi Goutieres syndrome or chilblain lupus.
“Thus, lupus and autoinflammatory syndromes have stimulated efforts to develop targeted therapies, and clinical trials have been initiated, including IFNAR antibody (anifrolumab), IFN-Kinoid, anti-TLR7, bortezomib and JAK-kinase inhibitors. Inhibitors of SLC15A4 may also be considered.”
Research in these areas is ongoing at his laboratory, he added.
Susan Bernstein is a freelance journalist based in Atlanta.
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