Toll-like Receptors in Autoimmune Disease
Past Arthritis Foundation grant recipient Ann Marshak-Rothstein, PhD, of Boston University made a seminal observation connecting innate and adaptive immunity. She discovered that DNA – now also seen for RNA – is able to incite an innate immune reaction. DNA and RNA are capable of stimulating immune system cells, both as antigens in and of themselves and as stimulators of Toll-like receptors. Marshak-Rothstein recently wrote a review article for Nature Reviews Immunology explaining how Toll-like receptors may be involved in systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and Sjögren’s syndrome.
According to Marshak-Rothstein, certain autoantigens can be autoadjuvants: that is, they have the capacity to activate the innate immune system directly and therefore promote self-directed immune responses.
Toll-like receptors 7 (TLR7) and 9 (TLR9), found within the cells of the innate immune system, recognize and bind to nucleic acid sequences from bacteria and viruses. Nucleic acid sequences are what combine to build DNA and RNA. When the TLRs form complexes with the nucleic acid sequences, an immune reaction is launched. Marshak-Rothstein put forth data to show that the body’s own DNA and RNA from dead or dying cells may be recognized by TLR7 and TLR9, initiating an autoimmune response.
Data accumulated through Marshak-Rothstein’s lab and others have supported the idea that TLR7 and TLR9 are involved in autoimmunity. To examine the hypothesis further, mice specially bred to develop a lupus-like disease but that are deficient in TLR7 or TLR9 were tested. It was found that these mice have altered autoantibody production and disease expression compared with the mice that have functioning TLRs.
“Instead of viewing autoimmunity as an overzealous response to host antigens by the adaptive immune system, we must also consider the possibility that, at least in some cases, autoimmunity results from an overzealous response to exogenous or endogenous ligands by the innate immune system,” states Marshak-Rothstein.