Systemic lupus erythematosus (SLE) is a disease that affects an estimated 5 million people worldwide, and the disease usually presents between the ages of 15 and 44. Roughly 90% of the cases are in adult women although adult men and younger individuals of both sexes can develop SLE. Symptoms can include pain, extreme fatigue, hair loss, cognitive issues, and physical impairments. Many patients experience cardiovascular disease, strokes, disfiguring rashes, and painful joints although for some there may be no visible symptoms. No cure exists and the progression of the disease is variable from person to person, but medications can control the illness in most patients allowing them to live a normal lifespan. Unfortunately, most of the medications are immunosuppressants that can increase the risk of infection or have adverse effects on growth and development in younger patients.
SLE is classified as an autoimmune disease. Normally our immune system is trained to recognize and ignore our own cells and molecules, so-call self-antigens. An autoimmune disease occurs when the body’s immune defense system becomes confused and begins to attack the self-antigens rather than foreign invaders such as bacteria and viruses. If this self-attack persists then damage to bodily organs can occur and disease symptoms will manifest. Both genetics and environmental factors are implicated in the initiation of SLE although the specific underlying cause is usually unknown. More than 50 genes have been associated with SLE, and this complexity implies that there is no one pathway to SLE. Instead, multiple distinct combinations of genes may predispose different individuals to SLE. Additionally, even in identical twins, when one develops SLE there is only a 30% chance that the other twin will develop SLE. This low genetic concordance supports the need for some environmental trigger to initiate the disease process, possibly a chemical exposure or a viral infection.
A new publication in the journal Nature gives another clue about one pathway for the development of lupus. A 7-year-old Spanish girl with lupus was found to have a mutation in a gene called TLR7. Previous studies had shown a linkage between TLR7 and lupus, but no mutations in the gene were known for SLE patients. The TLR7 gene encodes a protein known as Toll-like receptor 7 (TLR7). TLR7 is part of our innate immune system and functions to detect single-stranded RNA (ssRNA), a signature molecule for invading RNA viruses. Once ssRNA is detected by TLR7 it activates the immune response to attack the pathogen. The 7-year-old patient had a single nucleotide base pair of her DNA which altered one amino acid in her TLR7 protein: amino acid number 264 changed from tyrosine to histidine. This small mutation caused her TLR7 protein to now respond to the compound guanosine which is commonly present in our cells. Changing the activation signal for TLR7 resulted in continual activation of the immune system, including B cells producing self-reacting antibodies. Normally this type of B cell is eliminated quickly to prevent self-damage, but the mutant TLR7 proteins promoted the survival of these harmful B cells. When this TLR7 mutation was introduced into mice it caused lupus, confirming the direct importance of TLR7 as a promoter of SLE. This study implies that anything that changes or enhances the activity of TLR7 potentially may increase the risk of SLE. In humans, TLR7 is located on the X chromosome giving women two active copies compared to men who only have one copy of this gene. This double gene dose of TLR7 likely contributes to the greater risk of SLE in women than men. This solid confirmation of TLR7’s importance in at least some SLE cases suggests that TLR7 and other associated proteins are candidates for therapeutic intervention. While TLR7 effects are unlikely to be the sole pathway for SLE development, many patients could likely benefit from TLR7-directed therapies. Blocking the signaling from TRL7 to B cells could prevent the accumulation of the harmful B cells and their self-reacting antibodies. Hopefully, specific protein-targeted compounds could provide clinical benefits with fewer side effects than the general immunosuppressive drugs.
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