New Drug Target For Lupus Revealed by Researchers
A new study led by a research team from TSRI (The Scripps Research Institute), in the United States, managed to identify the key events that are involved in lupus. The findings of the study suggest that if this specific pathway is blocked, a potential new therapy for the autoimmune diseases could be developed. The study was published a couple of days ago in the online journal Proceedings of the National Academy of Sciences.
According to the scientists, the absence of a certain molecule with signalling properties found inside immune cells, can be linked to a slower developing process of autoimmunity in laboratory mice suffering from lupus. Researchers report that these mice suffered less damage to their immune systems, compared to normal laboratory mice. Argyrios Theofilopoulos, the senior author of the study, says that their research could lead to the development of an inhibitory drug capable of treating not only lupus, but other autoimmune diseases as well.
There are various therapies available for the condition known as SLE (systemic lupus erythematosus), however none of them are able to target the causes of the disease. Precedent studies suggest that environmental and genetic factors are responsible for the complex autoimmune reaction that triggers the onset of SLE. One of the main immune interaction is that of the autoantibodies. These are antibodies turned against the “self” nucleic acids and proteins. SLE is one of the numerous conditions that mimic the symptoms of other diseases. Its symptoms vary from one patient to another and can appear and disappear unpredictably. The most common symptoms accused by SLE patients include rash, fever, joint pains, fatigue and myalgias. If left untreated, the complications that arise with the onset and progression of lupus are fatal.
One of the most commonly used therapies for SLE patients are immunosupressives. However, these drugs can raise the risks for other diseases, such as infectious diseases and cancer. Theofilopoulos and his research team have been the vanguard of SLE research for many years. Recently, they discovered a more powerful class of immunostimulatory compounds, known as type 1 interferons. These compounds are closely related to lupus and its autoimmunity cycle.
The autoimmunity cycle in lupus begins when immune cells are unable to recognize different nucleic acids and proteins as “self” molecules and consider them to be “non-self”. Subsequently, the immune cells start releasing type 1 interferons. This upregulates the antibody response with the formation of autoantibodies, which are responsible for presenting the so-considered “non-self” molecules to the cells that produce type 1 interferon. Investigations performed in an enclosed laboratory environment, on a Petri dish suggests that the cells responsible for producing type 1 interferons are pDCs (plasmacytoid dendritic cells). In the current study, Theofilopoulos and his team further investigated the role of these cells in laboratory mice that suffered from SLE.
The leader of the experiments, and first author of the study was associate professor Roberto Baccala. Bacalla and Theofilopoulos have been working on research regarding lupus for the past 20 years. In collaboration with Keiko Ozato, one of the experts on immune cell genetics, the research team was able to investigate if a pDC deficit can stop lupus from developing. Professor Ozator created a strain of laboratory mice with no pDCs, due to the lack of the gene responsible for their development. “When we watched the animals for the usual development of lupus, we found that autoantibodies were practically non-existent, and all the other lupus-like manifestations were drastically reduced”, reported Baccala.
The next objective of the research team was to find out exactly how pDCs influence the onset and development of SLE. For this step, with the help of collaborator Bruce Beutler, the team created another strain of laboratory mice that were lacking the gene SLC15A4. This gene is responsible only for the ability of pDCs to produce type 1 interferon, whilst growing normally in all other aspects. The next step of their study was to detect whether the specially designed strain of mice would still develop SLE. Researchers report that normally, in lupus patients, two toll-like receptors (TLRs) – TLR7 and TLR9, are responsible for mistaking nucleic acids and proteins as “non-self”, instead of “self”. However, the absence of the SLC15A4 gene, caused the laboratory mice to be unresponsive to stimuli that would normally cause an autoimmune response. “The usual lupus-like signs significantly decreased, and survival was extended”, reported Baccala.
Theofilopoulos and Baccala are confident that SLC15A4 is a potential target for a new SLE therapy. A drug that would target SLC15A4 could potentially suppress only the immune cells directly responsible for SLE, without affecting the rest of the immune system. The research team is currently trying to develop a new pharmacological compound capable of inhibiting the production of type 1 interferon. This inhibition would be possible if the expression of the SLC15A4 gene could be blocked.