By Alfie French
For decades, autoimmune diseases have posed a major challenge for biologists to understand and for patients to live with. How do you begin to treat a disease not caused by an invasion of foreign pathogens (harmful bacteria, viruses or fungi) or the presence of an identifiable tumour but instead a continuous attack from the body’s own line of defence?
Lupus is an autoimmune disease with unknown causes, most commonly found in women. Its symptoms include prolonged joint and muscle pain, chronic fatigue and skin rashes following sunlight exposure.
A pioneering study by the Scripps Research Institute published in Nature Chemical Biology titled ‘Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity’ has advanced our understanding of treating Lupus and introduced a new experimental technique which is poised to help develop treatments for other autoimmune diseases.
Previous studies have identified the protein SLC15A4 as having an increased abundance in the APCs (Antigen-presenting cells, a component of the immune system) of patients with Lupus and Crohn’s disease as well as discovering that mutated forms of this protein are associated with a decreased risk of these diseases. Due to the protein being embedded in a membrane that encloses vesicles within the cell, it has been extremely difficult for scientists to obtain information on its molecular shape or the mechanism by which it functions.
The Scripps Research Institute experiment introduced countless small protein fragment molecules to living cells and monitored for any interactions with SLC15A4 in cells obtained from Lupus patients. They found that the binding of molecules to SLC15A4 leads to a decrease in the number of cytokines produced by the cell.
Cytokines are small proteins which are released into the surrounding tissue and signal cells to create an inflammatory and immune response. In essence, a cell releases specific cytokines to ‘raise the alarm’ and trigger the immune system to go ‘attack mode’. By inhibiting the production of cytokines associated with the presence of SLC15A4, these small binding molecules can form the basis of a treatment to bring the overzealous immune system of lupus patients back towards a healthy level of activity. The researchers commented, “We didn’t know until now whether pharmaceutically blocking SLC15A4 could lessen some of the cellular signs of lupus, but in this paper, we showed that it does”.
Subsequent tests were done to confirm the binding of molecules to SLC15A4 caused the change in cytokine activity. The treatment did not affect cells which lacked the gene for SLC15A4. Further analysis revealed that one of the molecules (AJ2-30) not only disabled SLC15A4’s cytokine-promoting function but also caused the protein to be degraded by the cell, providing good evidence that the treatment may reduce the symptoms of Lupus disease for a longer period of time than initially thought.
Clinical trials will be required to know if this can lead to a safe and effective medication for Lupus patients. More exciting is the plethora of possibilities to use these new techniques to investigate ways to treat other diseases. Concerning their findings, the researchers asserted, “this not only helps move forward research on SLC15A4, but also validates our overall approach. This general strategy can be applied to lots of other challenging drug targets”.
The future looks increasingly bright for autoimmune disease treatment. Increased genetic screening will lead to the identification of genes linked to more autoimmune disorders. In 2022, Alphafold, an Artificial Intelligence program capable of determining a protein’s shape by analysing the gene which codes for it, was unveiled.
As this technology advances, we will increasingly be able to understand the molecular mechanisms of many disease- causing processes within cells and produce treatments to regulate these sub-microscopic systems. Time will tell if we are witnessing the dawn of a new age of autoimmune disease treatment.
Image: Glenn Francis via Wikimedia Commons