This project, led by Dr. Yun Liang, aimed to understand how factors like diet and biological differences between men and women influence autoimmune diseases. Autoimmune diseases like lupus are much more common in women, while men are more often affected by infections and cancer. These sex differences in immune response are not well understood, partly because women have historically been underrepresented in medical research. One promising area of research focuses on a molecule called VGLL3, which is found at higher levels in women and is linked to autoimmunity.
The project made significant strides in understanding how VGLL3 contributes to lupus inflammation. High levels of VGLL3 were found to increase the activity of specific lupus-related genes, and high levels of another molecule, called IL17C, suggest a link between VGLL3 and IL17C in driving inflammation in lupus. The study revealed a complex interplay between VGLL3 and immune regulation pathways, especially under conditions of stress. Overall, these findings offer valuable insights into potential therapeutic approaches for lupus.
The Challenge
Immune-related diseases like autoimmune disorders, infections and cancer are significant health issues in Wisconsin and beyond. Autoimmune diseases like lupus are much more common in women, while men are more often affected by infections and cancer. These sex differences in immune response are not well understood, partly because women have historically been underrepresented in medical research. This gap in understanding has created a need for new approaches to treat immune-related diseases.
One promising area of research focuses on a molecule called VGLL3, which is found at higher levels in women and is linked to autoimmunity. While VGLL3 does not cause disease in healthy women, it may play a role in autoimmunity when combined with other health factors like poor nutrition.
Project Goals
This project’s goal was to understand how factors like diet and biological differences between men and women influence autoimmune diseases, with a focus on the molecule VGLL3. This goal was addressed through two specific aims:
Define VGLL3’s role in autoimmune responses during nutritional stress.
Evaluate VGLL3 inhibition as a potential treatment.
Results
This project made significant progress toward its goal. First, researchers explored how VGLL3 contributes to inflammation in lupus using cell-based models. They investigated whether increased VGLL3 levels affect the behavior of immune cells and the expression of genes associated with lupus. While they did not observe changes in immune cell movement toward cells with high VGLL3 levels, they did find that certain lupus-related genes were more active in the presence of elevated VGLL3. Additionally, they found that a molecule called IL17C, which is influenced by VGLL3, is present in higher levels in the skin cells of lupus patients. This suggests a potential link between VGLL3 and IL17C in lupus-related inflammation. Finally, by blocking IL17C, they were able to reduce the activity of genes influenced by VGLL3, highlighting the importance of IL17C in VGLL3-mediated inflammation.
Next, the team sought to understand how VGLL3 and its interaction with IL17C contribute to the immune dysfunction in lupus, particularly under conditions of stress. They identified hundreds of genes regulated by VGLL3, with some pathways overlapping between normal and stressed conditions. These pathways included those involved in cell signaling and response to DNA damage. They also found unique pathways influenced by VGLL3 depending on the nutrient status, indicating a complex interplay between the molecule and various signaling pathways involved in immune regulation.
Finally, mouse models were utilized to explore whether inhibiting VGLL3 could be a potential treatment strategy for lupus. They observed that high expression of VGLL3 led to increased expression of IL17C, mirroring their findings from the cell-based models. Nutrient deficiency increased VGLL3 levels in mouse skin, suggesting VGLL3 plays a role in responding to stress in living organisms. Overall, these findings highlight VGLL3’s involvement in immune regulation and stress response pathways, providing insights for future therapeutic interventions that target VGLL3 and its related pathways.
