Impact of a Lupus-Associated PRKG1 Variant on Type I Interferons and Immune Dysregulation
This award is partially supported by AstraZeneca.
Systemic lupus erythematosus is a complex disease with variable symptoms and links to many permanent changes in our genetic makeup that are known as gene variants. Previous research by other lupus investigators has shown that the variation in the PRKG1 gene, which has functions in many biological processes, is associated with high levels of inflammatory substance produced by cells in the body that is called interferon alpha. Interferon alpha is thought to cause lupus development and progression.
Dr. Ruth Fernandez Ruiz will use LRA’s Postdoctoral Award to study differences in the amount of interferon alpha produced by immune cells such as plasmacytoid dendritic cells, which are the lead producer of inflammatory interferons, in patients with and without the PRKG1 genetic risk variant. Two additional immune T cell types called Th17 and regulatory T cells are of interest to Dr. Fernandez Ruiz as well due to their key role in controlling lupus-associated inflammation. By studying the plasmacytoid dendritic cells and two types of T cells from patients with and without the PRKG1 genetic risk variant, the research team will identify new biological pathways that can be targeted to reduce the inflammation in lupus patients related to high levels of interferon alpha.
What this study means for people with lupus:
This study led by Dr. Fernandez Ruiz will provide researchers with a better understanding of PRKG1 genetic variation and the related pathways that may yield new potential lupus drug targets for lupus patients with the PRKG1 risk variant.
Systemic Lupus Erythematosus (SLE) is characterized by systemic inflammation, loss of tolerance to self-antigens, and dysregulated type I interferon (IFN) responses. SLE remains one of the top 10 causes of death in young women. IFN-a contributes to both SLE susceptibility and severe manifestations, including renal disease. A study from our group compared patients with high versus low IFN-a and identified a single nucleotide polymorphism in the PRKG1 gene (rs7897633) as the top hit in European ancestry patients. However, the mechanisms by which PRKG1 polymorphisms impact the innate and adaptive immune systems remain unknown. PRKG1 codes for the cyclic GMP-dependent protein kinase I (PKGI). Activation of PKGI leads to the inhibition of RhoA and Rho-associated kinases (ROCK). Hence, variation in PRKG1 expression is expected to modify the activity of the RhoA-ROCK pathway.
This pathway regulates key cytoskeletal components associated with actin and microtubule polymerization, which are critical for plasmacytoid dendritic cells (pDC) clustering, cell adhesion, and IFN-a. Patients with SLE exhibit higher ROCK activity in circulating immune cells compared to healthy individuals. ROCK inhibitors decrease IFN-a production by pDC, promote the suppressive function of regulatory T cells, and downregulate the ability of Th17 cells to secrete IL-21 and IL-17 in humans and murine models of lupus. These cytokines play critical roles in immune dysregulation in SLE, promoting B cell maturation and the formation of autoreactive plasma cells. We seek to evaluate the functional effects of the PRKG1 rs7897633 variant and its role in innate and adaptive immune phenotypes in SLE, with the long-term goal of identifying new therapeutic targets and the development of patient stratification techniques to optimize the benefits of these agents. Our proposed aims are to: 1) Evaluate the impact of PRKG1 genotype on PRKG1 expression, RhoA/ROCK activity, cell adhesion and IFN-a production by pDC. We hypothesize that the PRKG1 risk allele will result in reduced PRKG1 expression and function, and increased RhoA/ROCK activity. This could influence cytoskeletal dynamics, leading to greater pDC adhesion and clustering, and increased type I IFN production. 2) Assess whether the PRKG1 genotype affects the frequency and functional activity of Th17 and Treg cells. We hypothesize that the PRKG1 risk allele is associated with enhanced Th17 subset differentiation and function, and lower Treg expansion and functional activity after exposure of naïve CD4+ T cells to specific polarizing conditions. Our expected outcomes and significance include to elucidate the relationships between PRKG1 genotype, type I IFN, and CD4+ T cell differentiation and function. These studies could identify new therapeutic targets and allow for individualized treatment targeting the RhoA/ROCK pathway.