Unexpected role(s) for IRF5 risk variants in SLE pathogenesis
Scientists know that for many people some of the risk for lupus is genetic—that is, inherited through their family line. The gene for interferon regulatory factor 5 (IRF5), a key player in the immune system, has been strongly linked to a higher risk for lupus. This means that some versions of the IRF5 gene are more likely to be found in people with lupus, although carrying the high-risk gene does not guarantee that a person will develop lupus. Dr. Barnes wants to understand how these different, high-risk versions of IRF5 help turn a healthy immune system into one that drives an autoimmune attack that leads to lupus. With her Novel Research Grant, she will compare IRF5 in people who carry high-risk versions of the IRF5 gene but do not have lupus with IRF5 in healthy people with low-risk versions of the gene. This study explores a very early stage in lupus development and may reveal why the immune system is triggered to begin an autoimmune attack.
What this study means for people with lupus
Dr. Barnes’ research focuses on people who are at high risk of developing lupus because of their genes, yet who have healthy immune systems and no signs of autoimmunity. If she finds differences in IRF5 that help steer the immune system down a path toward lupus, her study may reveal new targets for the treatment or, even, the prevention of lupus.
The common feature that defines autoimmune diseases, such as systemic lupus erythematosus (SLE), is the breakdown of immune tolerance and the subsequent malfunction of the immune system, resulting in inflammation and tissue destruction. SLE, in particular, is complex and variable with loss of self-tolerance, persistent autoantibody production, enhanced type I interferon expression, complement activation, inflammation and tissue damage. While the primary causes of SLE are still obscure, the disorder is highly heritable and replicated genetic linkages at several sites have been reported. Genetic variants within or near the transcription factor interferon regulatory factor 5 (IRF5) have been robustly associated with SLE in every major ancestral group tested. Four IRF5 risk variants – the CGGGG insertion/deletion, rs2004640, rs10954213, and rs10488631 – strongly associate with SLE and make up the IRF5 risk haplotype. IRF5 is a central mediator of both innate and adaptive immunity, in part, through its regulation of pro-inflammatory cytokine expression. Current dogma suggests that IRF5 risk variants contribute to SLE disease pathogenesis by increasing IRF5 expression, resulting in elevated pro-inflammatory cytokine production. This is primarily based on associative studies in genotyped SLE patients. We instead have begun to examine IRF5 genotype-phenotype effects in healthy donors that carry the homozygous risk or non-risk haplotype. In these studies, we have not detected a significant difference in IRF5 expression between leukocyte subsets from healthy risk and non-risk donors. Instead, we found that healthy risk donors (as compared to non-risk) have significantly elevated levels of constitutive IRF5 activation in pDC and already show characteristics of SLE, including significantly elevated circulating plasmablasts, spontaneous NETosis, pDC activation, and positive anti-nuclear antibody (ANA) staining. Based on these preliminary findings, we hypothesize that genetic risk conferred by IRF5 variants is not at the level of IRF5 expression but instead at the generation of SLE antigenic triggers and IRF5 activation. The following Specific Aims have been designed to address this hypothesis: 1) Determine the contribution of an IRF5 risk haplotype to IRF5 expression, activation and blood cell phenotype in healthy donors, 2) Identify the cellular trigger that initiates IRF5 genetic risk, and 3) Determine whether IRF5 inhibition reverses phenotypic changes associated with IRF5 genetic risk and SLE. Given the association of IRF5 variants with SLE risk and the common distribution of IRF5 risk and non-risk variants across the population, determining how IRF5 genetic variants and dysregulated IRF5 function contribute to disease onset and severity will aid in developing new therapeutic strategies targeting IRF5 for the prevention and treatment of SLE.