Where did you earn your degrees and subsequent training?
I graduated from the Medical School at the Jordan University of Science and Technology. I did my residency in internal medicine at the University of Oklahoma Health Sciences Center in Oklahoma City, and then my rheumatology fellowship at the University of Michigan.
My research is generally focused on understanding the genetic and epigenetic basis of lupus and other autoimmune diseases to provide better understanding of disease etiology and pathogenesis, and use these data to identify and then test novel potential disease targets for therapy.
You can broadly divide my career so far into two parts, genetics and epigenetics. We significantly contributed to establishing a role for epigenetic dysregulation in the pathogenesis of lupus. We also provided important insights from studying epigenetic changes in multiple other autoimmune diseases, including Sjogren’s syndrome, Behçet’s disease, giant cell arteritis, and systemic sclerosis. We have identified a role for DNA methylation changes in determining clinical disease heterogeneity, disease progression and flares, and differences in disease susceptibility between ethnicities in lupus patients. Further, we identified evidence for genetic-epigenetic interaction in disease pathogenesis, and used epigenetic profiling studies followed by functional work to identify specific epigenetic regulators and epigenetic marks as novel targets for therapy and diagnosis, respectively.
Using a similar international collaborative effort with over 30 academic centers in North America, Turkey, and the UK we put together the largest effort to study the genetics of Takayasu arteritis, a very rare large vessel vasculitis. Our worked established a number of genetic risk loci for Takayasu arteritis, several are potentially targetable for therapy. Prior to our work in this diseases the only established and confirmed genetic association for Takayasu arteritis was in the HLA region and specifically with HLA-B*52, which we also confirmed and extended.
Who are your collaborators inside and outside of the University of Michigan?
I collaborate with many colleagues at UM, both within and outside of the Department of Internal Medicine. We also established an extensive national and international collaborative network built to study some of the less common immune-mediated disease such as Behcet’s disease and Takayasu arteritis. The work we do is very collaborative in nature, and requires the collection of samples from many centers to succeed. In addition, we are part of the Autoimmunity Center of Excellence collaborative network sponsored by NIAID.
What is the most interesting project you are currently working on and what do you hope its impact will be?
We have several very interesting projects ongoing currently in the lab. To give you an example, we recently evaluated DNA methylation changes that correlated with increased disease activity in lupus patients. Lupus is a relapsing remitting disease, and as DNA methylation changes are dynamic, we hypothesized that if we understood how DNA methylation patterns change in CD4+ T cells while in the naïve T cell stage, before activation and differentiation, then we can identify early epigenetic changes that predispose to disease flares. We reported an epigenetic landscape shift in naive CD4+ T cells with increased disease activity that favors non-Th1 T cell activation and opposes regulatory T cell differentiation. With bioinformatics analyses followed by microRNA studies in these same cells, we identified increased EZH2, a member of the transcriptional repressive complex PRC2, as a potential driver for this pro-inflammatory epigenetic shift. We subsequently showed that the expression of miR-26a and miR-101, which are sensitive to glucose availability and which target EZH2, negatively correlated with disease activity in lupus patients. Recent data from other groups suggest that glycolysis is increased in lupus T cells and that restoring normal glucose metabolism might be of therapeutic benefit. Our data indicate that EZH2 is upregulated and both miR-26a and miR-101 are downregulated in CD4+ T cells from lupus patients. We also demonstrate that inhibiting glycolysis in lupus CD4+ T cells restores expression levels of miR-26a and miR-101, allowing us to propose an epigenetic model of lupus flares, linking immunometabolism to pathogenic epigenetic consequences. Based on these data, we hypothesized that EZH2 upregulation induces pro-inflammatory epigenetic changes in lupus CD4+ T cells, and that inhibiting EZH2 or key EZH2-regulated genes will provide a novel therapeutic approach for lupus. Using genome-wide DNA methylation analysis with and without EZH2 overexpression, we identified a role for EZH2 in mediating CD4+ T cell adhesion via epigenetic de-repression of Junctional Adhesion Molecule-A (JAM-A). JAM-A was overexpressed in lupus CD4+ T cells, and was downregulated by EZH2 inhibitors. CD4+ T cell adhesion to endothelial cells was increased in lupus, and blocking JAM-A or inhibiting EZH2 abrogated this adhesion. Our data uncovered a novel role for EZH2 in T cell adhesion in lupus, mediated by epigenetic de-repression and upregulation of JAM-A. EZH2 inhibitors are currently in clinical trials in cancer. In the context of our findings, the pharmacologic repurposing of EZH2 inhibitors for lupus may represent a novel therapeutic approach. We actually are seeing dramatic therapeutic effect for EZH2 inhibitors in our animal model studies. We are not in the process of exploring initiating a clinical trial in lupus patients based on this findings.
What do you hope to have achieved by the time you reach retirement? In other words, what would you consider to be “your life’s work”?
Retirement is not something I would consider as long as I am able to work. The diseases we study are challenging and patients will continue to suffer until the underlying cause of autoimmunity is revealed. What I hope to achieve is to get us at least a step closer to solving the mystery of autoimmunity. What I will consider to be my “life’s work” is to successfully mentor and help develop who will be future leaders and productive researchers in autoimmunity. This will be most rewarding to me, as it will have a lasting impact beyond anyone’s own scientific contribution.
What else would you like the readers to know about you or your work?
I would like readers to know that without the support of our patients by providing samples and enrolling in our studies, we will not be able to move the field forward. We are therefore most grateful to our patients and healthy control volunteers who participate in our studies.