Autoimmune diseases are extremely challenging to treat and are among the leading causes of death and disability in the United States. These high-burden chronic diseases affect more than 50 million Americans—7.5% of the population. “A striking feature is their far greater prevalence in women,” Johann E. Gudjonsson, MD, PhD points out. Women represent 80% of patients with autoimmune diseases, which are the second highest cause of chronic illness in women.
Until Dr. Gudjonsson’s recent discoveries, the underlying cause of this sex bias had remained a mystery. Detection efforts had focused on the logical suspects for sex-biased diseases—hiding somewhere on the sex chromosomes, involving the influence of sex hormones or both.
Dr. Gudjonsson recently found the culprit—a previously unknown inflammatory pathway, with neither an X or Y chromosome nor sex hormone connections, that promotes female-biased autoimmunity. Genes in this network are associated with multiple autoimmune diseases, including lupus, scleroderma, and Sjögren’s syndrome. “It suggests new avenues for therapeutic development,” Dr. Gudjonsson says. And his mid-career Sun Pharma Research Award is enabling him to progress toward this goal.
Genes in this network are associated with multiple autoimmune diseases, including lupus, scleroderma, and Sjögren’s syndrome.
Dr. Gudjonsson has made significant contributions to the molecular understanding of psoriasis, among other diseases, but he was not focused on psoriasis or on autoimmune disease in women when he made novel discovery. He was simply doing something he has always loved—following a novel question that has sparked his curiosity to see where it would take him. Dr. Gudjonsson explains that this curiosity has always been an important part of his life.
Early on, it fueled his desire to become a physician-investigator when he was a medical student in Iceland. Then it led him to dermatology because of the skin’s visual accessibility and ease of sampling. He became fascinated by the immunology and genetics of psoriasis, which became his primary research focus and soon took him to the University of Michigan for its outstanding psoriasis-related training and research capabilities.
Several years ago, Dr. Gudjonsson found himself with data from “a lot of biopsies from healthy skin that we had collected during a psoriasis project,” he recalls. “We decided to use this data pool to ask a very simple question—what are the genetic differences between male and female skin?”
After identifying these sex-biased genes, “we were surprised to discover that most of them lie outside the X and Y chromosomes, and that women’s skin is more immunologically active.” These immune-related genes were not random but feed into an immune network that has been implicated in autoimmune diseases.
First, Dr. Gudjonsson and his team determined that expression of these genes is unrelated to the effect of sex hormones. “Then we found the regulator of this gender-biased immune activity, a transcription cofactor called Vestigial-like-3 (VGLL3) that is also more highly expressed in the cells and tissues of women, and may have a role in fine-tuning their immune responses.”
“We decided to use this data pool to ask a very simple question—what are the genetic differences between male and female skin?”
The profound implications of what Dr. Gudjonsson and his group had discovered were not apparent until they over-expressed this immune regulator in mouse skin. “We were very excited when the mice developed an inflammatory skin phenotype with striking similarities to cutaneous lupus,” he notes.
And even more—they developed all the autoantibodies associated with systemic lupus (SLE), and with deposition of immune complexes in skin and kidneys. This novel mouse model links together the female factor VGLL3 with autoantibody production,” he continues. “And we discovered that TNFSF4 and IL-70-cytokines that are critical to the development and behavior of both T-cells and B-cells—were both prominently expressed. It could certainly link overactivity of this female-biased immune network with autoimmune disease.”
Dr. Gudjonsson’s research strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity
Dr. Gudjonsson’s research strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity, and points to TNFSF4 and IL-7 as potential therapeutic targets.
Now his mid-career Sun Pharma Research Award is allowing him to take his preliminary data indicating a fundamental mechanism in autoimmunity, and pursue this in depth in his SLE mouse model and in human SLE subjects. “I’m extremely grateful for this award,” Dr. Gudjonsson says. “This research will provide critical insights into autoantibody formation in SLE.” He anticipates that these insights will potentially apply to other autoantibody-mediated autoimmune diseases as well, and ultimately identify a game-changing therapeutic target.
The Dermatology Foundation thanks Sun Pharma for their generous gift of $1 million to fund three midcareer awards for outstanding investigators driving progress in treating challenging inflammatory skin diseases.
Dr. Gudjonsson is Arthur C. Curtis Professor of Skin Molecular Immunology, and Professor of Dermatology, University of Michigan. He has received previous research support from the Dermatology Foundation: 2005 Research Fellowship (Novel Xeno- transplantation Model for Psoriasis); 2008 Research Grant (Biological Effects of Genetic Variation in the IL-12B and IL-23R Genes in Psoriasis); and 2010-12 Physician Scientist CDA (The Influence of the Cytokine Network in Psoriasis on Clinical Phenotype and Treatment Response).