Award: Arthritis and Related Autoimmune Disease Research Grant
Biography: Dr. Nikhil Jiwrajka is an Instructor of Medicine in the Division of Rheumatology at the University of Pennsylvania. He obtained his medical school degree from the Johns Hopkins University School of Medicine and then completed his internal medicine residency and rheumatology fellowship training at the University of Pennsylvania, where he also received a master’s degree in translational research. Dr. Jiwrajka’s clinical practice focuses on the care of patients with systemic sclerosis and autoimmune interstitial lung disease. His current research program centers on systemic sclerosis, specifically the immunologic and epigenetic mechanisms underlying its female sex bias and how these mechanisms contribute to autoimmunity and fibrosis. As a physician-scientist in the laboratory of Dr. Montserrat Anguera, Dr. Jiwrajka has focused on the contributions of X-chromosome-linked epigenetic factors to the female sex bias of systemic sclerosis, leveraging both patient samples and animal models. More specifically, he studies X-Chromosome Inactivation (XCI), an epigenetic mechanism that operates exclusively in individuals with more than one X chromosome in order to balance X-linked gene dosage with that of XY individuals. XCI is both initiated and maintained by the long noncoding RNA XIST, which coats the inactive X chromosome and recruits additional repressive epigenetic modifications to reinforce transcriptional silencing. Given the number of X-linked genes with roles in immune function, his work explores the hypothesis that impaired maintenance of XCI in immune cells results in the de-repression of X-linked proinflammatory and profibrotic genes, thus driving inflammation and fibrosis in a female-biased fashion.
Research Summary: Systemic sclerosis (scleroderma) is a severe autoimmune disease that affects many more women than men. We do not know why women are more likely to have scleroderma, but new research suggests that the X chromosome may play an important role. Because women (XX) have two X chromosomes and men (XY) have one, one of the two X chromosomes in each female cell is randomly turned off in a process called X-Chromosome Inactivation (XCI). XCI balances the X-linked genetic information between the sexes. Maintaining this balance is important, because too much information from the X chromosome can cause the immune system to become overactive. We previously found that in women with lupus, another autoimmune disease that is more common in women, XCI doesn’t work properly in important immune cells called B cells. This defect leads to too much activity from the X chromosome, which can cause the immune system to become overactive and contribute to features of the disease. We think that women with scleroderma might have a similar XCI defect in their B cells, but no one has studied this before. In this study, I hypothesize that B cells from women with scleroderma also have defective XCI, and that this defect contributes to the inflammation and scar tissue seen in this disease through an overdose of information from the X chromosome. I will first use a special mouse model with faulty XCI in its B cells to see how this defect affects the development of inflammation and scarring seen in scleroderma. Next, I will study B cells from patients with scleroderma to look for signs of faulty XCI. By exploring the basis of scleroderma’s female bias, this work could reveal new disease mechanisms and thus lead to new treatments for this disabling disease.
