Associate Clinical Professor of Pediatrics
Division of Rheumatology and Rehabilitation,
Children’s Hospital of Los Angeles and USC School of Medicine
Dr. Brown was an M.D., Ph.D. recipient who did her thesis work in the laboratory of the Nobel Laureate J. Michael Bishop and as a BIRCWH Scholar studied the relationship between the glucocorticoid receptor and autoimmunity with her mentor, Lou Muglia in Pediatrics. She published a paper describing her work in 2007 in the journal Blood, and joined the faculty as an Assistant Professor of Pediatrics at Children’s Hospital in Los Angeles, CA, and the University of Southern California, where she currently is focused on clinical work. She is currently an Associate Clinical Professor of Pediatrics in the Division of Rheumatology and Rehabilitation at Children’s Hospital in Los Angeles, CA and USC. She is Principal or Sub-Investigator on multiple clinical studies testing therapeutics for juvenile rheumatoid arthritis.
BIRCWH Scholar from 07/01/2004 until 06/30/2007
Glucocorticoid Regulation of Autoimmunity
Autoimmunity is an often devastating phenomenon that afflicts more women than men. As a pediatric rheumatologist, I see many girls and young women suffering from excessive and inappropriate immune responses, which generate damaging inflammation that can disfigure, cripple, or kill them. Glucocorticoids are a mainstay of treatment: they have a broad range of anti-inflammatory activity that can relieve pain, improve function, and minimize the long-term consequences of systemic inflammation. However, they also have a broad range of adverse effects, such as avascular consequences of systemic inflammation. However, they also have a broad range of adverse effects, such as avascular necrosis of bone, osteoporosis, and diabetes. The long-term goal of my research is to improve our understanding of how these drugs act, so that we can develop new therapies that provide equally efficacious control of autoimmunity but have fewer side effects.
Glucocorticoids act through the glucocorticoid receptor (GR), regulating the transcription of many genes. The receptor is ubiquitously expressed, however, which can make it difficult to verify whether specific events are cell autonomous or the downstream effect of GR action on another tissue. Tissue-specific GR knockout mice allow us to isolate effects due GR action in a single tissue, while allowing for the full panoply of homeostatic and tissue-tissue interactions seen only in the intact animal. Mice lacking GR in T-lymphocytes (TGRko mice) demonstrate grossly normal T-cell development, but overact to polyclonal T-cell activation. We are now investigating on TGRko response to antigen-specific T-cell activation using murine models of multiple sclerosis (MS) and systemic lupus erythematosus (SLE), both autoimmune syndromes with strong female predominance. We hypothesized that the TGRko mice would have a more severe course because endogenous Glucocorticoids will not be able to downregulate the pro-inflammatory pathways of NF-kB, and p38, resulting in increased cyclooxygenase-2 (COX -2) in T cells. Preliminary experiments suggest a more severe course in TGRko mice during experimental autoimmune encephalomyelitis (EAE), and we are verifying that these pathways are upregulated in the TGRko mice.
I. We will explore the pathology of EAE in TGRko mice—is there recruitment of inflammatory cells or evidence of increased activity of the cells that are recruited?
a. Evaluate the CNS lesions by histology and by MRI.
b. Isolate and quantitate inflammatory cells in the CNS and periphery.
c. Examine the cytokine profiles in serum, CSF, and intracellularly in immunoregulatory cells.
II. Characterize pro-inflammatory signaling in TGRko T-cells in vitro and in vivo.
a. Measure activity of NF-kB and p38 pathways.
b. Examine whether downstream products of COX-2 are upregulated in TGRko mice during EAE, and see if the course of EAE in TGRkos is normalized by a COX-2 inhibitor.
III. Determine whether TGRko mice also have a more severe course in a murine model of lupus nephritis.
a. Backross the TGRko alleles onto the MRL 1pr genetic background to make MRL/TGRko mice.
b. Determine whether the MRL/TGRko mice have a more severe course of glomerulonephritis, evaluating symptom onset, severity, and pathology.
c. If glomerulonephritis is more severe in MRL/TGRko mice, we will look for dysregulation of the pathways discussed above, evaluating relevant histology, cytology, and cytokine profiles.