Robert A. Barrington, PhD
Biography
Dr. Robert A. Barrington received his Ph.D. with distinction in Immunology from Loyola University at Chicago in 1998. He received post-doctoral training at Harvard Medical School, and later served as junior faculty within the Department of Pediatrics at Children’s Hospital in Boston, MA.
Before joining the Department of Microbiology & Immunology at USA, Dr. Barrington spent 1.5 years within the Clinical Diagnostics Division of Olympus America, Inc.
Research
Immune Regulation and Rare Immunologic Diseases
Dr. Barrington's research focuses on studying molecular and cellular pathways regulating immune hyperresponsiveness in rare diseases including Hyper-IgE Syndrome, Herpes Stromal Keratitis, and Autoimmune Pulmonary Alveolar Proteinosis.
Though any particular rare disease affects less than 1 in 2000 people, collectively 10% of the global population (~475 million people) are affected by a rare disease. Rare diseases create a significant economic burden, including an estimated $1 trillion spent in medical costs within the United States. Worldwide efforts have led to identification of genetic causes for many rare diseases; however, it can take years for proper diagnosis (the average time to diagnosis is 7 years), and effective treatments exist for only ~6% of these disorders. The Barrington lab employs preclinical and clinical models to investigate underlying mechanisms mediating rare immunologic diseases with the goal that any insights gained will lead to novel, effective therapeutic strategies.
Major areas of interest in Dr. Barrington's lab include:
Hyper-IgE Syndrome and Trained Immunity
Hyper-IgE Syndrome (HIES) is a rare primary immunodeficiency in children characterized by eczema/atopic dermatitis, recurrent Staphylococcal skin abscesses, recurrent lung infections, eosinophilia, and high levels of IgE. The genetic cause of HIES is an autosomal dominant mutation in STAT3, a transcription factor with pleiotropic and sometimes contradictory roles within the immune system.
Using a preclinical model for HIES whereby cells express a mutant STAT3, his lab is testing whether reprogramming innate immune cells (i.e. trained immunity) can attenuate allergic responses. They do this by triggering cellular receptors that alter epigenetic programs. Somatic cells likely contribute to HIES pathogenesis as well; therefore, they are additionally investigating whether engaging conserved receptors on non-immune cells ameliorate disease pathogenesis.
Gamma Delta T cells and Protection from HSV-1 Corneal Infection
Another major project area is illuminating major immune pathways that protect and/or damage corneas during infection. Dr. Barrington and his team of researchers focus on the immune response generated against Herpes Simplex Virus 1 (HSV-1), a neurotropic virus that is the leading cause of infectious blindness in developed countries. While the adaptive immune responses to HSV-1 limits viral spread, these responses are also responsible for corneal damage that leads to blindness.
His laboratory observed that a minor population of innate-like adaptive immune cells, called gamma delta T cells, provide protection early following HSV-1 infection in corneas. Gamma delta T cells differ significantly from conventional T cells that drive corneal pathogenesis; therefore, they hypothesize that the activity of gamma delta T cells can be harnessed to limit corneal damage after HSV-1 infection. Intriguingly, there are subsets within the gamma delta T cell pool, so they utilize single cell RNA sequencing to reveal the particular functions of these cell subsets. To facilitate these functional measurements, Dr. Barrington's lab has also developed a novel system in vitro that recapitulates events occurring during infection.
Underlying pathways regulating Autoimmune Pulmonary Alveolar Proteinosis
The last major project in Dr. Barrington's laboratory examines immune mechanisms responsible for autoimmune pulmonary alveolar proteinosis (aPAP). Autoimmune PAP is a rare syndrome defined by the accumulation of pulmonary surfactant in the alveoli leading to respiratory insufficiency. Pulmonary surfactant levels are maintained in part by GM-CSF, a pleiotropic cytokine that is required for the differentiation, maintenance, and function of alveolar macrophages. In aPAP, IgG autoantibodies are produced that neutralize GM-CSF thereby denying alveolar macrophages and leading to increased surfactant levels. Interestingly, GM-CSF-specific IgG autoantibodies are also detectable in healthy individuals, raising a key question of how immunological tolerance is regulated in healthy and pathologic settings.
They recently identified the first non-primate model for aPAP. In this model, the development of aPAP is dependent on B cell-T cell interactions. Their current focus is to determine whether there are differences in disease-causing GM-CSF-specific IgG in individuals with and without disease to reveal underlying molecular pathways. A separate area of focus are preclinical studies to identify potential therapeutic intervention to prevent and/or block autoantibody production.