Laboratory of Cory Perugino, D.O.
Email: cperugino@mgh.harvard.edu
Overview
The Perugino lab at Mass General Brigham’s (MGB) Center for Immunology and Inflammatory Diseases (CIID) studies human immunology to understand how chronic inflammation drives fibrosis, particularly in the context of autoimmunity. Our lab uses blood and tissue samples from patients with IgG4-related disease, systemic sclerosis, and post-infectious Lyme arthritis to study immune cells that accumulate at disease sites. These include CD4+ cytotoxic T lymphocytes (CD4+ CTLs), regulatory T cells (Tregs), and age-associated B cells (ABCs). We emphasize expertise in flow cytometry, in vitro assays, antigen discovery strategies, and multi-omics approaches to dissecting immune cell types.
Research Projects
Stepwise epigenetic programming drives the differentiation of three functionally distinct CD4+ T cell subsets in human type 1 immunity
CD4+ cytotoxic T lymphocytes (CD4+ CTLs) are polyfunctional T cells linked to chronic inflammation and tissue damage. The molecular determinants of their development remain unknown, and we lack targeted therapies to interfere with these cells. In collaboration with the Pillai lab of the Ragon Institute and the Mahajan lab of Brigham and Women’s Division of Engineering in Medicine, we are examining the phenotype, function, and differentiation steps of CD4+ CTLs using advanced in vitro and molecular techniques. We previously implicated CD4+ CTLs as key drivers of tissue injury in IgG4-related disease (IgG4-RD) and systemic sclerosis and are now focused on elucidating how these cells are derived in the setting of chronic inflammation. The long-term goal of this work is to identify therapeutic targets to modulate CD4+ CTLs to arrest and prevent tissue damage and fibrosis.
Specific autoantibodies define distinct groups of patients in IgG4-related disease
The molecular basis of IgG4-RD remains unknown and definitive evidence for it having an autoimmune etiology is lacking. Additionally, we lack diagnostic blood tests and continue to rely on biopsy plus tertiary referral evaluation to diagnose this disease. In collaboration with the Pillai lab of the Ragon Institute, we have been studying self-antigenic drivers of the B cell response in IgG4-RD for over a decade. We previously identified galectin-3 and interleukin 1 receptor antagonist as key autoantigens in IgG4-RD and are now expanding these efforts to broadly screen the IgG repertoire of dozens of patients for reactivity against the human proteome. The longer-term goal of this work is to elucidate the underlying basis for the loss of tolerance in IgG4-RD and discover specific autoantibodies that can be used clinically as diagnostic tests for this disease.
Broad Screening of Inflammation-Associated Proteins Identifies Serum CCL19 as a Novel Biomarker of Disease Activity in IgG4-Related Disease
IgG4-RD is a slow moving, often asymptomatic disease that insidiously causes organ damage and morbidity and clinicians have limited tools to measure disease activity. This project is part of a larger ongoing effort to identify optimal biomarkers to monitor disease activity in IgG4-RD. We recently identified CCL19 as a novel biomarker in this disease by screening nearly 100 different inflammation related proteins and used detailed clinical correlations to infer disease relevance. Our lab is now turning attention to understanding the cellular source and function of CCL19 at the tissue level and examining additional candidate biomarkers using our large repository of IgG4-RD patient samples.
FoxP3Lo Helios+ T cells and their role in autoimmune inflammation
Breach of tolerance against self-antigens is a defining feature of autoimmunity. Regulatory T cells (Tregs) evolved to maintain self-tolerance by acting on and regulating pro-inflammatory, effector T cells. However, relatively little is clearly established about the phenotype and functionality of Tregs in the context of IgG4-RD or systemic sclerosis. Leveraging carefully done flow cytometry, functional assays, and molecular techniques, we are dissecting subsets of Tregs using samples from patients with these autoimmune diseases. A long-term translational goal of this work is to identify novel approaches to augment the Treg response in settings of autoimmunity.
Defining the functions of B cells and antibodies across the continuum of Lyme arthritis
The incidence of Lyme disease continues to markedly increase each year in the United States. Lyme disease is caused by tick-bite transmission of the bacterium, Borrelia burgdorferi, which can result in a range of clinical outcomes including acute and chronic infections, as well as post-infectious autoimmunity. While these outcomes are well established, we remain unable to predict which patients will eventually develop post-infectious (autoimmune) Lyme arthritis (PILA). This project aims to elucidate the evolution of antibody and B cell function across the continuum of Lyme disease manifestations, including PILA. In collaboration with the Anthony and Steere Labs of the CIID, we are examining B cells and post-translational modifications of IgG4 antibodies across distinct clinical phases of Lyme disease with the long-term goal of providing crucial insights for the prognostication and/or treatment of these conditions.