Precision Immunology Institute

Autoimmunity

Autoimmune diseases arise when the body mounts an immune response against a specific organ or tissue. Therapeutic interventions against autoimmunity are hampered because the molecular and cellular entities targeted by the immune system are largely unknown. In addition, how the components of the immune system interact to mediate autoimmune inflammation is not well understood. PrIISM investigators are using multidisciplinary approaches to develop effective treatments for a variety of autoimmune diseases. These include T and B cell autoimmune diseases associated with primary immune deficiencies, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and autoimmune liver diseases.

Basic and clinical immunologists at the PrIISM Institute are using whole genome and exome sequencing to identify new monogenic causes of autoimmunity; next generation sequencing-based tools for discovering autoantigens; highly multiplexed analytical strategies to generate integrated perspectives onto autoimmune pathogenesis; development of therapeutic monoclonal antibodies; profiling the signatures of cytokines, chemokines and other soluble proteins at the local and systemic level to identify potential autoimmune biomarkers; computational approaches and single cell analyses to improve the diagnosis and individualized therapy of patients with autoimmune diseases. This collective approach by PrIISM scientists is aimed towards elucidating autoimmune disease pathogenesis and development of improved diagnostic, prophylactic, and therapeutic modalities.

Investigators with a major focus in autoimmunity include:

Konstantina Alexandropoulos, PhD is an Associate Professor of Medicine at the Department of Medicine/Division of Clinical Immunology at the Icahn School of Medicine at Mount Sinai and head of the T cell-mediated Autoimmunity and Inflammation Laboratory. Research in the laboratory is focused on understanding the process of T cell tolerance and how disturbances in this process results in T cell-mediated autoimmune diseases such as inflammatory bowel disease and autoimmune hepatitis. The laboratory has uncovered mechanisms that regulate central T cell tolerance through the elimination of self-reactive T cells in the thymus, as well as peripheral tolerance that regulate self-reactivity in peripheral organs. Other research projects in the laboratory focus on elucidating T cell development/activation and leukocyte trafficking under physiologic and disease conditions.

Area(s) of Focus:
Autoimmunity
Inflammatory Bowel Disease
Vascular Inflammatory Diseases

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Minji Byun, PhD is an Assistant Professor of Medicine at the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai. The Byun laboratory studies genetic basis of rare immune disorders, including, but not limited to, primary immunodeficiency disorders and lymphoproliferative diseases. This lab investigates both inherited (germline) and acquired (somatic) mutations as cause of disease, which is identified using various human genetics tools including whole genome sequencing. The Byun laboratory also conducts functional studies of putative causative variants to validate their pathogenicity, and to elucidate molecular and cellular mechanisms underlying immune dysregulation.

 

Area(s) of Focus:
Immunodeficiency
Autoimmunity 

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Dr. Paolo Cravedi is a scientist physician with a strong interest in kidney transplantation and autoimmune glomerular diseases. During his clinical training as nephrologist in Italy, he designed clinical research studies in kidney transplant recipients and in individuals with renal diseases aimed at prolonging survival of the graft or the native kidneys, respectively. His studies have contributed to defining the organ allocation system currently used in many countries around the world.

He subsequently completed his postdoctoral training at the Icahn School of Medicine at Mount Sinai, where he identified unanticipated immune effects of erythropoietin. While Dr. Cravedi’s lab is still interested in understanding the mechanisms of all reactive immune responses, it has more recently expanded its focus to study the pathogenesis of autoimmune glomerular disease.

Area(s) of Focus:
Transplant
Autoimmunity

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Primary immune deficiency diseases, first recognized more than six decades ago, include over 300 genetic defects, have provided unique and unparalleled opportunities to study the cellular, biochemical and molecular mechanisms required for a functional immune system. While individually rare, collectively these defects occur in about one out of 10,000 individuals and are found in infants, children, and adults of all ages. Our understanding of immunity owes much to human PIDD; these diseases have elucidated both common and rare defects of adaptive immunity and have opened the field of innate immunity in humans, a currently very rapidly expanding field. The Primary Immune Deficiency Program at the Icahn School of Medicine at Mount Sinai is now a 950 patient service, spanning medicine, pediatrics, and laboratory research. This program is based on a steady stream of new referrals from New York, the surrounding states, and other countries. Based on this work, Dr. Cunningham-Rundles has been continuously funded by the NIH for clinical research studies on human immune defects, while providing an interface for medical and post graduates, T32, and MD, PhD, and fellowship training programs. While there have been amazing advances in the understanding of many primary immune defects, the most common immune defects, those which impair B cell function, are still largely uncharted territory. These types of immune defects often become apparent in adult life and yet are considered primary immune defects with genetic basis. Our current work has identified selected genetic, cellular and micro-environmental influences are critical for normal B cell development and that defects in these processes result in immune deficiency, autoimmunity, and many facets of immune dysregulation.

Area(s) of Focus:
Allergy
Autoimmunity
Immunodeficiency 

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The Gulko laboratory focuses in rheumatoid arthritis and other forms of inflammatory arthritis, particularly in the mechanisms regulating disease severity and joint damage. The laboratory has developed a discovery strategy that uses genetic and genomic studies with synovial tissues and cells, as well as functional studies with synovial cells and Tregs. These strategies led to the discovery of a new role for the cation channel TRPV2 in the regulation of the destructive and invasive behavior of synovial fibroblasts and in arthritis. The lab recently positionally identified and functionally characterized the new arthritis gene HIP1, and identified new roles for nuclear receptors such as VDR and LXR, and CXCR3 in the regulation of synovial cell invasion. The laboratory aims to identify new key arthritis genes, characterize their function in Tregs and synovial cells and develop new and better treatments for patients. We have strong on-going collaborations within the Immunology Institute and with the Genomics Institute and Drug Discovery Institute.

Area(s) of Focus:
Autoimmunity

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Dirk Homann is an Associate Professor of Medicine (Diabetes Obesity and Metabolism Institute & Precision Immunology Institute). Trained as a physician and immunologist/virologist, Dr. Homann has a long-standing interest in autoimmune and infectious disease, in particular the generation, maintenance, modulation, pathogenic potential, and protective capacity of specific T cell immunity. Specific areas of preclinical investigation in the Homann laboratory include the long-term maintenance and aging of antiviral CD8+T cell memory, the effective regulation of T cell responses by diverse co-stimulatory and -inhibitory interactions, the role of chemokines in infectious and type 1 diabetic disease (T1D), and the concurrent therapeutic modulation of immune responses and beta cell survival in T1D. The overarching goal of these endeavors is the development, adaptation and optimization of therapeutic strategies that effectively curtail (autoimmunity) or embellish (infectious disease) T cell responses with prophylactic and/or curative intent. Over the past half-decade, Dr. Homann’s laboratory has expanded its research focus to human studies and currently pursues a high-dimensional deconvolution of the phenotype and histopathological space of the human pancreas in health and T1D disease.

Area(s) of Focus:
Autoimmunity

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Amir Horowitz, PhD is an Assistant Professor of Oncological Sciences at the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai. Dr. Horowitz’s laboratory studies human NK cells and the genetic and environmental determinants underlying their education and ability to respond in dynamic environments. Dr. Horowitz’s work is contributing to developing an understanding of adaptive NK cells and their roles in microbial infections, cancers, autoimmunity as well as following vaccination and hematopoietic cell transplantation (HCT). He was the first to demonstrate adaptive roles for NK cells in vaccine settings as a strategy to potentiate T cell memory and also pioneered the first studies of human NK cells by CyTOF. His research has led to the identification and characterization of numerous NK cell subsets with unique activity and antiviral (and anti-tumor) potential.

Area(s) of Focus:
Autoimmunity
Cancer Immunology

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Seunghee Kim-Schulze, PhD, is a Facility Director of Human Immune Monitoring Center (HIMC) and assistant professor of Medicine (Hem/Onc division) at the Icahn School of Medicine at Mount Sinai in New York. Dr. Kim-Schulze graduated with a PhD in biochemistry at University of Illinois, and undertook postgraduate fellowship training at the Northwestern medical school, Imperial College in London, UK and Columbia University Cancer center in New York, focused on cellular immunology in cancer. She was recruited to the Icahn School of Medicine at Mount Sinai in 2009 to establish the human immune monitoring facility under the guidance of Dr. Miriam Merad with the mission of identification of novel immune biomarkers of disease and response to therapy in patients with cancer and inflammatory disease. Dr. Kim-Schulze studies critical immune responses in cancer patients undergoing investigational cancer vaccines, check point blockade and the combinatorial therapies via the genomic, cellular and proteomic analysis. Dr. Kim-Schulze has developed multiple clinical protocols for the trials for the cancer immunotherapies and conducted laboratory correlative studies leading to peer-reviewed publications. She has identified the high PD-1 expression in tumor infiltrating immune cells of melanoma patients had poor prognosis compare to the ones with low level of expression before anti-PD-1 antibody became the revolutionary immune modulating FDA-approved for multiple indications. Her work also supports shared immune signatures between various cancers and proinflammatory disease. Currently, she is profiling the signatures of cytokines, chemokines, and other soluble proteins at the local and systemic level to identify the potential biomarkers in various disease including cancer, inflammatory bowel disease, autoimmune, neurology, psychiatry, and cardiovascular disease.

Area(s) of Focus:
Autoimmunity
Cancer Immunology
Inflammatory Bowel Disease
Neuroimmunology
Transplant 

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Uri Laserson, PhD, is an Assistant Professor in the Department of Genetics and Genomic Sciences at ISMMS. Using next-generation DNA sequencing and large-scale DNA synthesis, his lab builds high-throughput/high-dimensional assays and computational tools for genomics and immunology. The lab uses these tools to study how the adaptive immune system uses antibodies and TCRs in a number of contexts, such as host-microbiome interactions or anti-tumor immunity. Before starting his lab, he spent four years in Silicon Valley working on big data and genomics at Cloudera (2012-2016). His graduate training started in the Math department at MIT, followed by work on high-throughput immunogenomics in George Church's lab at Harvard (2006-2012). During that time, he co-founded Good Start Genetics, one of the first companies to offer next-generation sequencing in a clinical setting. His thesis research also helped lay some of the groundwork for AbVitro, which was acquired by Juno Therapeutics in 2016. 

Area(s) of Focus:
Autoimmunity 
Cancer Immunology
Inflammatory Bowel Disease
Microbiome and Host Pathogen Interaction 

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Dr. Sergio Lira received his MD from the Universidade Federal de Pernambuco in Brazil (1982) and his PhD in Physiology and Pharmacology from the University of California at San Diego (1988). He did his postdoctoral training at the Roche Institute for Molecular Biology in Nutley, NJ. After his postdoctoral training he worked for 11 years in the pharma sector, first at Bristol-Myers Squibb (1992-1996) and then at Schering-Plough (1996-2002). Dr Lira joined Mount Sinai in 2002 as the Irene Diamond Associate Professor of Immunology. In 2007 he became the co-Director of the Immunology Institute (with Dr. Lloyd Mayer), and in 2013 was promoted to Director, a position he occupied until 2016. He is currently The Leona M. and Harry B. Hemsley Charitable Trust Professor of Immunology. His research focuses on the role of immune cells and the microbiome in mucosal inflammation and cancer. He has organized international meetings in this field, including the 2003 Keystone Symposium on Chemokines and the 2006 Gordon Research Conference on Chemotactic Cytokines. He was elected to the Henry Kunkel Society in 2006 and to the Association of American Physicians in 2008. Dr. Lira was a Visiting Professor at the Southern Medical University in Guangzhou, China (2013-2016) and is a member of the Board of Scientific Counselors of the National Cancer Institute (2013-present).

Area(s) of Focus:
Inflammatory Bowel Disease
Autoimmunity
Cancer Immunology
Microbiome
Skin Inflammatory Disease

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Thomas M. Moran, PhD is the Director of the Center for Therapeutic Antibody Development (CTAD) at the Icahn School of Medicine at Mount Sinai. The Center within the Drug Discovery Institute produces monoclonal antibodies against target that include infectious agents, cell receptors, secreted proteins, and cell surface markers. CTAD is a cutting edge monoclonal antibody facility and has established collaboration with Regeneron Pharmaceuticals to use the Velocimmune mice to produce mAb for some projects. This second generation humanized mouse is superior to previous versions in that the mouse constant regions allow interaction with mouse immune elements leading to stronger humoral responses. Dr. Moran has published widely on immunity to virus infection using both mouse models and studies using samples from human subjects. He served as the overall director of the NIH funded Center for Investigating Viral Immunity and Antagonism (CIVIA) that focused on studies of human immunology and infectious disease by advancing technological methodologies, supporting inventive research, serving as a conduit for collaboration. Dr. Moran was PI for the now concluded Viral Immunity in Pregnancy study (VIP). This was a study of changes that occur in women during pregnancy with an emphasis on understanding their enhanced susceptibility to infection.

CTAD works in all the areas of interest aimed at developing therapeutic monoclonal antibodies. Currently projects in Cancer, Infectious Disease, Autoimmunity and Neuroimmunology are being pursued.

Area(s) of Focus:
Cancer Immunology
Microbiome and Host Pathogen Interaction
Autoimmunity
Neuroimmunology

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Stuart Sealfon is the Glickenhaus Professor of Neurology, Professor of Neurobiology, and Pharmacological Sciences and Director of the Center for Advanced Research on Diagnostic Assays. His group applies systems biology approaches, including mathematical modeling, bioinformatics and high throughput experimentation, to the study of cellular responses to infection, hormone exposure and physical activity.  He is a Principal Investigator of the new NIH MoTrPAC Physical Activity Molecular Mapping Consortium and has directed an NIAID-supported Immune Modeling Center for 13 years. Active research areas include developing and implementing computational algorithms for biomarker discovery, big data mining and gene network prediction, identifying blood RNA expression signatures to improve the diagnosis and individualized therapy of diseases, identifying the mechanism of frequency-dependent signal decoding in cells, developing experimental based mathematical models of the early emergent response to influenza virus infection and vaccination. His research involves data intensive high throughput experimentation to generate high dimensional datasets of molecular responses and relationships and single cell studies in conjunction with top down computational analysis and algorithm development and bottom up stochastic and deterministic mathematical modeling to interpret these datasets. His research team comprises a fully integrated group of theoretical scientists (physics, statistics, computer science, engineering) and experimentalists (immunology, cell biology, molecular biology).

Area(s) of Focus:
Autoimmunity 
Neuroimmunology

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Hideki Ueno, MD, PhD, is Professor at the Department of Microbiology at ISMMS and the most recent faculty recruit of GHEPI. Dr. Ueno’s laboratory is focused on understanding dendritic cells and CD4+ helper T cell subsets in humans, an area in which he is an internationally renowned expert, with an overall goal of understanding the adaptive immune system in healthy human subjects and determining how their alterations are associated with vaccine responses and various human diseases. Dr. Ueno successfully secured grant funding while at Baylor, allowing him to establish a robust research program there. He has also obtained funding from NIH and non-federal sources like the Lupus Research Institute.

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