Based on one of the largest primary immunodeficiency clinics in the Northeast (and possibly in the US) established by Charlotte Cunningham-Rundles, this program focuses on the mechanisms and treatment of primary human immune defects. The clinic referral population spans all age groups from infants to the elderly. A central research focus for some years has been on the pathogenesis and treatment of B cell defects, however due to the complex nature of B cell activation; the genetic causes of B cell failure are multiple and include defined molecular defects in the bone marrow, lymph node and cellular compartments. Using whole genomic sequencing we have now elucidated new causes of B cell failure, leading to unique clinical manifestations. Based on experience as an established program, Mount Sinai is also New York State referral center for infants identified by newborn screening, with suspected severe T cell defects. This program also reinforces the work of the Pediatric Hematology Division as infants with severe defects require stem cell transplantation.
Another unique Immune deficiency program at the Icahn School of Medicine at Mount Sinai was established by Paula Busse for patients with genetic and acquired forms of C1 inhibitor deficiency. Also of the largest in the nation, this program had led to a number of clinical trials with novel agents designed to prevent the medical complications of this severe immune defect. Furthermore, several investigators joined the program recently, adding expertise in various areas of immune deficiency research. Dusan Bugonovic studies type I interferonopathies, Minji Byun investigates genetic causes of rare inflammatory disorders, Yuval Itan conducts research on large-scale computational discovery of genes and pathways causing immune deficiencies and PJ Maglione uses translational research in primary immunodeficiency to identify new therapeutic targets for immunological disease.
The Primary Immunodeficiency program has been supported by a long-running program grant and several R01s, a NIH supported national cooperative grant, industry funds, clinical trials, and substantial funding from the Jeffrey Model Foundation. More recently, additional outreach work will be funded by a new Clinical Sequencing Exploratory Research (CSER). The work with New York State (NYS) has led to a new NYS grant to Mount Sinai, from the Department of Health, and funded by the Center for Disease Control.
A confounding feature of human immune deficiency is immune dysregulation. For this reason, patients with primary immune defects are likely to develop inflammatory and autoimmune diseases. One consequence of this has been the increasing use of targeted biologics in subjects with known gene defects. With the growth of selected and targeted therapies for immune based diseases as a whole, some years ago the Clinical Immunology team established a biologics infusion program. This has now grown to a new Non-Cancer Infusion Center, incorporating biologic treatments for an increasing number of immune based diseases referred from a number of other services within the Mount Sinai Health System.
The Clinical Immunology Division along with the Pediatric Division of Allergy and Clinical Immunology serves as a stellar teaching site for the Allergy and Clinical Immunology Fellowship program at the Icahn School of Medicine at Mount Sinai, Downstate Medical Center, and Winthrop University Hospital. With increasing focus on genetic diagnosis, the Immunodeficiency Program increasingly relies upon genetic testing for diagnosis and for design of best therapeutic strategies.
Investigators with a major focus in immunodeficiency include:
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.
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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 the 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.
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