STANFORD UNIVERSITY, SCHOOL OF MEDICINE DEPARTMENT OF PEDIATRICS, DIVISION OF STEM CELL TRANSPLANTATION AND REGENERATIVE MEDICINE PRESENTS

JOLAN WALTER, MD, PhD Assistant Professor, Harvard Medical School Director of Pediatric Immunodeficiency Program, Massachusetts General Hospital for Children

CHALLENGES OF A NEW ERA: COMBINED IMMUNODEFICIENCIES WITH

IMMUNE DYSREGULATION Dr. Walter has graduated with an MD and PhD from University of Pecs, Hungary. She has trained in Pediatrics at Children’s Hospital of the King’s Daughters, Eastern Virginia Medical School and in Allergy/Immunology at Boston Children’s Hospital. During her training, she conducted research both in the fields of Virology and Immunology. Dr. Walter serves as the Director of the Pediatric Immunodeficiency Program at Massachusetts General Hospital for Children where her translational research focuses on patients with common variable immunodeficiency and mitochondrial disorders with immunodeficiency. As a principal investigator, she also conducts translational and basic science research at the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital where her team focuses on understanding the spectrum and biology of human disease associated with immune dysregulation and autoimmunity. As a prototype of these conditions, Dr. Walter’s laboratory studies patients and murine models with defects in recombination activating genes 1 and 2 (RAG1/RAG2). She investigates checkpoints in B cell tolerance and mechanisms driving hyperinflammation. Dr. Walter works closely with experts at Boston Children’s Hospital, including Dr. Luigi Notarangelo, an international figure in primary immunodeficiencies. Her long-term goal is to define strategies for early detection of susceptible individuals and novel targeted approaches to treatment.  

TUESDAY

AUGUST 4 1:00PM Lorry I. Lokey Stem Cell Research Building (SIM1)

ROOM G1002

 

 

   

JOLAN WALTER, MD, PhD ABSTRACT

 

 

Primary immunodeficiencies (PID) are no longer defined by infections alone. Based on recent publications including an analysis of data from USIDNet repository, autoimmune complications are key components of many PIDs. As PID patients with non-infectious complications are prone for increased morbidity and mortality, early detection of an underlying defect and targeted therapy are of utmost importance. Although autoimmune cytopenias are the most frequent features of autoimmunity, the autoantibody spectrum in PIDs can be versatile and disease-specific including autoantibodies targeting the endocrine organs or even cytokines. As a prototype of these conditions, our group studies patients and murine models with defects in recombination activating genes 1 and 2 (RAG1/RAG2). These enzymes initiate V(D)J recombination and thereby allow pre-immune diversification of the T and B cell repertoire. RAG deficiencies represent a unique group of primary immunodeficiencies. Pathogenic RAG mutations result in a wide range in Rag activity. Associated clinical and immunological phenotypes are broader than previously thought: these range from severe infections and early mortality to subtle presentation with delayed onset combined immunodeficiency with granulomatous disease and autoimmunity (CID-G/AI). The autoimmune phenotype may also vary, from the sole presence of autoantibodies and cytopenias to localized destructive vasculitis. Based on observations in patients and mouse models of RAG deficiency, we have described impaired central and peripheral checkpoints in B cell tolerance, a previously overlooked component of the pathology of this disorder. In joint collaboration with Dr. Notarangelo we have access to the largest retrospective multicenter repository of biological samples from RAG deficient patients, with a spectrum of clinical and immunological phenotypes. Via three separate assays, in collaboration with Dr. Utz group from Stanford and Dr. Holland from the NIH, we have demonstrated that hypomorphic RAG mutations in humans are associated with production of a broad spectrum of autoantibodies, including anti-cytokine antibodies to IFN-a and IFN-ω. Furthermore, we have shown that injection of TLR-3/7/9 agonists in mice with a homozygous hypomorphic Rag1 mutation induces enhanced inflammatory responses and promotes autoantibody production. These findings may provide mechanistic insights into the pathophysiology of inflammatory and autoimmune manifestations in patients with RAG deficiencies. To model the inflammatory and autoimmune manifestation among patients with CID-G/AI phenotype, we generated a novel murine model using a more permissive rag2 homozygous mutation (C186A, Phe62Leu) with 20% RAG activity that is carried by the CID+G/AI patient from Stanford. This patient is truly unique that generates anti-cytokine autoantibodies and currently not transplanted, yet. We anticipate that anti-cytokine autoantibodies may be induced with rag2 homozygous mutation in our model and will serve as a tool to investigate the generation of these antibodies. Beyond examining impaired B cell tolerance checkpoints, my team is also focusing on the disrupted synopsis of innate lymphocytes, microbiome and regulatory T cells in the pathogenesis of RAG-dependent primary immunodeficiency. Altogether, my research using animal models and humans has helped to highlight the generation of autoantibodies and autoimmune manifestations as an important and challenging aspect of primary immunodeficiencies. Our goal is to achieve early identification of susceptible individuals by developing and validating novel biomarkers. With the murine models, patient samples and molecular tools available to us, we intend to advance the field of primary immunodeficiencies. Our models also allow to bridge gaps between the basic science and pressing clinical challenges to identify and treat autoimmune and inflammatory disorders.  

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