Immune mediated diseases pose a significant health burden, and the complexity of these conditions hinder development of targeted therapies. Autoimmune manifestations in primary immune deficiencies (PID) with specific genetic defect can provide a simplified model for autoimmune diseases and allow close examination of the role of specific molecules to establish tolerance and may identify novel strategies for treating immune-mediated diseases. Autoantibody or cytokine signatures and specific biomarkers identified in these models can guide future interventions. We seek to evaluate mechanisms of B cell dysregulation and additional triggers of autoimmunity in a distinct murine model with a rag1 hypomorphic mutation and among patients with Recombinase Activating gene (RAG) defects. Among patients with pathogenic RAG mutations, impairment of RAG activity varies and is associated with clinical and immunological phenotypes broader than previously considered. These range from severe infections and early mortality (SCID, Omenn syndrome) to subtle presentation with late onset granulomatous disease associated with autoimmunity (from mild cytopenias to localized destructive vasculitis). Our published data on a rag1 hypomorph murine model indicated impaired receptor editing (a disruption of central B cell tolerance) and increased levels of B cell activating factor (BAFF) secondary to lymphopenia that might contribute to the rescue of self-reactive B cell in the periphery (a disruption of peripheral tolerance). In addition our preliminary data shows that TLR stimulation mimicking viral infections can further increased the titer and diversity of the autoantibody repertoire. The relative importance of these mechanisms in B cell dysregulation is unclear. Evaluating the autoreactive B cell repertoire at distinct stages of B cell maturation with or without the use of anti- BAFF monoclonal autoantibodies would allow us to compare the relative importance of the disruption in central versus peripheral tolerance mechanisms in RAG-deficient mice. TLR stimulation experiments, mimicking chronic viral infections, may identify additional specific triggers for amplification of autoimmunity. The central goal of this proposal is to achieve detailed knowledge of B cell mediated autoimmunity both in a murine model as well as among humans with RAG mutations. Understanding the pathogenesis of B cell dysregulation in these conditions not only has implications for the treatment of the affected patients, but may also provide insights into mechanisms common to multiple autoimmune diseases.

Public Health Relevance

Self-reactive antibodies and autoimmune manifestations are increasingly recognized as a key feature of primary immunodeficiencies, especially among patients with partial loss of gene function (hypomorphic mutations). Among these patients the clinical and immunological phenotype is broader than previously thought and may include the presence of self-reactive cells or clinical manifestations of autoimmunity ranging from mild disease to destructive autoimmune complications. The generation and characterization of mouse models with hypomorphic mutations provide a unique opportunity to investigate the disruption of central and peripheral tolerance mechanisms, and secondary triggers (such as viral infections) that lead to autoimmunity in primary immunodeficiencies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI103035-03
Application #
8704877
Study Section
Transplantation Biology &Immunology-2 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2012-08-28
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
John, Tami; Walter, Jolan E; Schuetz, Catherina et al. (2016) Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency. J Clin Immunol 36:725-32
Kumánovics, Attila; Lee, Yu Nee; Close, Devin W et al. (2016) Estimated disease incidence of RAG1/2 mutations: A case report and querying the Exome Aggregation Consortium. J Allergy Clin Immunol :
Notarangelo, Luigi D; Kim, Min-Sung; Walter, Jolan E et al. (2016) Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol 16:234-46
Buchbinder, David; Baker, Rebecca; Lee, Yu Nee et al. (2015) Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol 35:119-24
Walter, Jolan E; Rosen, Lindsey B; Csomos, Krisztian et al. (2015) Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J Clin Invest 125:4135-48
Mathieu, Anne-Laure; Verronese, Estelle; Rice, Gillian I et al. (2015) PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. J Allergy Clin Immunol 135:1578-88.e5
Walter, Jolan E; Lo, Mindy S; Kis-Toth, Katalin et al. (2015) Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol 135:272-3
Lee, Yu Nee; Frugoni, Francesco; Dobbs, Kerry et al. (2014) A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol 133:1099-108
Chen, Karin; Wu, Wilfred; Mathew, Divij et al. (2014) Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J Allergy Clin Immunol 133:880-2.e10
Kwan, Antonia; Abraham, Roshini S; Currier, Robert et al. (2014) Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA 312:729-38

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