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MHV68 Infection in a Novel rag2 F62L/F62L Mouse Model Based on a Patient with CID-G/AI Phenotype
EP25562
Poster Title: MHV68 Infection in a Novel rag2 F62L/F62L Mouse Model Based on a Patient with CID-G/AI Phenotype
Submitted on 13 Feb 2017
Author(s): Csomos K1, Ujhazi B1, Stoltz K2, Ijspeert H3, Mei Yan4, Quan-Zhen Li4, Csizmadia E5, Butte MJ6, Coppola D7, van der Burg M3, Tarakanova V2, Walter JE1,8
Affiliations: 1Division of Pediatric Allergy & Immunology, Department of Pediatrics, University of South Florida, Tampa, FL, USA; 2 Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA;  3 Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; 4 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 5 Department of Medicine-Gastroenterology, Beth Israel Deaconess Hospital, Boston, MA, US; 6 Department of Pediatrics, University of California, Los Angeles, CA, USA; 7 Moffitt Cancer Center, Tampa, FL, USA; 8 Division of Pediatric Allergy & Immunology, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
This poster was presented at USF Health Research Day 2017
Poster Views: 1,777
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Poster Information
Abstract: Objective: Immunodeficiencies secondary to partial RAG1/2 mutations have a widening autoimmune clinical spectrum and autoantibodies, including those targeting cytokines. Herpes virus infections are often observed prior to the onset of autoimmunity.
 
Methods: To study this phenomenon, a novel murine model was designed with rag2F62L/F62L (mut/mut) modeling a patient with partial Rag deficiency (19.6% Rag2 recombinase activity), history of autoimmune cytopenia and complicated herpes virus infection. Mice were infected with mouse gammaherpesvirus-68 (MHV-68) and cellular and humoral response were monitored. B cell tolerance checkpoints were examined.
 
Results :At baseline mut/mut mice had increased use of proximal IgH J genes consistent with partial Rag activity. Although viral latency was comparable, antibody generation to virus and self-antigens were increased and larger lymphoid infiltrates (lung, liver, kidney) were noted in mut/mut versus wt/wt mice (p<0.05). Receptor editing in bone marrow Fraction D B cells, serum B cell activating factor (BAFF) levels and regulatory T compartments did not differ significantly.
 
Conclusions: MHV-68 infection in our rag2 mouse model induced increased antibody responses to virus and self and inflammatory disease in end organs. Major mechanism of inflammatory infiltrates and autoantibody generation is yet to be determined
Summary: Combined immunodeficiency with granuloma and autoimmunity (CID-G/AI) is a frequent clinical phenotype associated with hypomorphic RAG mutations in humans. Our mouse model with rag2 pF62L mutation serves excellent model to study the development of autoimmunity and tolerance breaks after virus infection on hypomorphic RAG background. References: Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.
Walter JE; J Clin Invest. 2016
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