Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice This information is current as David R. Gibb, Jingchun Liu, Prabitha Natarajan, Manjula of September 23, 2021. Santhanakrishnan, David J. Madrid, Stephanie C. Eisenbarth, James C. Zimring, Akiko Iwasaki and Jeanne E. Hendrickson J Immunol 2017; 199:1041-1050; Prepublished online 19 June 2017; Downloaded from doi: 10.4049/jimmunol.1700401 http://www.jimmunol.org/content/199/3/1041 Supplementary http://www.jimmunol.org/content/suppl/2017/06/17/jimmunol.170040 http://www.jimmunol.org/ Material 1.DCSupplemental References This article cites 67 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/199/3/1041.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice David R. Gibb,* Jingchun Liu,* Prabitha Natarajan,* Manjula Santhanakrishnan,* David J. Madrid,† Stephanie C. Eisenbarth,*,‡ James C. Zimring,x,{,‖ Akiko Iwasaki,‡,# and Jeanne E. Hendrickson*,† During RBC transfusion, production of alloantibodies against RBC non-ABO Ags can cause hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Multiple studies have established that certain inflammatory disorders and inflammatory stimuli promote alloimmune responses to RBC Ags. However, the molecular mechanisms underlying these findings are poorly understood. Type I IFNs (IFN-a/b) are induced in inflammatory conditions associated with increased alloimmunization. By developing a new transgenic murine model, we demonstrate that signaling through the IFN-a/b receptor is required for inflammation-induced alloimmunization. Additionally, mitochondrial Downloaded from antiviral signaling protein–mediated signaling through cytosolic pattern recognition receptors was required for polyinosinic- polycytidylic acid–induced IFN-a/b production and alloimmunization. We further report that IFN-a, in the absence of an adjuvant, is sufficient to induce RBC alloimmunization. These findings raise the possibility that patients with IFN-a/b–mediated conditions, including autoimmunity and viral infections, may have an increased risk of RBC alloimmunization and may benefit from personalized transfusion protocols and/or targeted therapies. The Journal of Immunology, 2017, 199: 1041–1050. http://www.jimmunol.org/ uring allogeneic RBC transfusion, most non-ABO Ags on recipients and as many as 30–50% of transfusion-dependent pa- RBCs are not routinely matched between donor units and tients with sickle cell disease (1–7). Such responses can cause D recipients. Hence, transfusion exposes recipients to nu- potentially fatal hemolytic transfusion reactions (8, 9). Moreover, merous RBC alloantigens, including Kell, Duffy, and Kidd, which substantial morbidity and mortality can occur for patients who induce formation of Ag-specific IgG alloantibodies in 3–10% of all have alloantibodies against multiple Ags. Units of compatible RBCs are more difficult to locate, resulting in delays in therapy, and in extreme cases, death from lack of compatible blood (10, *Department of Laboratory Medicine, Yale University School of Medicine, New 11). However, the majority of transfusion recipients do not form by guest on September 23, 2021 † Haven, CT 06520; Department of Pediatrics, Yale University School of Medicine, alloantibodies and tools allowing prediction of such responses are New Haven, CT 06520; ‡Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; xBloodworks Northwest Research Institute, Seat- not currently available. Thus, characterization of factors that { tle, WA 98102; Department of Laboratory Medicine, University of Washington promote RBC alloantibody responses could allow for identifica- School of Medicine, Seattle, WA 98195; ‖Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195; and tion of at-risk patients and intervention to mitigate alloimmuni- #Howard Hughes Medical Institute, Chevy Chase, MD 20815 zation and its detrimental effects. ORCIDs: 0000-0003-3703-7635 (M.S.); 0000-0002-1244-208X (S.C.E.); 0000-0002- Recent human studies have confirmed earlier mouse experiments 7824-9856 (A.I.); 0000-0002-7928-3132 (J.E.H.). indicating that the inflammatory state of transfusion recipients can Received for publication March 17, 2017. Accepted for publication May 23, 2017. influence the frequency of RBC alloantibody responses. Elevated This work was supported by grants from the National Blood Foundation (R13672) (to alloimmunization rates have been reported for patients with acute D.R.G.) and the National Institutes of Health/National Heart, Lung, and Blood In- chest syndrome, febrile transfusion reactions, and autoimmune stitute (R01 HL126076) (to J.E.H.) and (T32 HL007974-14) (to Brian Smith, Chair of the Department of Laboratory Medicine, Yale University School of Medicine). diseases, including systemic lupus erythematosus (SLE) and in- D.R.G., A.I., J.C.Z., S.C.E., and J.E.H. planned the experiments completed by D.R.G., flammatory bowel disease (12–15). Also, similar to prior murine J.L., P.N., M.S., D.J.M., and J.E.H; J.C.Z. generated K1 mice. All authors made studies, a recent human study reported that inflammation associ- experimental suggestions. D.R.G. wrote the initial draft of the manuscript, and all authors edited the manuscript and approved the final version. ated with different infections can have distinct effects. Patients with viremia were reported to have increased rates of alloimmu- This work was presented in abstract form at the annual meeting of the American Society of Hematology, December 3, 2016, San Diego, CA. nization, whereas patients with Gram-negative bacterial infections Address correspondence and reprint requests to Dr. Jeanne E. Hendrickson, Yale had lower rates (16). These associations indicate that specific University Departments of Laboratory Medicine and Pediatrics, 330 Cedar Street, pathways activated in some inflammatory conditions, such as Clinic Building 405, PO Box 208035, New Haven, CT 06520. E-mail address: [email protected] autoimmunity and viral infections, promote RBC alloimmunization. However, examination of these pathways, including inflammatory The online version of this article contains supplemental material. cytokine signaling, has only just begun (17, 18). Abbreviations used in this article: cDC, conventional DC; DC, dendritic cell; HEL, hen egg lysozyme; IFNAR1, IFN-a and -b receptor 1; IRF, IFN regulatory factor; Given the large number of antigenic differences between human MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation– donors and recipients, multiple groups have used murine trans- associated gene 5; MHCII, MHC class II; pDC, plasmacytoid DC; poly(I:C), polyinosinic-polycytidylic acid; rIFN-a, recombinant IFN-a; RIG-I, retinoic acid fusions models that allow examination of alloimmune responses to inducible gene-I; RLR, retinoic acid inducible gene-I–like receptor; SLE, systemic a single donor RBC Ag (19–21). In the absence of an adjuvant, lupus erythematosus; TRIF, TIR-domain–containing adaptor protein inducing IFN-b; transfusion of mouse RBCs expressing human or model RBC Ags WT, wild type; YFP, yellow fluorescent protein. results in low-level alloimmune responses in some donor models and Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 no response in others. However, treatment of transfusion recipients www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700401 1042 IFN-a/b REGULATES RBC ALLOIMMUNIZATION with inflammatory pathogen-associated molecular patterns has been important regulator of antiviral immunity and autoimmune pa- shown to induce or enhance RBC alloimmune responses (22). thology. IFN-a/b includes a single IFN-b and 13 IFN-a proteins Cotransfusion with CpG DNA or pretreatment with polyinosinic- that signal through a ubiquitously expressed dimeric receptor, polycytidylic acid [poly(I:C)], a mimetic of viral dsRNA, was shown consisting of IFN-a and -b receptor 1 (IFNAR1) and IFNAR2. to induce alloimmunization to human glycophorin A expressed on Signal transduction results in the expression of numerous IFN- mouse RBCs (21, 23). In addition, poly(I:C) has been shown to en- stimulated genes that inhibit viral replication and dissemination hance the magnitude of alloimmune responses in all models studied (31). Studies have also demonstrated that IFNAR signaling can to date, including donor RBCs expressing hen egg lysozyme (HEL), promote