title: CNS-targeted autoimmunity leads to increased influenza mortality in mice.
abstract: The discovery that central nervous system (CNS)-targeted autoreactive T cells required a process of licensing in the lung revealed an unexpected relationship between these organs. The clinical and immunological significance of this finding is bidirectional in that it showed not only a mechanism by which T cells become pathogenic before entering the CNS, but also the potential for this process to influence lung immunity as well. Epidemiological studies have shown that people with multiple sclerosis (MS) suffer from increased morbidity and mortality from infectious diseases, independent of immunosuppressive therapies. Respiratory infections account for a large percentage of deaths of people with MS. In this study, to investigate the mechanisms responsible for this enhanced susceptibility, we established a comorbid model system in which mice with experimental autoimmune encephalomyelitis (EAE) were administered a sublethal dose of influenza. Whereas mice with either EAE alone or influenza alone survived, 70% of comorbid mice died as a result of uncontrolled viral replication. Immunological analyses revealed that the induction of EAE led to a surprising alteration of the lung milieu, converting an effective stimulatory influenza-reactive environment into a suppressive one. These results provide mechanistic information that may help to explain the unexpected immunological interactions.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Glenn
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Matthew D
authors.identifier: 0000-0001-6614-569X
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Pei
authors.initials: P
authors.lastname: Xue
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Yee
authors.identifier: 0000-0002-5357-8776
authors.initials: Y
authors.lastname: Chan-Li
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Samuel
authors.identifier: 0000-0003-1340-8796
authors.initials: S
authors.lastname: Collins
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Peter A
authors.identifier: 0000-0002-7776-6472
authors.initials: PA
authors.lastname: Calabresi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Maureen R
authors.initials: MR
authors.lastname: Horton
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 whartenby@jhmi.edu.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Katharine A
authors.identifier: 0000-0001-6077-7899
authors.initials: KA
authors.lastname: Whartenby
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001921:Brain / Q000276:immunology*; D002465:Cell Movement; D015897:Comorbidity; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000401:mortality; D005260:Female; D008168:Lung / Q000821:virology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D009976:Orthomyxoviridae Infections / Q000401:mortality*; D014779:Virus Replication
chemical_list: D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse