title: Viral immune surveillance: Toward a TH17/TH9 gate to the central nervous system.
abstract: Viral cellular immune surveillance is a dynamic and fluid system that is driven by finely regulated cellular processes including cytokines and other factors locally in the microenvironment and systemically throughout the body. It is questionable as to what extent the central nervous system (CNS) is an immune-privileged organ protected by the blood-brain barrier (BBB). Recent evidence suggests converging pathways through which viral infection, and its associated immune surveillance processes, may alter the integrity of the blood-brain barrier, and lead to inflammation, swelling of the brain parenchyma and associated neurological syndromes. Here, we expand upon the recent "gateway theory", by which viral infection and other immune activation states may disrupt the specialized tight junctions of the BBB endothelium making it permeable to immune cells and factors. The model we outline here builds upon the proposition that this process may actually be initiated by cytokines of the IL-17 family, and recognizing the intimate balance between TH17 and TH9 cytokine profiles systemically. We argue that immune surveillance events, in response to viruses such as the Human Immunodeficiency Virus (HIV), cause a TH17/TH9 induced gateway through blood brain barrier, and thus lead to characteristic neuroimmune pathology. It is possible and even probable that the novel TH17/TH9 induced gateway, which we describe here, opens as a consequence of any state of immune activation and sustained chronic inflammation, whether associated with viral infection or any other cause of peripheral or central neuroinflammation. This view could lead to new, timely and critical patient-centered therapies for patients with neuroimmune pathologies across a variety of etiologies.
  
  
  BACKGROUND
  BBB - blood brain barrier, BDV - Borna disease virus, CARD - caspase activation and recruitment domains, CD - clusters of differentiation, CNS - central nervous system, DAMP - damage-associated molecular patterns, DENV - Dengue virus, EBOV - Ebola virus, ESCRT - endosomal sorting complex required for transport-I, HepC - Hepatitis C virus, HIV - human immunodeficiency virus, IFN - interferon, ILn - interleukin-n, IRF-n - interferon regulatory factor-n, MAVS - mitochondrial antiviral-signaling, MBGV - Marburg virus, M-CSF - macrophage colony-stimulating factor, MCP-1 - monocyte chemotactic protein 1 (aka CCL2), MHC - major histocompatibility complex, MIP-α β - macrophage inflammatory protein-1 α β (aka CCL3 & CCL4), MIF - macrophage migration inhibitory factor, NVE - Nipah virus encephalitis, NK - natural killer cell, NLR - NLR, NOD - like receptor, NOD - nucleotide oligomerization domain, PAMP - pathogen-associated molecular patterns, PtdIns - phosphoinositides, PV - Poliovirus, RIG-I - retinoic acid-inducible gene I, RIP - Receptor-interacting protein (RIP) kinase, RLR - RIG-I-like receptor, sICAM1 - soluble intracellular adhesion molecule 1, STAT-3 - signal tranducer and activator of transcription-3, sVCAM1 - soluble vascular cell adhesion molecule 1, TANK - TRAF family member-associated NF- . B activator, TBK1 - TANK-binding kinase 1, TLR - Toll-like receptor, TNF - tumor necrosis factor, TNFR - TNF receptor, TNFRSF21 - tumor necrosis factor receptor superfamily member 21, TRADD TNFR-SF1A - associated via death domain, TRAF TNFR - associated factor, Tregs - regulatory T cellsubpopulation (CD4/8+CD25+FoxP3+), VHF - viral hemorrhagic fever.
authors.affiliation: UCLA School of Dentistry Oral Biology & Medicine ; Evidence-Based Decision Practice-Based Research Network.
authors.forename: Andre
authors.initials: A
authors.lastname: Barkhordarian
authors.affiliation: UCLA David Geffen School of Medicine Psychiatry.
authors.forename: April D
authors.initials: AD
authors.lastname: Thames
authors.affiliation: UCLA School of Dentistry Oral Biology & Medicine.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Du
authors.affiliation: UCLA School of Dentistry Oral Biology & Medicine.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Jan
authors.affiliation: UCLA School of Dentistry Oral Biology & Medicine.
authors.forename: Melissa
authors.initials: M
authors.lastname: Nahcivan
authors.affiliation: UCLA School of Dentistry Oral Biology & Medicine.
authors.forename: Mia T
authors.initials: MT
authors.lastname: Nguyen
authors.affiliation: UCLA School of Dentistry Oral Biology & Medicine.
authors.forename: Nateli
authors.initials: N
authors.lastname: Sama
authors.affiliation: UCLA School of Dentistry Oral Biology & Medicine ; Evidence-Based Decision Practice-Based Research Network.
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiappelli
keywords: M1 & M2 macrophages; TH17; TH17/TH9 BBB gateway model; Tregs; blood-brain barrier; neuroinflammation; viral immune surveillance and evasion; “gateway theory”