title: Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy.
abstract: Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease characterized by chronic inflammation in the spinal cord. We hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that patients with HAM/TSP have extraordinarily high levels of the chemokine CXCL10 (also known as IP-10) and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of patients with HAM/TSP. Co-culture of human astrocytoma cells with CD4+ T cells from patients with HAM/TSP revealed that astrocytes produce CXCL10 in response to IFN-γ secreted by CD4+ T cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system and that anti-CXCL10 neutralizing antibody can disrupt this migration. In short, we inferred that human T-lymphotropic virus type 1-infected cells in the central nervous system produce IFN-γ that induces astrocytes to secrete CXCL10, which recruits more infected cells to the area via CXCR3, constituting a T helper type 1-centric positive feedback loop that results in chronic inflammation.
authors.affiliation: Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Tomoo
authors.initials: T
authors.lastname: Sato
authors.forename: Utano
authors.initials: U
authors.lastname: Tomaru
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Natsumi
authors.initials: N
authors.lastname: Araya
authors.forename: Naoko
authors.initials: N
authors.lastname: Yagishita
authors.forename: Ariella
authors.initials: A
authors.lastname: Coler-Reilly
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yudoh
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Steven
authors.initials: S
authors.lastname: Jacobson
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015490:HTLV-I Infections / Q000134:cerebrospinal fluid / Q000150:complications*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000209:etiology* / Q000473:pathology*; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic / Q000150:complications / Q000209:etiology / Q000821:virology; D013997:Time Factors
chemical_list: D000906:Antibodies; D018925:Chemokines; D005904:Glial Fibrillary Acidic Protein
keywords: CXCL10; CXCR3; HAM/TSP; HTLV-1; astrocyte