Premium
A destructive feedback loop mediated by CXCL 10 in central nervous system inflammatory disease
Author(s) -
Roberts Wendy K.,
Blachère Nathalie E.,
Frank Mayu O.,
Dousmanis Athanasios,
Ransohoff Richard M.,
Darnell Robert B.
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24494
Subject(s) - cxcl10 , cxcr3 , immunology , chemokine , antigen , medicine , antigen presenting cell , t cell , biology , immune system , chemokine receptor
Objective Paraneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high‐titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients. Methods CSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow‐up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen. Results Here we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3 + cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen‐specific cognate interactions between T cells and antigen‐presenting cells (APCs) when interferon‐γ (IFNγ) receptors were present on the T cell. Interpretation These results support a model in which antigen‐specific T cell stimulation by PND APCs triggers IFNγ, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation. Ann Neurol 2015;78:619–629