Optic neuritis: chemokine receptor CXCR3 and its ligands

Abstract

Aim: To study the involvement of the chemokine receptor CXCR3 and its ligands (CXCL9/Mig, CXCL10/IP-10, CXCL11/ITAC) in optic neuritis (ON). Methods: 30 patients with ON and 10 non-inflammatory neurological disease controls were included. The patients underwent a phlebotomy, lumbar puncture, and MRI scan. CXCR3 expression was studied on blood and cerebrospinal fluid (CSF) T cells by flow cytometry. CXCL9, CXCL10, and CXCL11 were measured in plasma and CSF by ELISA. Results: CSF concentrations of CXCL10, but not of CXCL9 and CXCL11, were significantly higher in ON patients than in controls. CSF concentrations of CXCL10 correlated with the CSF leucocyte count in ON patients, and CXCR3 expressing cells were significantly enriched in the CSF. Conclusion: These data show that the CSF concentration of the CXCR3 ligand CXCL10 is selectively increased in CSF from ON patients, and CXCR3 positive cells are recruited to the subarachnoid space. O ptic neuritis (ON), frequently encountered by ophthalmologists, often represents the onset of multiple sclerosis (MS).1 MS is an inflammatory disease of the central nervous system (CNS).2 The characteristics of the inflammatory lesion in the CNS are demyelination and axonal pathology with cellular infiltration characterised by the presence of phagocytic macrophages, T cells, and B cells. The inflammatory cell recruitment from the vascular bed to the perivascular space, and from here on to the CNS parenchyma, is the result of a multistep process, which is orchestrated in part by chemokines 3 4 ; in other words, chemokines direct tissue invasion of specific inflammatory cells. The chemokine family is ever growing-now with more than 40 members. However, we and others have shown that the chemokine CXCL10 (also known as interferon inducible protein (IP)-10) and its receptor CXCR3 could be key players in the immunopathogenesis of MS, even though other receptor/ligand systems may also be of significance. [5][6][7][8][9][10] CXCL10 is produced by astrocytes in the CNS during active inflammation and will attract CXCR3 expression cells into the site of inflammation.5 6 Since CXCR3 is expressed on activated Th1 CD4+ and CD8+ T cells (and on B cells), the inflammatory composite around the CXCL10 producing astrocytes will be dominated by these cell types.We have shown that CXCR3 expressing T cells and B cells are enriched in the cerebrospinal fluid (CSF) during acute relapses of MS, 11 and in histopathology material CXCR3 + T cells in were primarily localised around CXCL10 positive astrocytes. The localised production of CXCL10 results in elevated CSF levels in patients compared to controls, and the CXCL10 levels correlate with the CSF leucocyte count. These findings provide strong cumulative evidence supporting a pivotal role for CXCR3 and its ligand CXCL10 in T cell recruitment to the brain in MS and, hence, that blocking this recruitment system might limit CNS inflammation in MS.However, because most of the available data were obtained in established MS, and since the importance of commen...

Therapeutic targeting of chemokine signaling in Multiple Sclerosis

“…Additionally, the expression of CXCR3 on peripheral CD4-positive T cells has been reported to correlate with MRI in patients with MS [31]. However, no relation between CXCR3 expression and MRI activity was found in another study [81]. In the CSF of patients with MS, levels of CXCL10 [29,82] and CXCL9 [29] are significantly incremented, and correlate with MRI activity.…”

“…In the CSF of patients with MS, levels of CXCL10 [29,82] and CXCL9 [29] are significantly incremented, and correlate with MRI activity. Interestingly, in optic neuritis, CXCR3 expression in the CSF correlated with the increased expression of its ligand CXCL10 and with the presence of oligoclonal bands in CNS, which usually is indicative of MS [81].…”

Early prognosis of multiple sclerosis

“…They also found significantly negative correlations for both CD25 and CD4 regulatory T cells in the CSF with disease activity (Jensen et al, 2004). Sorensen et al (2004) have demonstrated a selective increase in CXCL10 (IP-10), a ligand for the chemokine receptor CXCR3, in the CSF of patients presenting with isolated ON. Sellebjerg et al (2000) found that CIS patients had a greater number of cells in the CSF-secreting antibodies against myelin basic protein and phospholipid protein than controls and that such secretion was associated with disease activity.…”

New directions in optic neuritis and multiple sclerosis

“…This finding was correlated with increased oligoclonal bands in the CSF. Therefore, they suggest a role for therapy that would block CXCR3 [25]. Finally, a study of four patients from Denver demonstrated the clonal expansion of B cells and plasma cells in association with an antigen-targeted response in their cerebrospinal fluid [26].…”