Br J Ophthalmol 88(9): 1146-1148

Optic neuritis: chemokine receptor CXCR3 and its ligands

The MS Clinic, Department of Neurology, University of Copenhagen, Glostrup Hospital, 2600 Glostrup, Denmark

Correspondence to:
T L Sørensen
Department of Ophthalmology, University of Copenhagen, Herlev Hospital, 2720 Herlev, Denmark; kd.tenldad@slnebrot

Accepted 2004 Feb 29.

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.

Keywords: multiple sclerosis, optic neuritis, chemokines, chemokine receptors, CXCR3, CXCL10

Abstract

Optic 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.^5–¹⁰ 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.^6,⁷ 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 commencing therapy very early in the disease course is increasingly recognised, we initiated a prospective study of patients with ON in order to investigate whether the CXCR3/CXCL10 axis has a similar role in patients presenting with a clinically isolated syndrome suggestive of MS. Since the CXCR3 receptor also has two other ligands (CXCL9, also known as Mig; and CXCL11, also known as ITAC), which have not been studied in this group of patients, we included CXCL9 and CXCL11 in our analysis. We correlated our data with measures related to the risk of developing MS (T2 weighted MRI lesions and IgG oligoclonal bands in CSF) or reflecting disease activity (CSF pleocytosis and number of gadolinium (Gd) enhancing lesions on MRI). We find that CXCL10 levels are elevated in the CSF of ON patients, and that CXCR3 expressing cells in the CSF correlate with the presence of oligoclonal bands in the CSF. This could suggest that CXCR3 blocking agents could be beneficial for all patients with ON.

Abbreviations

CNS, central nervous system
CSF, cerebrospinal fluid
MRI, magnetic resonance mage
MS, multiple sclerosis
ON, optic neuritis
PBMC, peripheral blood mononuclear cells

Abbreviations

REFERENCES

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