Multiple sclerosis: chemokine receptor expression on circulating lymphocytes in correlation with radiographic measures of tissue injury.
BACKGROUND
Leukocytes expressing inflammatory chemokine receptors (CKRs), most consistently CCR2, CCR5, and CXCR3, have been identified in multiple sclerosis (MS) tissue lesions and provide attractive therapeutic targets. Our previous studies found large inter-individual differences in expression of these CKRs but stable levels over time within subjects. This observation suggests a CKR "set-point" within individuals, which might relate to inflammatory injury in MS. We evaluated the correlation between CKR levels and magnetic resonance imaging (MRI) measures of disease activity.


METHODS
Fifty-five relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients were prospectively followed with annual CKR and MRI studies. Multiparameter flow cytometry was used to determine CCR2, CCR5, and CXCR3 expression on CD4 and CD8 cells. Simultaneous cranial MRIs were performed, and quantitative measures of T2, T1, and gadolinium lesions, brain parenchymal fraction (BPF), and whole brain and fractionated magnetization transfer ratio (MTR) were performed using automated software. Spearman's rank correlations evaluated the relationship between CKR levels and MRI measures.


RESULTS
Significant correlations were observed between CXCR3 expression on CD8 cells and measures of new (T1) and total (T1, T2) lesion volumes, lesion MTR, and BPF; higher levels of CXCR3 expression were correlated with greater injury on MRI (|r| = 0.27-0.42). In contrast, CD4 cell CKR expression was only minimally correlated with MRI measures.


CONCLUSIONS
Over 2 years, we observed significant correlations between the percent of CD8 cells expressing CXCR3 and MRI measures of MS inflammatory activity and tissue destruction. These observations are consistent with a pathogenic role for cytotoxic T cells in MS brain and have significant implications regarding T-cell targeted therapeutic strategies.
Fox
R J
RJ
Department of Neurology, Mellen Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. foxr@ccf.org
Kivisakk
P
P
Fisher
E
E
Tucky
B
B
Lee
J C
JC
Rudick
R A
RA
Ransohoff
R M
RM
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D008214:Lymphocytes; D008279:Magnetic Resonance Imaging; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D054390:Receptors, CCR2 / Q000502:physiology*; D054367:Receptors, CXCR3 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*
C515334:CCR2 protein, human; D054390:Receptors, CCR2; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine