Imaging correlates of leukocyte accumulation and CXCR4/CXCL12 in multiple sclerosis.
OBJECTIVE
To compare leukocyte accumulation and expression of the chemokine receptor/ligand pair CXCR4/CXCL12 in magnetic resonance imaging-defined regions of interest (ROIs) in brains from patients with chronic multiple sclerosis. We studied the following ROIs: normal-appearing white matter (NAWM); regions abnormal only on T2-weighted images (T2 only); and regions abnormal on T2- and T1-weighted images with an abnormal magnetization transfer ratio (T2/T1/MTR).


METHODS
Case-control study.


METHODS
Cleveland Clinic.


METHODS
Brain tissue was acquired from 5 patients with secondary progressive multiple sclerosis (MS) and 5 nonneurological controls.


METHODS
Magnetic resonance imaging pathological correlations were performed on the 5 cases. Based on imaging characteristics, 30 ROIs were excised.


METHODS
Using immunohistochemical analysis, we evaluated myelin status, leukocyte accumulation, and CXCR4/CXCL12 expression in the MS ROIs and white matter regions from the 5 nonneurological controls.


RESULTS
Eight of 10 T2/T1/MTR regions were chronic active or chronic inactive demyelinated lesions, whereas only 2 of 10 T2-only regions were demyelinated and characterized as active or chronic active lesions. Equivalent numbers of CD68+ leukocytes (the predominant cell type) were present in myelinated T2-only regions as compared with NAWM. Parenchymal T cells were significantly increased in T2/T1/MTR ROIs as compared with T2-only regions and NAWM. Expression of CXCR4 and phospho-CXCR4 were found on reactive microglia and macrophages in T2-only and T2/T1/MTR lesions. CXCL12 immunoreactivity was detected in astrocytes, astrocytic processes, and vascular elements in inflamed MS lesions.


CONCLUSIONS
Inflammatory leukocyte accumulation was not increased in myelinated MS ROIs with abnormal T2 signal as compared with NAWM. Robust expression of CXCR4/CXCL12 on inflammatory elements in MS lesions highlights a role of this chemokine/receptor pair in central nervous system inflammation.
Moll
Natalia M
NM
Neuroinflammation Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Cossoy
Michael B
MB
Fisher
Elizabeth
E
Staugaitis
Susan M
SM
Tucky
Barbara H
BH
Rietsch
Anna M
AM
Chang
Ansi
A
Fox
Robert J
RJ
Trapp
Bruce D
BD
Ransohoff
Richard M
RM
D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D015415:Biomarkers; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D054377:Chemokine CXCL12 / Q000032:analysis / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000276:immunology / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000276:immunology / Q000473:pathology; D011237:Predictive Value of Tests; D019718:Receptors, CXCR4 / Q000032:analysis / Q000276:immunology*
D015415:Biomarkers; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4