CCL5 and CCR5 genotypes modify clinical, radiological and pathological features of multiple sclerosis.
Chemokines mediate selective recruitment of leukocyte subsets into the CNS during inflammatory episodes. We hypothesised that functional polymorphisms in CCR5 and CCL5 influence perivascular leukocyte infiltration, inflammation, axonal loss, and remyelination, and disease course. Therefore, we determined genotypes at four possibly functional polymorphisms in CCR5 and CCL5 for 637 patients and 92 brain donors with multiple sclerosis (MS). For a subset of 192 patients, MRI data were available. We found that low-producer allele CCL5-403*G was associated with reduced risk of severe axonal loss, whereas high-producer allele CCL5-403*A was associated with a worse clinical disease course measured by the MS Functional Composite Score and MS Severity Score. Low-producer allele CCR5+303*G was associated with reduced T2 hyperintense and T1 hypointense lesion volumes on MRI, and high-producer allele CCR5+303*A with early age at onset. Furthermore, low-producer allele CCR5Delta32 was associated with reduced T2 lesion volume, lower black hole ratio on MRI, and with a higher percentage of lesions with signs of remyelination, histopathologically. In summary, our multifaceted study supports the notion that polymorphisms in CCL5 and CCR5 modify the course of MS.
van Veen
Tineke
T
Department of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, The Netherlands.
Nielsen
Jessica
J
Berkhof
Johannes
J
Barkhof
Frederik
F
Kamphorst
Wouter
W
Bö
Lars
L
Ravid
Rivka
R
Verweij
Cor L
CL
Huitinga
Inge
I
Polman
Chris H
CH
Uitdehaag
Bernard M J
BM
D000328:Adult; D000368:Aged; D002490:Central Nervous System / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D018946:Chemokine CCL5 / Q000235:genetics* / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D009186:Myelin Sheath / Q000276:immunology / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D011859:Radiography; D019713:Receptors, CCR5 / Q000235:genetics* / Q000276:immunology; D012680:Sensitivity and Specificity; D014855:Wallerian Degeneration / Q000235:genetics / Q000276:immunology / Q000503:physiopathology
C483024:CCL5 protein, human; D018946:Chemokine CCL5; D005819:Genetic Markers; D019713:Receptors, CCR5