CCR5Delta32 polymorphism effects on CCR5 expression, patterns of immunopathology and disease course in multiple sclerosis.
Four distinct patterns of tissue injury have been described in multiple sclerosis (MS) lesions. Infiltrating monocytes in lesions of all patterns co-express CCR1 and CCR5. However, in pattern II lesions, the number of CCR1 cells is decreased, while the number of CCR5 expressing cells is increased in late active versus early active regions. In contrast, CCR1 and CCR5 cells were equal in all regions of pattern III lesions. These suggest distinct inflammatory microenvironments in pattern II and III lesions and support MS pathological heterogeneity. A deletion in CCR5 (CCR5*Delta32), which encodes a truncated, non-functional protein, has been associated with late onset of MS and a favorable prognosis. We studied the association of CCR5*Delta32 with the course and severity of MS in 221 patients from a population-based cohort in Olmsted County, MN, and with patterns of immunopathology in 94 patients with biopsy-derived, pathologically confirmed demyelinating disease participating in the MS Lesion Project. The frequency of the genotypes in 221 patients from Olmsted County, MN, was 167 (75.6%) wild type, 52 (23.5%) heterozygotes, and 2 (0.9%) homozygotes. There was no association of carrier status for the CCR5*Delta32 mutation with disease severity as analyzed using the disease severity score (ranking of EDSS/duration stratified by duration), age of onset, gender or disease course (bout onset versus primary progressive). Due to low frequency of homozygotes no conclusion can be made regarding their relation to heterozygosity or wild-type status. The frequency of genotypes in the 94 biopsies was 77 (81.9%) wild type, 15 (16.0%) heterozygotes and 2 (2.1%) homozygotes. Carrier status for the CCR5*Delta32 mutation was not associated with patterns of immunopathology in MS. Despite similar numbers of T-lymphocytes, there were no CCR5+ T-cells nor was CCR5 expressed in the CNS of a homozygous CCR5*Delta32 MS patient, and heterozygous patients had reduced CCR5 expression compared to wild type patients. CCR5*Delta32 has a dose effect on CCR5 expression in the CNS, but is neither necessary for development of MS, nor CD3+ T cell recruitment into the CNS. Furthermore it does not segregate with patterns of immunopathology in MS. We did not find an association between CCR5*Delta32 mutation and disease severity and age of onset in MS.
Kantarci
Orhun H
OH
Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Morales
Yazmín
Y
Ziemer
Patricia A
PA
Hebrink
David D
DD
Mahad
Don J
DJ
Atkinson
Elizabeth J
EJ
Achenbach
Sara J
SJ
De Andrade
Mariza
M
Mack
Matthias
M
Ransohoff
Richard M
RM
Lassmann
Hans
H
Bruck
Wolfgang
W
Weinshenker
Brian G
BG
Lucchinetti
Claudia F
CF
D000328:Adult; D015152:Blotting, Northern / Q000379:methods; D002452:Cell Count; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000235:genetics*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013601:T-Lymphocytes / Q000502:physiology
D012333:RNA, Messenger; D019713:Receptors, CCR5