TY - JOUR
T1 - CCR5Δ32 polymorphism effects on CCR5 expression, patterns of immunopathology and disease course in multiple sclerosis
AU - Kantarci, Orhun H.
AU - Morales, Yazmín
AU - Ziemer, Patricia A.
AU - Hebrink, David D.
AU - Mahad, Don J.
AU - Atkinson, Elizabeth J.
AU - Achenbach, Sara J.
AU - De Andrade, Mariza
AU - Mack, Matthias
AU - Ransohoff, Richard M.
AU - Lassmann, Hans
AU - Bruck, Wolfgang
AU - Weinshenker, Brian G.
AU - Lucchinetti, Claudia F.
N1 - Funding Information:
This study has been supported by National Multiple Sclerosis Society grants to Dr. Weinshenker (NMSS RG2870-B-5) and Dr. Lucchinetti (NMSS RG 3185-A-2), and by M01 RR00585, General Clinical Research Centers Program, and National Institute of Health grant to Dr. Ransohoff (NIH: PO1 NS 38667).
PY - 2005/12
Y1 - 2005/12
N2 - 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*Δ32), 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*Δ32 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*Δ32 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*Δ32 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*Δ32 MS patient, and heterozygous patients had reduced CCR5 expression compared to wild type patients. CCR5*Δ32 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*Δ32 mutation and disease severity and age of onset in MS.
AB - 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*Δ32), 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*Δ32 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*Δ32 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*Δ32 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*Δ32 MS patient, and heterozygous patients had reduced CCR5 expression compared to wild type patients. CCR5*Δ32 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*Δ32 mutation and disease severity and age of onset in MS.
KW - CCR5 expression
KW - CCR5Δ32 polymorphism
KW - Immunopathology
KW - Multiple sclerosis
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U2 - 10.1016/j.jneuroim.2005.07.025
DO - 10.1016/j.jneuroim.2005.07.025
M3 - Article
C2 - 16182378
AN - SCOPUS:27344458516
SN - 0165-5728
VL - 169
SP - 137
EP - 143
JO - Advances in Neuroimmunology
JF - Advances in Neuroimmunology
IS - 1-2
ER -