The CCR5 Deletion Mutation Fails to Protect Against Multiple Sclerosis

Bennetts, Bruce; Teutsch, Suzy; Buhler, Marc M; Heard, Robert; Stewart, Graeme J.

doi:10.1016/s0198-8859(97)00207-3

Cited by 101 publications

(58 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although coexpression of chemokine receptors was not addressed in the current studies, such double-positive cells could constitute no more than a minority of the infiltrating population. The relatively modest enrichment of CCR5-positive cells in MS CSF is therefore consistent with the recent observation that individuals homozygous for nonfunctional mutant forms of CCR5 remain susceptible to MS (73). Given elevated levels of IP-10 and Mig in MS CSF, it was of interest to determine whether cells bearing cognate receptors accumulated in the CSF.…”

supporting

confidence: 73%

Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

Sørensen¹,

Tani²,

Jensen³

et al. 1999

J. Clin. Invest.

944

750

View full text Add to dashboard Cite

Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-γ-inducible protein of 10 kDa (IP-10); monokine induced by interferon-γ (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

show abstract

supporting

confidence: 73%

Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

Sørensen¹,

Tani²,

Jensen³

et al. 1999

J. Clin. Invest.

944

750

View full text Add to dashboard Cite

show abstract

“…39 In contrast to these two studies, another report failed to demonstrate any difference. 40 Although these reports have demonstrated later age at onset and increased disease intervals in CCR5 ⌬32 mutants compared to wild-type alleles, these observations were not on postmortem samples and did not predict for overall survival. On the basis of the suggested links between cytokines and MS, and for the reasons given earlier, we sought to examine the possible association between CCR5 and MS.…”

Section: Discussionmentioning

confidence: 89%

Association of CCR5 Δ32 deletion with early death in multiple sclerosis

Gade-Andavolu

Comings

MacMurray

et al. 2004

Genetics in Medicine

View full text Add to dashboard Cite

Purpose: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 ⌬32 deletion in this disorder. Methods: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 ⌬32 deletion allele. Results: An increased frequency of 32-bp deletion allele was found to be associated with early death (P ϭ 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58). Conclusion: A strong association of the CCR5⌬32 deletion with early death could serve as a prognostic marker for MS. Genet Med 2004:6(3):126 -131. Key Words: multiple sclerosis, polymerase chain reaction, chemokine receptor, experimental autoimmune encephalomyelitisMultiple sclerosis (MS) is a chronic demyelinating disorder pathologically characterized by an infiltration of monocytes and T-lymphocytes into the brain parenchyma, destruction of oligodendrocytes, and the loss of myelin. The role of chemokines and chemokine receptors is particularly important in MS, where myelin-destructive inflammation occurs inside the blood-brain barrier and is related to the influx of peripheral proinflammatory T cells into the CNS. Chemokines play a significant role in the migration of monocytes and T cells and also have been implicated in the onset or progression of MS and experimental autoimmune encephalomyelitis (EAE). 1,2 CCR5, a seven transmembrane spanning G protein-coupled receptor, is a specific binding site for the CC-chemokines and is expressed on T-helper cells. Several studies have ascribed to CCR5 surface expression levels an important role in HIV-1 entry and pathogenesis, 3 and a CCR5 ⌬32 mutation (homozygous deletion) almost invariably protects from HIV-1 infection. 4,5 The heterozygotes demonstrate a delay in progression of the disease 6 -8 lower viral loads and higher CD4 ϩ counts. 9Aberrant production of chemokines has been described in humans and experimental CNS demyelinating lesions. 10,11 ␤-Chemokine receptors were examined in postmortem MS CNS tissue by immunohistochemistry, and an elevated expression of CCR2, CCR3, and CCR5 was noted. 12-14 HHV6 virus was additionally found in the human brain specimens and a possible association with MS was suggested. [15][16][17] Chemokine receptor expression studies showed CCR5 and CXCR3 to have annualized increase in T2 lesion loads, suggesting these chemokines play an important role in the development of new lesions in MS than in the long-te...

show abstract

“…A 32-basepair deletion in the coding region of CCR5 (CCR5 d32) abolishes CCR5 function and may impair entry of inflammatory cells into MS lesions. However, several studies did not find an association between CCR5 d32 and MS susceptibility (Bennetts et al, 1997;Chataway et al, 1999;Barcellos et al, 2000;Sellebjerg et al, 2000). A German case-control study of 201 RR/SPMS and 42 PPMS patients did not find an association of the CCR5 d32 with disease course (Haase et al, 2002).…”

Section: Chemokine (C-c Motif ) Receptor 5 (Ccr5)mentioning

confidence: 99%

Genetics of primary progressive multiple sclerosis

Cree

2014

Handbook of Clinical Neurology

View full text Add to dashboard Cite

The CCR5 Deletion Mutation Fails to Protect Against Multiple Sclerosis

Cited by 101 publications

References 31 publications

Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

Association of CCR5 Δ32 deletion with early death in multiple sclerosis

Genetics of primary progressive multiple sclerosis

Contact Info

Product

Resources

About