CCR5 Δ32, matrix metalloproteinase-9 and disease activity in multiple sclerosis

Abstract Chemokines and matrix metalloproteinases (MMPs) appear to be crucial in leukocyte recruitment to the central nervous system in multiple sclerosis (MS). CCR5 Δ32, a truncated allele of the CC chemokine receptor CCR5 gene encoding a non-functional receptor, did not confer protection from MS. CCR5 Δ32 was, however, associated with a lower risk of recurrent clinical disease activity. High CSF levels of MMP-9 activity were also associated with recurrent disease activity. These results directly link intrathecal inflammation to disease activity in patients with MS, suggesting that treatments targeting CCR5 or treatment with MMP inhibitors may attenuate disease activity in MS.

[1]  O. Olerup,et al.  HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. , 1992, Tissue antigens.

[2]  C. Mackay,et al.  The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. , 1998, The Journal of clinical investigation.

[3]  E. Reinherz,et al.  In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. , 1985, The New England journal of medicine.

[4]  C. Mackay,et al.  Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. , 1997, The American journal of pathology.

[5]  C. Poser.  Onset symptoms of multiple sclerosis. , 1995, Journal of neurology, neurosurgery, and psychiatry.

[6]  J. Olesen,et al.  Blood‐brain barrier impairment in acute optic neuritis evaluated by Gadolinium—DTPA enhanced MRI and CSF studies , 1996 .

[7]  J. Kurtzke.  Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[8]  K. Blennow,et al.  Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18-88 years of age. , 1993, European neurology.

[9]  A. A. Eisen,et al.  MRI in the diagnosis of MS , 1988, Neurology.

[10]  G. Ebers.  McAlpine's Multiple Sclerosis , 1998 .

[11]  Marc Parmentier,et al.  Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene , 1996, Nature.

[12]  Virginia Litwin,et al.  HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5 , 1996, Nature.

[13]  J. Newcombe,et al.  The Expression of Tissue‐type Plasminogen Activator, Matrix Metalloproteases and Endogenous Inhibitors in the Central Nervous System in Multiple Sclerosis: Comparison of Stages in Lesion Evolution , 1996, Journal of neuropathology and experimental neurology.

[14]  J. Olesen,et al.  Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS , 1998, Neurology.

[15]  M. Christiansen,et al.  Qualitative assessment of intrathecal IgG synthesis by isoelectric focusing and immunodetection: interlaboratory reproducibility and interobserver agreement. , 1996, Scandinavian journal of clinical and laboratory investigation.

[16]  T. Olsson,et al.  HLA-DR antigen expression on T cells from cerebrospinal fluid in multiple sclerosis and aseptic meningo-encephalitis. , 1987, Clinical and experimental immunology.

[17]  C. Mackay,et al.  Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes , 1998, The Journal of experimental medicine.

[18]  M. Cuzner,et al.  Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system , 1999, Journal of Neuroimmunology.

[19]  G. Opdenakker,et al.  Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders , 1992, Journal of Neuroimmunology.

[20]  C. Brosnan,et al.  The effects of macrophage depletion on the clinical and pathologic expression of experimental allergic encephalomyelitis. , 1981, Journal of immunology.

[21]  G. Bernardi,et al.  Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[22]  Jakob S. Jensen,et al.  Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. , 1999, The Journal of clinical investigation.

[23]  T. Sinkjaer,et al.  A new treatment of spasticity with repetitive magnetic stimulation in multiple sclerosis. , 1995, Journal of neurology, neurosurgery, and psychiatry.

[24]  Voon Wee Yong,et al.  Matrix metalloproteinases and diseases of the CNS , 1998, Trends in Neurosciences.

[25]  P. Goodfellow,et al.  HLA typing in the United Kingdom multiple sclerosis genome screen , 1998, Neurogenetics.

[26]  Steffen Jung,et al.  Macrophages in T cell line‐mediated, demyelinating, and chronic relapsing experimental autoimmune encephalomyelitis in Lewis rats , 1995, Clinical and experimental immunology.

[27]  M. Baggiolini,et al.  CCR5 is characteristic of Th1 lymphocytes , 1998, Nature.

[28]  C. Broder,et al.  CC CKR5: A RANTES, MIP-1α, MIP-1ॆ Receptor as a Fusion Cofactor for Macrophage-Tropic HIV-1 , 1996, Science.

[29]  G. Hansson,et al.  Adhesion molecule expression on cerebrospinal fluid T lymphocytes: Evidence for common recruitment mechanisms in multiple sclerosis, aseptic meningitis, and normal controls , 1993, Annals of neurology.

[30]  G. Stewart,et al.  The CCR5 deletion mutation fails to protect against multiple sclerosis. , 1997, Human immunology.

[31]  M. Daly,et al.  Genomewide scan of multiple sclerosis in Finnish multiplex families. , 1997, American journal of human genetics.

[32]  M. Esiri,et al.  The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. , 1997, Brain : a journal of neurology.

[33]  C. Mackay,et al.  The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Doerge,et al.  Genetic analysis of disease subtypes and sexual dimorphisms in mouse experimental allergic encephalomyelitis (EAE): relapsing/remitting and monophasic remitting/nonrelapsing EAE are immunogenetically distinct. , 1999, Journal of immunology.

[35]  Roland Martin,et al.  Inhibitors of dipeptidyl peptidase IV/CD26 suppress activation of human MBP-specific CD4+ T cell clones , 1998, Journal of Neuroimmunology.

[36]  J. Cossins,et al.  Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions , 1997, Acta Neuropathologica.

[37]  P. Eneroth,et al.  CSF neopterin as marker of disease activity in multiple sclerosis , 1987, Acta neurologica Scandinavica.

[38]  F. Sellebjerg,et al.  Costimulatory CD80 (B7-1) and CD86 (B7-2) on cerebrospinal fluid cells in multiple sclerosis , 1998, Journal of Neuroimmunology.

[39]  A. Iversen,et al.  Heterozygosity for a deletion in the CKR‐5 gene leads to prolonged AIDS‐free survival and slower CD4 T‐cell decline in a cohort of HIV‐seropositive individuals , 1997, AIDS.

[40]  M. Rodriguez,et al.  Indictment of the microglia as the villain in multiple sclerosis , 1997, Neurology.

[41]  G. Borm,et al.  Age-related changes of neuron-specific enolase, S-100 protein, and myelin basic protein concentrations in cerebrospinal fluid. , 1992, Clinical chemistry.

[42]  J. Uhm,et al.  Interferon β‐1b decreases the migration of T lymphocytes in vitro: Effects on matrix metalloproteinase‐9 , 1996 .

[43]  G. Opdenakker,et al.  Evaluation of gelatinases and IL-6 in the cerebrospinal fluid of patients with optic neuritis, multiple sclerosis and other inflammatory neurological diseases , 1994, Journal of Neuroimmunology.

[44]  R. Ransohoff,et al.  Etiology and pathogenesis of multiple sclerosis. , 1998, Seminars in neurology.

[45]  J. Newcombe,et al.  Expression of monocyte chemoattractant protein-1 and other β-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions , 1998, Journal of Neuroimmunology.

[46]  Richard A Koup,et al.  Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 Infection , 1996, Cell.

[47]  M. Baggiolini.  Chemokines and leukocyte traffic , 1998, Nature.

[48]  T. Olsson,et al.  Microsatellite polymorphisms in the gene promoter of monocyte chemotactic protein-3 and analysis of the association between monocyte chemotactic protein-3 alleles and multiple sclerosis development , 1999, Journal of Neuroimmunology.

[49]  R. Detels,et al.  Genetic susceptibility to multiple sclerosis , 1979, Neurology.

[50]  C. Kleeberger,et al.  CCR5 promoter polymorphism and HIV-1 disease progression , 1998, The Lancet.

[51]  S. Reingold,et al.  Defining the clinical course of multiple sclerosis , 1996, Neurology.

[52]  V. Perry,et al.  Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke , 1997, Neuropathology and applied neurobiology.

[53]  M. Christiansen,et al.  Cerebrospinal fluid measures of disease activity in patients with multiple sclerosis , 1998, Multiple sclerosis.

[54]  B. Uitdehaag,et al.  Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages , 1990, The Journal of experimental medicine.

[55]  Stephen C. Peiper,et al.  Identification of a major co-receptor for primary isolates of HIV-1 , 1996, Nature.

[56]  Nancy Sullivan,et al.  CCR5 Levels and Expression Pattern Correlate with Infectability by Macrophage-tropic HIV-1, In Vitro , 1997, The Journal of experimental medicine.

[57]  D. Silberberg,et al.  New diagnostic criteria for multiple sclerosis: Guidelines for research protocols , 1983, Annals of neurology.

[58]  J. Haines,et al.  A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex , 1996, Nature Genetics.

[59]  T. Springer.  Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[60]  L. Cosmi,et al.  Molecules associated with human Th1 or Th2 cells. , 1998, European cytokine network.

[61]  J J Goedert,et al.  Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene , 1996, Science.

[62]  H. Weiner,et al.  CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[63]  A. Luster,et al.  Chemokines--chemotactic cytokines that mediate inflammation. , 1998, The New England journal of medicine.

[64]  R. Ransohoff,et al.  Cutting Edge Commentary: Chemokine Regulation of Experimental Autoimmune Encephalomyelitis: Temporal and Spatial Expression Patterns Govern Disease Pathogenesis , 1998, The Journal of Immunology.

[65]  R. Holmdahl,et al.  Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats , 1998, Nature Genetics.

[66]  J. Olesen,et al.  A randomized, controlled trial of oral high-dose methylprednisolone in acute optic neuritis , 1999, Neurology.

[67]  R. Strieter,et al.  An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. , 1995, Journal of immunology.

[68]  E. Waubant,et al.  Interferon beta‐1b inhibits gelatinase secretion and in vitro migration of human T cells: A possible mechanism for treatment efficacy in multiple sclerosis , 1996, Annals of neurology.

[69]  R. Bravo,et al.  Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor. , 1998, Journal of immunology.

[70]  D. Hinds,et al.  A full genome search in multiple sclerosis , 1996, Nature Genetics.

[71]  C. Granger,et al.  Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis 1 Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827); the NINDS (NS26321); and Biogen Inc. 1 , 1999, Journal of Neuroimmunology.

[72]  W. Karpus,et al.  MIP‐1α and MCP‐1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphoctye differentiation , 1997, Journal of leukocyte biology.

[73]  P. Goodfellow,et al.  A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22 , 1996, Nature Genetics.

[74]  S. Kikuchi,et al.  Macrophage inflammatory protein-1 alpha in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases. , 1995, Journal of the neurological sciences.

[75]  L. Kappos,et al.  Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. , 1998, Brain : a journal of neurology.

[76]  P. Allavena,et al.  Differential Expression of Chemokine Receptors and Chemotactic Responsiveness of Type 1 T Helper Cells (Th1s) and Th2s , 1998, The Journal of experimental medicine.

[77]  D. Ledbetter,et al.  A YAC contig of the human CC chemokine genes clustered on chromosome 17q11.2. , 1996, Genomics.

[78]  H. Marquart,et al.  CC chemokine receptor 5 polymorphism in rheumatoid arthritis. , 1998, The Journal of rheumatology.