Genetic susceptibility to multiple sclerosis in Sardinians: an immunological study
Corresponding Author
S. Sotgiu
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Dr Stefano Sotgiu, Istituto di Clinica Neurologica, Universita di Sassari, Viale San Pietro, 10, 07100 -Sassari, ItalySearch for more papers by this authorC. Serra
Institute of Child Neuropsychiatry, University of Cagliari, via Ospedale, Cagliari, Italy
Search for more papers by this authorM. G. Marrosu
Laboratory of Virology, Department of Biomedical Sciences, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorA. Dolei
Institute of Child Neuropsychiatry, University of Cagliari, via Ospedale, Cagliari, Italy
Search for more papers by this authorM. Pugliatti
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorB. Murgia
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorI. Aiello
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorG. Rosati
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorCorresponding Author
S. Sotgiu
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Dr Stefano Sotgiu, Istituto di Clinica Neurologica, Universita di Sassari, Viale San Pietro, 10, 07100 -Sassari, ItalySearch for more papers by this authorC. Serra
Institute of Child Neuropsychiatry, University of Cagliari, via Ospedale, Cagliari, Italy
Search for more papers by this authorM. G. Marrosu
Laboratory of Virology, Department of Biomedical Sciences, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorA. Dolei
Institute of Child Neuropsychiatry, University of Cagliari, via Ospedale, Cagliari, Italy
Search for more papers by this authorM. Pugliatti
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorB. Murgia
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorI. Aiello
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorG. Rosati
institute of Clinical Neurology, University of Sassari, Viale San Pietro, Sassari, Italy
Search for more papers by this authorAbstract
Objectives - We studied the in vitro production of variably MS-related cytokines from Sardinian MS and healthy donors bearing the two “Sardinian” MS-associated HLA-DR alleles: DR3 and DR4, with the purpose to evidentiate possible differences in their immune response. Materials and methods - ELISA were used for detection of cellular products by mitogen-activated peripheral blood mononuclear cells. Results - PHA-activated HLA-DR4+/DR3- mononuclear cells produce significantly higher amounts of TNF-α compared with the DR3 +/DR4-, In addition, homozygous HLA-DR3+ mononuclear cells from MS patients produce significantly lower amounts of IL-10 than those from homozygous HLA-DR3+ healthy donors. Conclusion - The abnormal production of detrimental or regulatory cytokines may account for the genetic susceptibility to MS in different HLA-subgroups of Sardinian MS patients.
References
- 1 SEBOUN E, OKSENBERG JR, HAUSER LH. Molecular and genetic aspects of multiple sclerosis In: RN ROSENBERG, et al., eds. The Molecular and Genetic Basis of Neurological Disease (2nd edition). USA : Butterworth-Heinemann, 1997: 631–60.
- 2 MARROSU MG, MURRU MR, COSTA G et al. Multiple sclerosis in Sardinia is associated and in linkage-disequilibrium with HLA-DR3 and -DR4 alleles. Am J Hum Gen 1997: 61: 454–7.
- 3 CAVALU-SFORZA LL, PIAZZA A, MENOZZI P, MOUNTAIN J. Reconstruction of human evolution: bringing together genetic, archaeological, and linguistic data. Proc Natl Acad Sci USA 1988: 85: 6002–6.
- 4 WUCHERPFENNIG KW, STROMINGER JL. Molecular mimicry in T-cell mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995: 80: 695–705.
- 5 ZIPP F, WEBER F, HUBER S et al. Genetic control of multiple sclerosis. Increased production of lymphotoxin and TNF-alpha by antigen-specific T cell lines from HLA-DR2 positive individuals. Ann Neurol 1995: 38: 723–30.
- 6 HOHLFELD R. Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 1997: 120: 865–916.
- 7 WEINSHENKER BG, WINGERCLUK DM, Liu Q, BISSONET AS, SCHAID DJ, SOMMER SS. Genetic variation in the tumor necrosis factor alpha gene and the outcome of multiple sclerosis. Neurology 1997: 49: 378–84.
- 8 POCIOT F, BRIANT L, JONGENEEL CV et al. Association of tumor necrosis factor and class II major histocompatibility complex alleles with secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 1993: 23: 224–31.
- 9 GARCIA-MERINO A, ALPER CA, USUKU K et al. Tumor necrosis factor microsatellite haplotypes in relation to extended haplotypes, susceptibility to the diseases associated with the major histocompatibility complex, and TNF secretion. Hum Immunol 1991: 50: 11–21.
- 10 KIRK CW, DROOGAN AG, HAWKINS SA, MCMILLAN SA, NEVIN NC, GRAHAM CA. Tumor necrosis factor micro-satellites show association with multiple sclerosis. J Neurol Sci 1997: 147: 21–5.
- 11 VANDENBROECK K, MARTINO G, MARROSU MG et al. Occurrence and clinical relevance of an interleukin-4 gene polymorphism in patients with multiple sclerosis. J Neuroimmunol 1997: 76: 189–92.
- 12 POSER CM, PATY DW, SCHEINBERG L et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983: 13: 227–31.
- 13 HOHLFELD R, MEINL E, WEBER F et al. The role of autoimmune T lymphocytes in the pathogenesis of multiple sclerosis. Neurology 1995: 45(Suppl. 6): S33–S38.
- 14 WILSON AG, SYMONS J A, MCDOWELL TL, MCDEVITT HO, DUFF GW. Effects of a polymorphism in the human tumor necrosis factor a promoter on transcriptional activation. Proc Natl Acad Sci USA 1997: 94: 3195–9.
- 15 WINGERCHUK D, LIU Q, SOBELL J, SOMMER S, WEINSHENKER BG. A population based case-control study of the tumor necrosis factor alpha -308 polymorphism in multiple sclerosis. Neurology 1997: 49: 626–8.
- 16 MARROSU MG. Special populations - What they tell us about multiple sclerosis. In: MS Forum Modern Management Workshop, Boston , October 1995: 29–32.
- 17 RUDICK RA, RANSOHOFF RM, PEPPLER R, VANDERBRUG MEDENDORP S, LEHMANN P, ALAM J. Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis. Ann Neurol 1996: 40: 618–27.
- 18 SALMAGGI A, DUFOUR A, EOLI M et al. Low serum interleukin-10 levels in multiple sclerosis: further evidence for decreased systemic immunosuppression. J Neurol 1996: 243: 13–17.
- 19 GALLO P, PICCINNO MG, TAVOLATO B, SIDEN A. A longitudinal study on IL-2, sIL-2R, IL-4 and IFN-gamma in multiple sclerosis CSF and serum. J Neurol Sci 1991: 101: 227–32.
- 20 ROSATI G, AIELLO I, PIRASTRU MI et al. Epidemiology of multiple sclerosis in Northwestern Sardinia: Further evidence for a higher frequency in Sardinians compared to other Italians. Neuroepidemiology 1996: 15: 10–19.
