Immunogenetics of multiple sclerosis and optic neuritis: DNA polymorphism of HLA class II genes

Morling, Niels; Sandberg‐Wollheim, Magnhild; Fugger, Lars; Georgsen, Jørgen; Hylding-Nielsen, Jens J.; Madsen, Hans O.; Rieneck, Klaus; Ryder, Lars P.; Svejgaard, A.

doi:10.1007/bf00179795

Cited by 6 publications

(2 citation statements)

References 28 publications

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“…More recent studies have characterized HLA class I1 genes among CNMS patients using restriction fragment length polymorphism (RFLP) or polymerase chain reaction and sequence-specific oligonucleotides (PCR-SSO). These studies show that the DR15, DQ6, Dw2 haplotype is strongly associated with the disease (8,9), thus confirming the original findings from 1973, where a different technique for typing HLA class I1 antigens was used (10).…”

Section: Introductionsupporting

confidence: 81%

Multiple sclerosis in the Faroe Islands VI. Studies of HLA markers

Jersild

Riisom

et al. 1993

Tissue Antigens

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Occurrence of clinical neurologic multiple sclerosis (CNMS) among resident Faroese began between 1943 and 1973 and comprised three epidemics. The occupation by British forces for 5 years during World War II was interpreted to have been of major importance for the Occurrence of these epidemics and led us to believe that CNMS is the rare, late result of a single, widespread, systemic and specific infectious disease which we have labelled the primary MS affection (PMSA). In this study we describe the occurrence of genetic markers of the HLA system in 16 Faroese MS patients, 25 of their siblings, 30 unrelated healthy neighbors and spouses to MS patients, 18 healthy controls from areas where no MS cases have been detected, and 80 unrelated normal Faroese. These studies show no significant deviations of HLA class I antigens, whereas the class II antigens do deviate: 50% of the Faroese MS patients carry the HLA‐DR2 (DQ1/DRB 15) antigen, compared to a frequency of 15–20% among the control groups. Also the group of siblings of MS patients showed an increased frequency of DR4 (72%) compared to normal frequency among MS patients and other normal controls (43–47%). However, if DR15‐positive individuals were excluded, this difference was further reduced. If PMSA was widespread within this group, DR4 or some closely associated genetic marker may confer protection against PMSA developing into CNMS. The occurrence of CNMS in these epidemics seems therefore associated to HLA class II‐linked genetic factors similar to those found in studies of other caucasians with MS. This observation seems important in understanding the pathogenesis of this disease.

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Section: Introductionsupporting

confidence: 81%

Multiple sclerosis in the Faroe Islands VI. Studies of HLA markers

Jersild

Riisom

et al. 1993

Tissue Antigens

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“…The concordance rate of the identical twins can be as high as 30% (1)(2)(3). The HLA loci is perhaps the most important genetic element for MS susceptibility, because the HLA-DR2 allele has been identified as the most important susceptibility gene among Caucasians (4)(5)(6)(7)(8)(9)(10). Several additional loci have also been proposed (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

CD24 is a genetic modifier for risk and progression of multiple sclerosis

Zhou

Rammohan

Lin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

102

111

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Multiple sclerosis (MS) is a chronic neurological disease of unknown etiology, but a genetic basis for the disease is undisputed. We have reported that CD24 is required for the pathogenicity of autoreactive T cells in experimental autoimmune encephalomyelitis, the mouse model of MS. Here we investigate the contribution of CD24 to MS by studying single-nucleotide polymorphism in the ORF among 242 MS patients and 207 population controls. This single-nucleotide polymorphism results in replacement of alanine (CD24 a ) with valine (CD24 v ) in the mature protein. We found that the CD24 v/v renders a >2-fold increase in the relative risk of MS in the general population (P ‫؍‬ 0.023). Among familial MS, the CD24 v allele is preferentially transmitted into affected individuals (P ‫؍‬ 0.017). Furthermore, 50% of CD24 v/v patients with expanded disability status scale 6.0 reached the milestone in 5 years, whereas the CD24 a/v (P ‫؍‬ 0.00037) and CD24 a/a (P ‫؍‬ 0.0016) patients did so in 16 and 13 years, respectively. Moreover, our data suggest that the CD24 v/v patients expressed higher levels of CD24 on peripheral blood T cells than did the CD24 a/a patients. Transfection with CD24 a and CD24 v cDNA demonstrated that the CD24 v allele can be expressed at higher efficiency than the CD24 a alleles. Thus, CD24 polymorphism is a genetic modifier for susceptibility and progression of MS in the central Ohio cohort that we studied, perhaps by affecting the efficiency of CD24 expression on the cell surface.single-nucleotide polymorphism ͉ disease susceptibility ͉ autoimmunity ͉ costimulatory molecules ͉ T lymphocytes M ultiple sclerosis (MS) is a chronic disorder in the CNS that affects Ϸ0.1% of Caucasians of northern European origin (1). The incidence of MS is increased among family members of affected individuals. The concordance rate of the identical twins can be as high as 30% (1-3). The HLA loci is perhaps the most important genetic element for MS susceptibility, because the HLA-DR2 allele has been identified as the most important susceptibility gene among Caucasians (4-10). Several additional loci have also been proposed (8-12).One of the whole-genome scans suggested a linkage disequilibrium in distal 6q (8) whose identity has not been revealed. An interesting candidate in the region is CD24 (13), which we showed to be essential for the induction of experimental autoimmune encephalomyelitis (EAE) in mice (13). CD24 is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein with expression in a variety of cell types that can participate in the pathogenesis of MS, including activated T cells (14, 15), B cells (16), macrophages (17), dendritic cells (18), and local antigen-presenting cells in the CNS, such as vascular endothelial cells, astrocytes, and microglia (our unpublished observation). It is well established that in the mouse CD24 mediates a CD28-independent costimulatory pathway that promotes activation of CD4 and CD8 T cells (16)(17)(18)(19)(20)(21). In addition, CD24 has been shown to modulate the very l...

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