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Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease
O Olerup1, J Hillert, S Fredrikson
1Center for Biotechnology, Karolinska Institute, Huddinge Hospital, Sweden.
Summary
Multiple sclerosis (MS) genetic susceptibility differs between its clinical forms. Human leukocyte antigen (HLA) gene variations influence risk for chronic progressive MS and relapsing-remitting MS, suggesting distinct disease entities.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Human Genetics
Background:
- Multiple sclerosis (MS) is a complex neurological disorder with distinct clinical phenotypes.
- Genetic factors, particularly within the human leukocyte antigen (HLA) complex, are known to influence MS susceptibility.
- Understanding the genetic basis of different MS clinical forms may reveal distinct pathophysiological mechanisms.
Purpose of the Study:
- To investigate human leukocyte antigen (HLA) class II gene polymorphism in patients with multiple sclerosis (MS).
- To identify specific HLA associations with different clinical forms of MS: primarily chronic progressive (cMS) and relapsing-remitting (RRMS).
- To explore the genetic heterogeneity underlying MS clinical subtypes.
Main Methods:
- Restriction fragment length polymorphism (RFLP) analysis of Taq I-digested DNA was performed on 100 MS patients.
- Human leukocyte antigen (HLA) class II gene polymorphisms were analyzed using DRB, DQA, and DQB cDNA probes.
- Patients were categorized into primarily chronic progressive MS (n=26) and relapsing/remitting MS (n=74) groups.
Main Results:
- Both cMS and RRMS showed association with the DRw15,DQw6 haplotype.
- Primarily chronic progressive MS was associated with DQB1 patterns of DR4,DQw8, DR7,DQw9, and DRw8, DQw4, and negatively associated with DQw7.
- Relapsing-remitting MS was associated with the DQB1 pattern of DRw17,DQw2. These DQB1 alleles are in negative linkage disequilibrium with DRw15.
- Susceptibility markers acted additively, and different DQB1 alleles contributed to susceptibility and resistance in cMS and susceptibility in RRMS.
Conclusions:
- Distinct HLA class II gene polymorphisms are associated with primarily chronic progressive MS and relapsing-remitting MS.
- The identified immunogenetic heterogeneity supports the hypothesis that cMS and RRMS are distinct disease entities.
- DQB1 alleles play a significant role in determining susceptibility and resistance patterns in different MS clinical forms.