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Loading Rate of Exogenous and Autoantigenic Determinants on Major Histocompatibility Complex Class II Mediates
A E Mamedov1, M Yu Zakharova2,3, O O Favorova3
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia. bioaz12@gmail.com.
Abstract:
Genetic analysis of thousands of patients with multiple sclerosis (MS) and healthy Russian donors showed that the carriage of groups of HLA-DRB1*15 and HLA-DRB1*03 alleles is associated with the risk of MS, whereas the carriage of groups of HLA-DRB1*01 and HLA-DRB1*11 alleles is protective. Recombinant HLA-DRB1*01:01 with a high affinity can recognize the fragments of myelin basic protein (MBP), one of the autoantigens in MS. However, the comparison of the kinetic parameters of the load of MBP and viral HA peptides on HLA-DRB1*01:01, which is catalyzed by HLA-DM, showed a significantly lower rate of exchange of CLIP for MBP peptides. We assume that the observed protective properties of the group of HLA-DRB1*01 alleles may be directly associated with the ability of HLA-DRB1*01:01 to kinetically distinguish peptides of exogenous and endogenous nature.
Insights
Certain HLA-DRB1 alleles influence multiple sclerosis (MS) risk. Protective HLA-DRB1*01 alleles may prevent MS by distinguishing self-antigens from foreign peptides.
Area of Science:
- Immunogenetics
- Neuroimmunology
Background:
- Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system.
- Genetic factors, particularly human leukocyte antigen (HLA) genes, play a significant role in MS susceptibility.
- Specific HLA-DRB1 alleles have been associated with both increased risk and protection against MS.
Purpose of the Study:
- To investigate the association between specific HLA-DRB1 alleles and MS risk in a Russian population.
- To explore the molecular mechanisms underlying the protective effects of certain HLA-DRB1 alleles, focusing on their interaction with autoantigens.
Main Methods:
- Genetic analysis of HLA-DRB1 alleles in a cohort of MS patients and healthy controls.
- Biochemical assays to compare the binding and presentation kinetics of myelin basic protein (MBP) peptides and viral peptides by HLA-DRB1*01:01.
- Investigated the role of HLA-DM in peptide loading.
Main Results:
- Carriage of HLA-DRB1*15 and HLA-DRB1*03 alleles was associated with increased MS risk.
- Carriage of HLA-DRB1*01 and HLA-DRB1*11 alleles demonstrated a protective effect against MS.
- HLA-DRB1*01:01 showed high affinity for myelin basic protein (MBP) fragments.
- Kinetic analysis revealed a significantly slower loading of MBP peptides compared to viral peptides onto HLA-DRB1*01:01, indicating impaired presentation of endogenous antigens.
Conclusions:
- The study identifies specific HLA-DRB1 alleles conferring risk or protection for MS in a Russian cohort.
- The protective effect of HLA-DRB1*01 alleles may stem from their ability to kinetically discriminate between self (MBP) and non-self (viral) peptides.
- This suggests a mechanism where impaired presentation of autoantigens contributes to the protective phenotype.
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