The presence of glutamic acid at positions 71 or 74 in pocket 4 of the HLA-DRbeta1 chain is associated with the clinical course of multiple sclerosis.
BACKGROUND
Primary progressive multiple sclerosis (PP-MS) differs from relapsing-remitting or secondary progressive MS (RR/SP-MS) in ways suggesting differences in the pathogenic pathways. Susceptibility to both PP-MS and RR/SP-MS is linked to carriage of the HLA molecule DRB1*1501. Several serologically defined HLA-DR groups (DR1, DR4, DR6, and DR9) occur less often in RR/SP-MS than in controls. Some or all of the HLA-DR molecules encoded by alleles in these serologically defined groups have a negatively charged glutamic acid at residue 71 or 74 of the beta1 chain (beta1(71)/beta1(74)). Residues at these positions are important in the formation of pocket 4 in the antigen binding site of the HLA-DR molecule.


OBJECTIVE
To investigate whether the presence of alleles encoding HLA-DR molecules containing glutamic acid at beta1(71)/beta1(74) correlates with the course of MS.


METHODS
HLA-DR and HLA-DQ alleles and genotypes were analysed in 121 MS patients (50 with PP-MS) and 109 controls by molecular typing.


RESULTS
Alleles encoding HLA-DR molecules containing a glutamic acid at beta1(71)/beta1(74) occurred less often in patients with RR/SP-MS than in those with PP-MS or controls. In subjects not carrying the DRB1*1501 allele, a much higher proportion of PP-MS patients carried alleles encoding HLA-DR molecules containing a glutamic acid at beta1(71)/beta1(74) than did RR/SP-MS patients or controls.


CONCLUSIONS
The amino acid residues involved in determining the shape and charge of pocket 4 of the HLA-DR beta1 chain could influence the clinical course of MS by determining protection against RR/SP-MS or susceptibility to the development of PP-MS.
Greer
J M
JM
Neuroimmunology Research Centre, Department of Medicine, The University of Queensland, Herston, Queensland 4029, Australia. j.greer@medicine.uq.edu.au
Pender
M P
MP
D000483:Alleles; D001665:Binding Sites; D018450:Disease Progression; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D020528:Multiple Sclerosis, Chronic Progressive / Q000235:genetics* / Q000503:physiopathology
C488436:HLA DRB1*04:04 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D018698:Glutamic Acid