The presence of glutamic acid at positions 71 or 74 in pocket 4 of the HLA-DRb1 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 b1 chain (b171/b174). Residues at these positions are important in the formation of pocket 4 in the antigen binding site of the HLA-DR molecule. Objectives: To investigate whether the presence of alleles encoding HLA-DR molecules containing glutamic acid at b171/b174 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 b171/b174 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 b171/b174 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 b1 chain could influence the clinical course of MS by determining protection against RR/SP-MS or susceptibility to the development of PP-MS.