HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes

Abstract

Childhood B-cell precursor (BCP) ALL is thought to be caused by a delayed immune response to an unidentified postnatal infection. An association between BCP ALL and HLA class II (DR, DQ, DP) alleles could provide further clues to the identity of the infection, since HLA molecules exhibit allotype-restricted binding of infection-derived antigenic peptides. We clustered >30 HLA-DPB1 alleles into six predicted peptide-binding supertypes (DP1, 2, 3, 4, 6, and 8), based on amino acid di-morphisms at positions 11 (G/L), 69 (E/K), and 84 (G/D) of the DPbeta(1) domain. We found that the DPbeta11-69-84 supertype GEG (DP2), was 70% more frequent in BCP ALL (n=687; P<10(-4)), and 98% more frequent in cases diagnosed between 3 and 6 years (P<10(-4)), but not <3 or >6 years, than in controls. Only one of 21 possible DPB1 supergenotypes, GEG/GKG (DP2/DP4) was significantly more frequent in BCP ALL (P=0.00004) than controls. These results suggest that susceptibility to BCP ALL is associated with the DP2 supertype, which is predicted to bind peptides with positively charged, nonpolar aromatic residues at the P4 position, and hydrophobic residues at the P1 and P6 positions. Studies of peptide binding by DP2 alleles could help to identify infection(s) carrying these peptides.

Figure 1

Odds ratios for DPB1 supertype frequencies compared with normal newborns in relation to the age at diagnosis of BCP-ALL. Ages at diagnosis: 0–<3 years (white bar), 3–6 years (grey bar), >6 years (checked bar). Vertical limits are 95% confidence intervals. ^†One-sided, corrected Fishers P-values: 0–<3 years: DP4=0.018, DP3=0.012; DP1=0.012. 3–6 years: DP2=0.0006, DP1=0.012. >6 years: DP8=0.018; DP1=0.03.