References

Is HLA-DR4 or the HLA-DRB1*0402 allele associated with decreased risk for CML?

G Pawelec & W Wagner

Zentrum für Medizinische Forshung, ZMF, University of Tübingen, Tübingen, Gemany

Correspondence to: G Pawelec, Zentrum für Medizinische Forshung, ZMF, University of Tübingen, Waldhörnlestr 22, D-72076 Tübingen, Germany; Fax: 49 7071 295567

TO THE EDITOR

In a study involving a large number of CML patients, Posthuma et al¹ recently reported that there was a significantly reduced frequency of HLA-DR4 positivity in CML compared with a very large control population matched by country of origin and ethnicity. None of the other HLA-DR specificities tested showed such an association, with the exception of HLA-DR3, the effect of which was attributed to its linkage disequilibrium with a class I protective specificity, HLA-B8. They speculated that lack of protection by HLA-DR specificities other than DR4 may be due to their inability to bind and present antigenic peptides derived from bcr/abl fusion proteins, specifically b3/a2 peptides. However, previously published results of competition assays assessing the binding capacity of b3/a2 peptides to purified HLA-DR molecules do not support this proposition.² Thus, of nine different alleles tested, we found that only HLA-DR11 strongly bound b3/a2 peptides. This finding is consistent with an earlier report on DR11 anchor motifs.³ In T cell sensitization assays using healthy donors, three of five DR11+ donors showed evidence of responses to the peptides, whereas none of four DR4+ donors responded. However, the DR4+ donors tested were all HLA-DRB1*0401+, leaving open the possibility that one or more of the other DR4 family alleles might be able to bind and present b3/a2. Indeed, the competition assays had indicated weak binding to the 0402 allele, but not to 0401, 0403 or 0404. Furthermore, binding predictions for b3/a2-fusion peptides indicate a relatively weak putative binding to DRB1*0401 compared with stronger binding to DRB1*0101 (see http://www.uni-tuebingen.de/uni/kxi/), which is in line with the aforementioned in vitro binding studies. It would therefore be extremely interesting to know whether the protective effect of HLA-DR4 described by Posthuma et al is attributable to the presence of the DRB1*0402 allele. As the proportion of DR4+ persons carrying the 0402 specificity in whites is only around 20%, this would represent a highly significant effect for this subset of individuals. A survey of CML patients using more sophisticated HLA typing would be valuable in identifying whether protection is limited to this one particular DR4 family member. Evidence from other investigators for b3/a2 presentation by different DR4 alleles is sparse. One report mentioned an inability of 0404+ donors to respond to b3/a2, consistent with our binding data.⁴ The same group also noted heterogeneous responses amongst 0401+ donors, with three failing to respond.⁴ There have also been reports of HLA-DR1⁵ and DR15⁶ presentation, alleles which we found bound b3/a2 peptide measurably but extremely weakly.² However, there appear to be no data at all on b3/a2 presentation by DRB1*0402. Therefore, in the light of these considerations and the new data of Posthuma et al,¹ it would be extremely useful to investigate presentation by this allele, and to establish whether individuals carrying this allele are indeed resistant to CML.

²  Pawelec G, Max H, Halder T, Bruserud O, Merl A, da Silva P, Kalbacher H BCR/ABL leukemia oncogene fusion peptides selectively bind to certain HLA-DR alleles and can be recognized by T cells found at low frequency in the repertoire of normal donors Blood 1996 88: 2118–2124 MEDLINE

³  Newcomb JR, Creswell P Characterisation of endogenous peptides bound to purified HLA-DR molecules and their absence from invariant chain associated dimers J Immunol 1993 150: 499–507 MEDLINE

⁴  MacIntyre AR, Christmas SE, Clark RE The influence of class II HLA type on the lymphoproliferative response of normal donors to a bcr-abl fusion peptide Exp Hematol 1996 24: 1307–1311 MEDLINE

⁵  Mannering SI, McKenzie JL, Fearnley DB, Hart DN HLA-DR1-restricted bcr-abl (b3a2)-specific CD4⁺ T lymphocytes respond to dendritic cells pulsed with b3a2 peptide and antigen-presenting cells exposed to b3a2 containing cell lysates Blood 1997 90: 290–297 MEDLINE

⁶  ten Bosch GJ, Toornvliet AC, Friede T, Melief CJ, Leeksma OC Recognition of peptides corresponding to the joining region of p210 BCR-ABL protein by human T cells Leukemia 1995 8: 1344–1348

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