Page 75 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

but a reduced frequency in patients with high-grade CIN and cervical carcinoma. [6, 7, 9, 14-17]
A possible mechanism for this theory may be that the protective influence of the HLA-DRB1*13
allele is larger when the expression of viral oncogenes is limited, which is the case in low-grade
CIN lesions. Indeed, spontaneous regression of these lesions is more common in women with the HLA-DRB1*13 allele. Theoretically, this could prevent a persistent infection, thereby preventing 3 a transforming infection leading to high-grade CIN lesions. Once a high-grade CIN lesion has developed, the protective effect of HLA-DRB1*13 is most likely counterbalanced by the increased expression of viral oncogenes, which is reflected in the fact that the HLA-DRB1*13 allele does
not seem to increase spontaneous regression of high-grade CIN. Based on these findings, we postulate that the protective effect of HLA-DRB1*13 may be exerted mainly through a decreased susceptibility to high-grade CIN lesions, rather than through the promotion of spontaneous regression of these lesions. This may explain why an effect on the natural prognosis of high-grade lesions was not found in this study.
Our study indicates an HPV16 specific protective effect of the HLA-DRB1*13/14 allele group. None of the patients with an HLA-DRB1*13/14 allele had an HPV16 positive CIN lesion. This may imply that a specific HLA-DRB1*13/14 epitope is selectively protective against HPV16-induced CIN. A biological explanation for this could be that protective HLA molecules bind HPV16 with greater affinity than non-protective HLA molecules. Indeed, a study on HPV peptide sequences bound to several HLA-DR and -DQ molecules revealed that HPV16 peptide epitopes bind with higher affinity to the protective than to non-protective HLA-DR and -DQ molecules.[18] This may lead to a more effective immune response. Since HPV16 is more likely than other HPV types to induce high-grade CIN lesions, this could also explain the protective effect of HLA-DRB1*13 against the development of high-grade CIN lesions. However, previous studies have shown conflicting results regarding the association between HLA-DRB1*13/14 and HPV16. Several authors found an HPV16 dependent association between the HLA-DRB1*13 and HLA–DRB1*14 alleles and cervical carcinoma.[8, 19] Other authors, however, have not confirmed this finding.[9, 17, 20, 21] Eiguchi et al. performed the only study in patients with high-grade CIN (in combination with cervical carcinoma patients) and found a significant negative association between HPV16 and HLA-DRB1*13.[15] This is in agreement with our finding that HLA-DRB1*13 seems to protect against HPV16 induced high- grade CIN. In our hypothesis that HLA-DRB1*13 has a protective effect against the development of high-grade CIN, this could imply that this protective effect is caused preferentially through an increased immune response to HPV16. Further studies on HPV16 peptide epitopes and HLA- DRB1*13 in both low- and high-grade CIN should clarify this issue.
Our study is the first to assess the associations between HLA-DRB1*13/14 alleles and the natural history and HPV16 status in high-grade CIN, but several limitations must be addressed. A major limitation of the current study is the limited sample size. From the historical cohort of patients, sufficient material was available for HLA typing in 34 patients only. As the HLA complex is highly polymorphic, small patient populations may cause difficulties establishing significant results. Another limitation is that linkage disequilibrium was not assessed in this study. HLA-DRB1*13 has been shown to be in linkage disequilibrium with DQB1*06.[6, 14] Previous studies have not clarified whether the protective effect is caused by either the individual alleles or by the combination of
HLA as a prognostic biomarker
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