Beyond danger: unmethylated CpG dinucleotides and the immunopathogenesis of disease

Oligonucleotide sequences containing unmethylated cytidine phosphate guanos ine (CpG) motifs are known to have significant immunostimulatory properties . Because of these immunostimulatory effects, unmethylated CpG oligonucleot ides are thought to act as 'danger signals' that produce a favorable immune response by alerting the host to the presence of invading organisms or abn ormal cells. In contrast to this concept, we review the evidence that unmet hylated CpG sequences derived either from microbial agents or from endogeno us CpG-rich Alu motifs promote disease progression by inducing an aberrant or autoreactive immune response. Recognition of the negative effect of unme thylated CpG dinucleotides should lead to more effective immune strategics to combat infectious, inflammatory, autoimmune and malignant diseases. (C) 2000 Elsevier Science B.V. All rights reserved.