The “danger-signal” quality of dsRNA motifs. (a and b) dsRNAs prevent high-zone tolerance. C57BL/6 mice (a) or LPS-resistant C3H/HeJ mice (b) were injected with a tolerogenic dose of hIgG alone or together with pI:pC or pA:pU. Mice were subsequently boosted with an immunogenic dose of hIgG in CFA. The antibodies against hIgG were measured by ELISA at various intervals, as shown in the figure. As control, we included mice immunized with hIgG emulsified in CFA and represented the maximal titer on the graph (dashed line). Results are shown as mean ± SEM of endpoint titers (n = 5/group). Similar results were obtained in LPS-responsive mice (not shown). (c and d) dsRNA motifs display differential ability to mobilize immunity against influenza virus. C57BL/6 (c) or C3H/HeJ (d) mice were treated with pI:pC, pA:pU, or PBS 1 day before and 1 day after pulmonary infection with influenza virus. On day 5, the virus titer in the pulmonary tissue was estimated and represented as TCID₅₀/organ (mean ± SEM, n = 6/group). Results are representative of studies in TLR4^–/– and competent mice. (e) Schematic depiction of the involvement of dsRNA danger motifs in the regulation of immunity: detection of dsRNA motifs triggers a “master switch” for B and T cell responses to coexisting antigens. In the absence of danger signals, the magnitude of immunity is low if the antigen is limiting (immune ignorance), or immune tolerance develops if antigen is abundant.