This work by Eriksson et el. confirms that TLRs other than TLR4 are sufficient to activate DCs to induce autoimmune myocarditis. In addition, our new results demonstrates that TLR4 is redundant for that function. In a report, BEZ235 915019-65-7 Nishikubo et al. found that C3H/HeJ mice, with nonfunctional mutated TLR4, were resistant to the myosininduced autoimmune myocarditis. These findings seem to contradict our own experimental findings. The model, however, used by Nishikubo et al. is very different from the one we used, for the following reasons: Nishikubo et al. immunize mice with 100 mg of porcine cardiac myosin mixed with 1 mg of BCG in IFA into the footpad. We inject 25 mg, not of BCG but of Mycobacterium tuberculosis, per mouse and immunization. Furthermore, the antigen, porcine protein, versus recombinant mouse peptide, the time of the immunization boost, day 14 versus day 7 in our model, make it difficult to compare results obtained from the use of these two models since they are so obviously different. Nishikubo et al. attribute their finding of protection from autoimmune myocarditis to an intrinsic bias towards a TH2 phenotype in C3H/HeJ mice. In the model we are using a TH2 bias would not be protective: IFN-c-deficient mice develop fatal autoimmune myocarditis and IFN-c suppresses EAM. The model we are using for this study represents a model of an organ-specific autoimmune disease associated with a TH2 phenotype, in which IL-4 promotes the disease and IFN-c limits it. At the T cell and APC cell level, however, there is no contradiction between the two models. In both models, TLR4 signaling is not required for the activation of myosin-reactive T cells. Since in both EAM models the activation of heart pathogenic T cells is independent of functional TLR4, it is not surprising that C3H/HeJ develop BCG-porcine myosin induced myocarditis after blocking IL-4. In human disease, patients with DCM, coding polymorphisms of TLR4 were associated with significantly reduced improvement of left ventricular ejection fraction and left ventricular dilation at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. It will be of great interest to determine whether these human TLR4 coding polymorphisms increased or decreased TLR4 signaling in patients. The specific function of TLR4 in regulating the immune response to heart epitopes we describe here could be useful for treating autoimmune inflammatory conditions underlying human heart disease or cardiac ischemia-reperfusion injury. More important, our finding that one defined chemokine, CXCL1/ KC, abrogates autoimmune inflammatory heart disease opens the possibility for a new specific treatment for myocarditis and cardiomyopathy. Vascular headaches were traditionally associated with abnormal changes in blood flow in the intracranial vessels.