FIGURE 2.

Schematic view of the proposed mechanism underlying ATR. In the 1^st tick infestation (left panel), dendritic cells in the skin take up tick saliva antigens and move to the draining lymph node where they present tick antigens to naive CD4⁺ T cells, leading to the generation of IL-4-producing T cells. T cell-derived IL-4 stimulates B cells to produce tick antigen-specific IgE that in turn circulates in the peripheral blood and bind to the surface of blood-circulating basophils via FcεRI. Some of tick antigen-specific CD4⁺ T cells generated in the lymph node migrate into the skin throughout the body and are retained as skin-resident, memory CD4⁺ T cells. In the 2^nd tick infestation (right panel), such skin-resident, memory CD4⁺ T cells are stimulated with tick antigens to produce IL-3 that in turn promotes the recruitment of IgE-armed basophils from the peripheral blood to the tick-feeding site. IgE-armed basophils are activated with tick antigens to release histamine that acts on keratinocyte, resulting in epidermal hyperplasia that may interfere with tick attachment or blood feeding in the skin, and hence contribute to ATR. The role of skin mast cells in ATR remains elusive.