Role of basophils in the immune response to filariae

Filariae are arthropod-bornetissue-dwelling helminths that are a majorworldwide burden of disease. They typically cause a type 2 immune responsecharacterizedby eosinophilia, elevated serum levels of Ag- specific and polyclonal IgE, and increases in T-cell production of IL-4, IL-5, and IL-13. This type 2 response is likely helpful in controlling helminth infections. While it is clear that IL-4 plays a central role in driving type 2 responses, the exact factors responsible for triggering and maintaining prolonged type 2 immune responses in filarial infections remain unknown. These gaps in our knowledge are problematic becausethey impair our ability to develop helminth-specific vaccinesthat produce long-standing type 2 immune responses with high titers of Ag-specific IgE. Because they are the least common peripheral leukocyte andbecause they are difficult to work with, the role basophils play in the immune response to infectious diseases has largely gone unstudied. However,recent evidence demonstratesthat basophils are major contributorsto the IL-4 pool in ftlaria-infected humans, suggesting they may play an important role in the immune response to filarial infections. The objective of this appliation is to characterize the role basophils play in initiating and maintaining type 2 responses in filarial infections. The central hypothesis being tested is: sustained production of filarial-specific IgE by B cells enables basophils to coordinate a rapid Type 2 memoryresponse following filarial exposure by releasing large quantities of IL-4 and by driving naive T-cells toward a type 2 phenotype. This hypothesis will be addressed by pursuing the following aims. Specific Aim 1: To determine whether basophils can be activated by filarial antigen to release IL-4 non-specifically. Specific Aim 2: To determine whether Ag-specific IgE production and Ag-specific IgE-mediated basophil activation persists in the context of treated filarial infections. Specific Aim 3: To determine the role basophils play in driving naive T cells toward a type 2 phenotype.