Type 2 immune responses are associated with helminth infections, but they also drive allergic disorders. Collectively, helminth parasites are a major public health problem worldwide, and recent estimates suggest that 1.5 billion people have one or more of the common helminth infections, most of whom reside in low- and middle-income countries in endemic areas of Asia, Latin America, the Caribbean, and sub-Saharan Africa. On the other hand, not only the prevalence of allergic diseases is increasing dramatically worldwide, but, because of marked population movements that have come from globalization, helminth infection and allergic diseases have intersected with much greater frequency given that nearly half of the world's population harbors either helminth parasites or suffers from allergic diseases. Thus, it is important to understand the interplay between these two major public health problems.
We have previously demonstrated that allergic sensitization coincident with helminth infection in humans induces an augmented parasite-specific type 2-dominated immune response. Filarial parasite antigens induced a marked increase in the frequencies of a circulating polyfunctional Th2 CD4+IL-2+IL-4+IL-5+TNF-a+ T cells in the Peripheral Blood Mononuclear Cells (PBMCs) of a group of HDM-allergic individuals concomitantly infected with Loa loa filarial parasites when compared to non-allergic but filarial-infected patients. The frequency of parasite-specific Th2 cells correlated with serum IgE levels and the levels of circulating activated eosinophils (Gazzinelli-Guimaraes et al., 2016), findings that suggest that this antigen-specific T cell hyperresponsiveness drives Th2-associated inflammatory processes. More recently, while investigating the heterogeneity of these Th2 effectors subsets, we characterized their phenotype and function using multiparameter 25-color panel flow cytometry analysis in a cohort of 47 North American donors (either healthy volunteers or filarial-infected with or without coincident HDM sensitization) (Gazzinelli-Guimaraes et al., 2024). Ex vivo analysis by a two-level clustering tool identified two effector memory CD4+ T cell subsets (CD4+CD45RA-CCR7-CCR6-CCR4+CRTH2+ and CD4+CD45RA-CCR7-CCR6+CCR4+CRTH2+) capable of producing large amounts of Th2 cytokines, that were markedly increased in frequency among the filarial-infected subjects, that was increased even further if coincident HDM sensitization had occurred. Our single-cell gene expression analysis demonstrated that effector memory Th2 cells from individuals with concomitant HDM sensitization and filarial infection display the signature markers of pathogenic Th2 effector cells, including upregulation of Gata3, Il17rb (IL-25R), Cltf2 (TSLPR), Klrb1 (CD161), Il-4 and Il-13, and downregulation of Cd27 genes, when compared to non-allergic, filarial-infected patients. However, several unanswered questions remain: Were the individuals sampled at consistent clinical stages of their infection? How many months (or even years) into the infection were they when they were sampled? Did they exhibit a clinical allergy to HDM or other airborne allergens prior to contracting this infection? What was the impact of allergic sensitization on the burden of helminth parasites? These questions still require investigation, as they were not addressed due to the challenges of conducting such studies in uncontrolled endemic settings.