Allergic Sensitization Underlies Hyperreactive Antigen-Specific CD4+ T Cell Responses in Coincident Filarial Infection

Abstract

Among the various hypotheses put forward to explain the modulatory influence of helminth infection on allergic effector responses in humans, the IL-10 induced suppression of Th2-associated responses has been the leading candidate. To explore this helminth/allergy interaction more fully, parasite- and allergen--specific T cell responses CD4+ T cell responses in 12 subjects with filarial infections and coincident allergic sensitization (Fil+A+) were compared these to the responses to 3 appropriate control groups [Fil−A− (n=13), Fil−A+(n=12), Fil+A−(n=11)]. The most important findings revealed that Fil+A+ had marked (p<0001 for all cytokines) increases in parasite antigen-driven Th2 (IL-4, IL-5, IL-13), Th9 (IL-9) and the regulatory (IL-10) cytokines when compared with Fil+A−. Moreover, using multiparameter flow cytometry, filarial parasite antigen induced a marked increase in not only the frequency of CD4+ T cells producing IL-4, IL-5, IL-2 and TNF-α in Fil+A+ when compared to Fil+A− patients but also in the frequencies of polyfunctional Th2-like (CD4+IL-4+IL-5+ and CD4+IL-2+IL-4+IL-5+TNF-α+) cells. The Th2-associated responses seen in the Fil+A+ group was correlated with serum IgE levels (p<0.01, r=0.5165 for IL-4; p<0.001, r=0.5544 for IL-5; and, p<0.001, r=0.4901 for IL-13), levels of circulating eosinophils (p<0.0116, r=0.5656) and their degranulation/activation products [major basic protein (p<0.001, r=0.7353) and, eosinophil derived neurotoxin (p<0.01, r=0.7059)]. CD4+ responses to allergen were not different (to a large extent) among the groups. Taken together, our data suggest that allergic sensitization coincident with filarial infection drives parasite antigen-specific T cell hyperresponsiveness, characterized largely by an augmented Th2-dominated immune response.

Mixed Th1 and Th2 Mycobacterium tuberculosis-specific CD4 T cell responses in patients with active pulmonary tuberculosis from Tanzania

“…Interestingly, CD4 T cells coexpressing IFN-γ and TNF-α and harboring a phenotype of effector-memory response were associated with active tuberculosis in HIV-uninfected [ 68 , 69 ] and HIV-infected TB patients [ 67 ]. Of note, polyfunctional helminth-specific CD4 T-cell responses were also recently associated to helminth biological activity [ 47 , 70 ].…”

Allergen presensitization drives an eosinophil-dependent arrest in lung-specific helminth development

“…Indeed, we have previously shown by using cells from Loa loa-infected travelers, who present clinically with allergic-type symptoms much more frequently than those born and bred in Loa loa-endemic regions of the world (78,79) and who had evidence of HDM allergic sensitization prior to the acquisition of their filarial infection, that there was a marked expansion of parasite antigen-specific CD4 + Th2 cells that were in turn associated with marked elevation of IgE and eosinophilia, in comparison with nonallergic but Loa loa-infected patients (39). Like these travelers, our data from this murine system suggest that allergic sensitization coincident with helminth infection drives an exaggerated eosinophil-rich pulmonary type 2 immune response in the lungs, mediated predominantly by the allergic sensitization that occurs In a primary exposure to Ascaris parasites, after penetrating the intestine at the level of the cecum or proximal colon, the infective L3-stage larvae migrate through the portal vessels to the liver and subsequently to the lungs in their quest to reach the airways.…”

“…Moreover, larvae Human population shifts have led to a reexamination of how helminth infections and allergy interface given that for many people allergic sensitization has preceded the acquisition of the helminth infection. Indeed, we have previously demonstrated that allergic sensitization to house dust mites (HDM), an environmental allergen, prior to the acquisition of a human filarial infection induces a markedly exaggerated parasite antigen-specific Th2-associated immune response (39). We hypothesized that this exaggerated type 2-dominated immune response could play a vital role in limiting parasite burden at the expense of parasite-associated morbidity.…”

Helminth parasites and immune regulation

“…For helminth infection in humans, the immune response during the early/acute phase of infection involves the induction of type 2-associated cytokines (IL-4, IL-5, IL-9, and IL-13) first by innate lymphocytes (ILC2) and later by effector antigen-specific polyfunctional CD4 T cells 32 . This relatively early phase also induces high antigen-specific IgG4 and IgE levels as well as peripheral and tissue eosinophilia and expanded populations of AAM 33 , 34 .…”