A mechanism for the induction of type 2 immune responses by a protease allergen in the genital tract

Abstract

The genital mucosa is a barrier that is constantly exposed to a variety of pathogens, allergens, and external stimuli. Although both allergen exposure and parasite infections frequently occur in the genital area, the mechanism by which immune responses-particularly type 2 immunity-are induced has rarely been studied in the genital mucosa. Here, we demonstrate the induction of T helper type 2 (Th2) immunity in the genital mucosa in response to a model allergen, the protease papain. Intravaginal papain immunization induced type 2 immunity in a manner that was dependent on protease activity and the estrous phase of the mice. In addition, IL-33 was released from the vaginal epithelia after intravaginal papain immunization, leading to the activation of type 2 innate lymphoid cells (ILC2s). Moreover, the IL-33-MyD88 (myeloid differentiation primary response gene 88) signaling pathway was critical for the induction of type 2 immunity. We also found that Th2 differentiation in response to intravaginal papain treatment requires a specific dendritic cell (DC) subset that is controlled by interferon regulatory factor 4 (IRF4). These findings suggest that type 2 immunity is induced by a unique mechanism in the genital tract, which is an important, but often overlooked, barrier surface.A llergic disorders, such as asthma, atopy, and helminth infections, are major concerns across the globe because their prevalence is increasing (1, 2). These inflammatory and infectious diseases are commonly involved in "type 2 immunity." Type 2 immunity is characterized by the induction of T helper type 2 (Th2) cells, which secrete cytokines such as IL-4, -5, and -13, as well as by IgE production. Th1 and Th17 responses, which are induced by viral, bacterial, and fungal infections, are well studied. Pattern recognition receptors recognize pathogen-specific molecules, and dendritic cells (DCs) control Th cell differentiation by acting as antigen-presenting cells and producing cytokines required for Th cell differentiation. However, the mechanisms underlying the recognition of allergens and helminth infections and the subsequent induction of Th2 and IgE responses are much more complex. Although recent studies have demonstrated many aspects of innate and adaptive type 2 immunity (3-7), these results were derived from mouse models by using s.c. needle injections or allergen sensitization and helminth infections of the lungs and intestines.The vaginal tract is a mucosal barrier that is constantly exposed to a variety of pathogens, allergens, and external stimuli. In addition, this mucosal barrier has the unique feature of being under the control of the hormonal cycle. During the estrous cycle, the thickness of the epithelial layers, the immune cell populations within the vagina, and the receptors expressed on the vaginal epithelial cells change. Thus, the host responses to external stimuli within the vaginal tract are also dependent on the estrous cycle. In this context, the vaginal mucosa should be considered distinct from other mucosal barriers,...

IRF4 and STAT3 activities are associated with the imbalanced differentiation of T-cells in responses to inhalable particulate matters

“…S2A, B). Although prior study show that protease activity contributes to the immunogenicity of PM by induction of Th2 responses [39], there is no significant protease activity (1.08-fold of the blank control) in the PM samples we used at a concentration of 10 mg/ml (Fig. S2C).…”

Impact of Helminth Infections on Female Reproductive Health and Associated Diseases

“…Furthermore, administration of recombinant IL-33 or protease-mediated induction of IL-33 in the vagina resulted in heightened susceptibility to HSV-2 (165). Oh et al (166) elaborated on this model of IL-33-mediated type 2 immune FIGURE 2 | Genital Schistosomiasis: In S. haematobium infected women, eggs can become lodged in the cervix, resulting in inflammation around the schistosome eggs (granula) and bystanders tissue damage. Genital schistosomiasis is common and can impair vaginal immunity and increase Human Immunodeficiency Virus (HIV) risk (129)(130)(131)(132)(133).…”

R‐Ras deficiency does not affect papain‐induced IgE production in mice

“…IL‐33 can regulate “effector cytokine,” such as IL‐5 and IL‐13, expression in Th2 cells in concert with Stat5 activating cytokines, independently of antigens . IL‐33 has been shown to be indispensable for papain‐induced IgE production in murine lung and genital tract . We found that the percent of IL‐33R positive cells was reduced in R‐Ras KO CD4 T cells (Fig.…”

“…4B). Papain has been shown to induce Th2 polarization in multiple studies, determined by the IL-4 production of T cells [17,28,30] and T cell recall responses upon in vitro restimulation with papain [17,28,31,32]. We measured the mRNA expression of transcription factors associated with T cell differentiation from splenocytes by qPCR after papain-immunization.…”