Mark C. Siracusa

Soil-Transmitted Helminth Infections Are Associated With an Increase in Human Papillomavirus Prevalence and a T-Helper Type 2 Cytokine Signature in Cervical Fluids

BACKGROUND An ecological correlation between invasive cervical cancer incidence and burden of soil-transmitted helminths (STH) is hypothesized to explain the excess in detectable human papillomavirus (HPV) infection in Latin America, via a global T-helper type 2 (Th2)-biased mucosal immune response secondary to STH infection. METHODS The association between current STH infection and HPV prevalence was compared in regions of Peru where STH is or is not endemic. Adjusted prevalence ratios (PRs) with robust variance were estimated as an effect measure of STH infection on HPV prevalence in each study site. Soluble immune marker profiles in STH-infected and STH-uninfected women were compared using Spearman rank correlation with the Sidak correction. RESULTS Among women in the helminth-endemic region of the Peruvian Amazon, those with STH infection women had a 60% higher prevalence of HPV, compared with those without STH infection (PR, 1.6; 95% confidence interval, 1.0-2.7). Non-STH parasitic/protozoal infections in the non-STH-endemic population of Peru were not associated with HPV prevalence. In Iquitos, A Th2 immune profile was observed in cervical fluid from helminth-infected women but not helminth-uninfected women. CONCLUSIONS A proportion of the increased HPV prevalence at older ages observed in Latin America may be due to a population-level difference in the efficiency of immunological control of HPV across the lifespan due to endemic STH infection.

Carbonic anhydrase enzymes regulate mast cell–mediated inflammation

Car enzyme inhibition prevents mast cell responses and inflammation following Trichinella spiralis infection or the induction of food allergy–like disease.

Skin-derived TSLP systemically expands regulatory T cells

Regulatory T cells (Tregs) are a subset of CD4+ T cells with suppressive function and are critical for limiting inappropriate activation of T cells. Hence, the expansion of Tregs is an attractive strategy for the treatment of autoimmune diseases. Here, we demonstrate that the skin possesses the remarkable capacity to systemically expand Treg numbers by producing thymic stromal lymphopoietin (TSLP) in response to vitamin D receptor stimulation. An ∼2-fold increase in the proportion and absolute number of Tregs was observed in mice treated topically but not systemically with the Vitamin D3 analog MC903. This expansion of Tregs was dependent on TSLP receptor signaling but not on VDR signaling in hematopoietic cells. However, TSLP receptor expression by Tregs was not required for their proliferation. Rather, skin-derived TSLP promoted Treg expansion through dendritic cells. Importantly, treatment of skin with MC903 significantly lowered the incidence of autoimmune diabetes in non-obese diabetic mice and attenuated disease score in experimental autoimmune encephalomyelitis. Together, these data demonstrate that the skin has the remarkable potential to control systemic immune responses and that Vitamin D-mediated stimulation of skin could serve as a novel strategy to therapeutically modulate the systemic immune system for the treatment of autoimmunity.

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

Purpose of ReviewIt is well established that T helper type 2 (TH2) immune responses are necessary not only to provide protection against helminth parasites but also to promote the detrimental inflammation associated with allergies and asthma. Given the importance of type 2 immunity and inflammation, many studies have focused on better understanding the factors that regulate TH2 cell development and activation. As a result, significant progress has been made in understanding the signaling pathways and molecular events necessary to promote TH2 cell polarization. In addition to the adaptive compartment, emerging studies are better defining the innate immune pathways needed to promote TH2 cell responses. Given the recent and substantial growth of this field, the purpose of this review is to highlight recent studies defining the innate immune events that promote immunity to helminth parasites and allergic inflammation.Recent FindingsEmerging studies have begun to elucidate the importance of cytokine alarmins such as thymic stromal lymphopoietin (TSLP), IL-25 (IL-17E), and IL-33 in promoting type 2 immunity and inflammation following helminth challenge or exposure to allergens. Specifically, recent reports have begun to define the complex cellular networks these alarmins activate and their contribution to type 2 immunity and inflammation.SummaryOur increased understanding of the pathways that regulate type 2 cytokine-mediated immunity and inflammation have revealed novel therapeutic targets to treat both helminth infections and allergic disease states.

The Therapeutic Potential of Targeting Cytokine Alarmins to Treat Allergic Airway Inflammation

Asthma is a heterogeneous disorder that results in recurrent attacks of breathlessness, coughing, and wheezing that affects millions of people worldwide. Although the precise causes of asthma are unclear, studies suggest that a combination of genetic predisposition and environmental exposure to various allergens and pathogens contribute to its development. Currently, the most common treatment to control asthma is a dual combination of β2-adrenergic receptor agonists and corticosteroids. However, studies have shown that some patients do not respond well to these medications, while others experience significant side effects. It is reported that the majority of asthmas are associated with T helper type 2 (TH2) responses. In these patients, allergen challenge initiates the influx of TH2 cells in the airways leading to an increased production of TH2-associated cytokines and the promotion of allergy-induced asthma. Therefore, biologics that target this pathway may provide an alternative method to treat the allergic airway inflammation associated with asthma. As of now, only two biologics (omalizumab and mepolizumab), which target immunoglobulin E and interleukin-5, respectively, are FDA-approved and being prescribed to asthmatics. However, recent studies have reported that targeting other components of the TH2 response also show great promise. In this review, we will briefly describe the immunologic mechanisms underlying allergic asthma. Furthermore, we will discuss the current therapeutic strategies used to treat asthma including their limitations. Finally, we will highlight the benefits of using biologics to treat asthma-associated allergic airway inflammation with an emphasis on the potential of targeting cytokine alarmins, especially thymic stromal lymphopoietin.

Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44

Graphical Abstract Figure. No caption available. SUMMARY B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well‐understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD‐secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44‐binding protein galectin‐9. When engaged by antigen, basophil‐bound IgD increased basophil secretion of interleukin‐4 (IL‐4), IL‐5, and IL‐13, which facilitated the generation of T follicular helper type 2 cells expressing IL‐4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil‐bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co‐ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2‐mediated immunity against common environmental soluble antigens. HIGHLIGHTSIgD interacts with basophils through the CD44‐binding protein galectin‐9IgD ligation by antigen elicits basophil release of Th2 cell‐associated cytokinesIgD‐activated basophils enhance B cell production of IgG1 and IgEIgD interferes with IgE‐mediated basophil degranulation &NA; The function of IgD has been mysterious. Shan et al. find that IgD recognized food antigens and targeted basophils through galectin‐9. IgD ligation by antigen induced basophil secretion of IL‐4, IL‐5, and IL‐13, which amplified Th2 cell‐mediated IgG1 and IgE production by B cells. IgD also constrained IgE‐mediated basophil degranulation.

First Responders: Innate Immunity to Helminths

Helminth infections represent a significant public health concern resulting in devastating morbidity and economic consequences across the globe. Helminths migrate through mucosal sites causing tissue damage and the induction of type 2 immune responses. Antihelminth protection relies on the mobilization and activation of multiple immune cells, including type 2 innate lymphocytes (ILC2s), basophils, mast cells, macrophages, and hematopoietic stem/progenitor cells. Further, epithelial cells and neurons have been recognized as important regulators of type 2 immunity. Collectively, these pathways stimulate host-protective responses necessary for worm expulsion and the healing of affected tissues. In this review we focus on the innate immune pathways that regulate immunity to helminth parasites and describe how better understanding of these pathways may lead to the development of new therapeutic strategies.

Basophils – Role in Immunity

Basophils are rare immune cells that were originally identified by the German scientist Paul Ehrlich over a century ago. Similar to mast cells, basophils are known to possess granules containing preformed effector molecules, bind immunoglobulin E (IgE), and expand in number in the context of type 2 cytokine responses. Despite these advances, the specific contributions of basophils to the induction of type 2 cytokine-mediated inflammation and protective immunity remain to be fully defined. Recent advances in flow cytometric techniques and murine model systems have allowed investigators to, for the first time, define the nonredundant functions of basophils in the context of several infectious insults. Here we will review these recent studies and discuss how they have significantly informed our greater understanding of basophil biology. Further, we will highlight how these recent conceptual advances may inform new therapeutic strategies to treat clinically important infections.