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The prevalence of asthma has markedly increased in recent decades. Asthma affects approximately ten percent of the population of the United States, and is the leading cause of childhood hospitalization. This epidemic has been attributed to air pollution, childhood immunizations and a more sanitary living environment. Allergic asthma is clinically characterized by airway hyperreactivity (AHR), increased mucus production and airway remodeling. On the cellular level, pulmonary eosinophilic infiltration and augmented levels of serum IgE arise as a consequence of a CD4+ Th2 cell response in the airway following exposure to allergen. It has been proposed that the chronic inflammation and associated airway events evident in this disease stem from a failure to regulate the underlying immune response. How these events are regulated in the healthy lung is yet unclear. In studies to investigate the mechanisms underlying such regulation we found that firstly, co-transfer of expanded natural CD4+ CD25+ Foxp3+ regulatory T cells (nTregs) mediated regulation of CD4+ Th17 effector cells as exemplified by diminished levels of IL-17 and decreased neutrophilic infiltration in the airways. In contrast, co-transfer of nTregs did not attenuate the lung inflammation elicited by CD4+ Th2 or Th1 polarized cells. Interestingly, using the C129. IL4GFP mice we found that nTregs have the capacity to inhibit IL-4 production and Th2 differentiation in vitro. Secondly, mice with genetically disrupted receptors (IP-/- ) for the lipid-mediator prostacyclin (PGI2), demonstrated increased airway inflammation, eosinophilic infiltration and airway hyperreactivity following immunization and repeated aerosol challenge with ovalbumin. Moreover these mice displayed reduced serum immunoglobulin levels. In summary, nTregs serve a specific function in controlling Th17 cell effector functions, but not Th1 or Th2 inflammation. Additionally, PGI2-IP signaling is an important pathway for inhibiting allergic pulmonary inflammation by controlling CD4+ Th2 cell effector functions.
Atopic asthma and allergic inflammation is most-commonly supported by a Th2-biased immune response. Research identifying new mechanisms important for promoting the differentiation, trafficking, and resolution of Th2 cells in asthma will be necessary for the development of novel therapies. When allergic triggers are inhaled, dendritic cells (DCs) process and present antigens to T cells, but the mechanisms utilized by DCs to promote Th2-specific differentiation are unclear. Herein, we identified interferon regulatory factor 4 (IRF4) in DCs to be necessary for the promotion of Th2 responses in vivo. Utilizing in vitro derived DCs, we found that IRF4 directly drives Il10 and Il33 expression in DCs for the promotion of Th2 differentiation. Following activation, migration of Th2 cells into sites of inflammation is mediated through chemokine receptors that are upregulated. We find regulator of G-protein signaling 3 (RGS3) to be abundantly expressed in activated T cells. Deletion of the RGS-domain of Rgs3 in mice resulted in augmented T cell recruitment to sites of allergen exposure, showing RGS3 has a dramatic effect on regulating activated T cell migration. Finally, Fas (CD95) on T cells is known to be necessary for normal resolution of Th2-mediated airway inflammation. We found that Fas on Th2 cells specifically signals through non-apoptotic pathways to drive resolution of airway inflammation, and that increasing T cell survival through apoptotic pathways failed to influence the resolution of Th2-mediate inflammation. Together, these findings address three mechanisms important for the development and resolution of Th2- mediated airway inflammation that represent novel targets for the advancement of Th2-therapies.
The complement anaphylatoxins (ATs) C3a and C5a are proinflammatory mediators contributing to the effector phase of allergic asthma. Recent studies suggest that ATs also play important immunoregulatory roles during allergen sensitization particularly at the interface of dendritic cells (DCs) and T cells. ATs exert their biological activities through interaction with three cognate receptors, namely the C3a receptor (C3aR), C5aR and C5a receptor-like 2 (C5L2). To investigate AT receptor-mediated regulation of pulmonary inflammation and maladaptive immunity, we have determined the immune responses in C3aR-, C5aR- and C5L2-deficient mice in models of house dust mite (HDM)- and ovalbumin (OVA)-induced experimental allergic asthma. Further, we directly examined the impact of AT receptor signaling in myeloid DCs (mDCs) on T cell activation and subsequent development of asthmatic phenotype. We found that HDM-treated C5aR-deficient mice (C5aRKOs) exhibited strong airway hyperresponsiveness (AHR), airway eosinophilia and dysregulated adaptive T and B cell responses, suggesting a protective immunoregulatory role for C5a in response to allergen exposure. Surprisingly, we observed that bone marrow-derived C5aR-deficient mDCs had an impaired ability to drive T helper type 2 (Th2) immunity, AHR and airway inflammation when adoptively transferred into the airways of naïve wild type (WT) mice. These data suggest that C5aR signaling in mDCs is required for efficient mDC function to activate naïve T cells and mediate allergen-induced inflammatory responses. Our findings further demonstrate that C5aR signaling in cell types other than mDCs accounts for its protective effect. Indeed, we found that C5aR signaling is required for pulmonary accumulation of tolerogenic plasmacytoid DCs expressing inhibitory B7-H1 and B7-DC molecules as a means to control Th2 cell effector functions. Contrary to C5aRKOs, C3aRKO and C5L2KO mice showed attenuated allergic phenotypes in response to inhaled allergens. Importantly, C5aR blockade in C3aRKOs resulted in a strong allergic phenotype similar to C5aRKOs. Further, we found reciprocal modulation of C5aR and C3aR in pulmonary DCs suggesting that C3aR signaling enhances the development of airway inflammation and maladaptive Th2 immunity indirectly through regulation of protective C5aR signaling. Interestingly, we observed that HDM-pulsed C3aR-deficient mDCs had the same potency as WT mDCs to drive Th2 immune responses, suggesting that C3aR signaling is not required for mDC-mediated activation of naïve T cells but important for proinflammatory effector functions mediated through infiltrating inflammatory cells during the allergic effector phase. In contrast, C5L2 and C5aR synergistically activated mDCs as evidenced by an impaired ability of C5L2-deficient mDCs to promote AHR, airway eosinophilia and B cell responses. Furthermore, we found a marked increase in pulmonary production of interferon-gamma and interleukin-17 associated with substantial airway neutrophilia in mice receiving C5aR- or C5L2-deficient mDCs, suggesting that C5a controls the differentiation of Th1 and Th17 cells as a potential mechanism to enhance Th2 cell development. In summary, our data presented in this thesis suggest that AT receptors exert critical and complex immunoregulatory functions that either promote or suppress the development of allergic asthma through regulation of DC-T cell interactions, effector cell and possibly pulmonary resident cell activities.
Severe asthma is a form of asthma that responds poorly to currently available medication, and its patients represent those with greatest unmet needs. In the last 10 years, substantial progress has been made in terms of understanding some of the mechanisms that drive severe asthma; there have also been concomitant advances in the recognition of specific molecular phenotypes. This ERS Monograph covers all aspects of severe asthma – epidemiology, diagnosis, mechanisms, treatment and management – but has a particular focus on recent understanding of mechanistic heterogeneity based on an analytic approach using various ‘omics platforms applied to clinically well-defined asthma cohorts. How these advances have led to improved management targets is also emphasised. This book brings together the clinical and scientific expertise of those from around the world who are collaborating to solve the problem of severe asthma.
Problem: Over the last century, atopic diseases like asthma have increased in prevalence throughout the world. Medical and surgical treatment for refractory asthma is expensive, and unaffordable to poor patients. Research over the last twenty years has shown a relationship between decreased helminth burden in populations and increased atopy, indicating that there may be a role for low-cost iatrogenic helminth infection in refractory asthma. Methods: A search in PubMed was utilized to search all journals to identify previous research conducted, results found, and derived conclusions for published articles relating to the effects of helminth infection on atopy. Articles that focused on epidemiologic support for the Hygiene Hypothesis, the modulating effect helminths have on immune systems, and treatment of diseases using helminthic therapy were included in the review. Results: A final number of 19 articles used for literature review was pooled from four searches. Conclusions: Epidemiologic research has demonstrated a relationship between helminth infection, specifically with Necatar americanus , and a decreased incidence of asthma. Basic research has proposed several mechanisms by which the effects helminths have on immune systems might reduce atopy. However, there have been no published randomized controlled trials testing the clinical usefulness of iatrogenic helminth infection in refractory asthma.
Asthma is a common chronic inflammatory disease. Pathogenic mechanism underlying asthma is complex. The inflammatory response of asthma includes lymphocytes (T, B cells), ILC2, eosinophils and other types of immune and inflammatory cells. T CD4+ T helper 2 cells (Th2 cells) are thought to play a central role in regulating the phenotype of allergic asthma. Asthma is often closely associated with Th1/Th2 cell imbalance. Non-coding RNAs (ncRNAs) are non-protein coding RNA molecules in the transcriptome, mainly including microRNAs (miRNAs), long non-coding RNAs and circRNAs, etc., which are widely found in eukaryotic transcriptome and participate in the regulation of a variety of biological processes. ncRNAs are considered to function as modulators of the immune system. Their biological changes represent an important mechanism for the development of immune-mediated diseases. This chapter mainly discusses the epigenetic regulation of Th2 cells and their cytokines in asthma by non-coding RNAs. It helps us to better understand the pathogenesis of asthma and find potential asthma biomarkers.
Among the topics reviewed are T and B cell tolerance, clonal deletion, suppressor cells, mechanisms of immune privileged sites and experimental models of tumor immunity. Oral tolerance, ultraviolet radiation and photosensitized effects on immunity, allograft management, T cell vaccination and regulation of immunity with T cell epitopes are discussed from the point of view of possible therapeutic application.
The Janeway's Immunobiology CD-ROM, Immunobiology Interactive, is included with each book, and can be purchased separately. It contains animations and videos with voiceover narration, as well as the figures from the text for presentation purposes.