Global strategy for asthma management and prevention

CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25− naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25− T cells into anergic/suppressor cells that are CD25+, CD45RB−/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor β (TGF-β). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-β induced Foxp3 gene expression in TCR-challenged CD4+CD25− naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-β and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-β–converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-β–induced suppressor T cells prevented house dust mite–induced allergic pathogenesis in lungs.

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Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3

The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses. Defining the cellular and molecular mechanisms of helper-T-cell differentiation should lead to rational strategies for manipulating immune responses for prophylaxis and therapy.

Functional diversity of helper T lymphocytes.

Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Despite its simplicity, recent progress has demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles, which are sometimes complex. Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function. In this review, the process of autophagy is summarized, and the role of autophagy is discussed in a process-based manner.

http://genesdev.cshlp.org/content/21/22/2861.full.pdf

Autophagy: process and function

https://www.cell.com/immunity/pdf/S1074-7613(10)00173-1.pdf

Alternative Activation of Macrophages: Mechanism and Functions

The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4 + T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.

https://science.sciencemag.org/content/sci/282/5397/2258.full.pdf

Interleukin-13: Central Mediator of Allergic Asthma

Interleukin-13: Central mediator of allergic asthma

▪ Abstract The incidence, morbidity, and mortality of asthma has increased worldwide over the last two decades. Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), and airway inflammation. The inflammatory response in the asthmatic lung is characterized by infiltration of the airway wall with mast cells, lymphocytes, and eosinophils. Although asthma is multifactorial in origin, the inflammatory process in the most common form of the disease (extrinsic asthma) is believed to be a result of inappropriate immune responses to common aero-allergens in genetically susceptible individuals. As such, it has been hypothesized that CD4+ T cells that produce a Th2 pattern of cytokines play a pivotal role in the pathogenesis of this disease. Through the release of cytokines such as IL-4, IL-13, and IL-5, these cells orchestrate the recruitment and activation of the primary effector cells of the allergic response, the mast cell and the eo...

Immunologic basis of antigen-induced airway hyperresponsiveness

Rising rates of allergic disease accompany the healthier benefits of a contemporary westernized lifestyle, such as low infant mortality It is likely that these twinned phenomena are causally related The hygiene hypothesis states that allergy and increased longevity are both consequences of reducing infectious stressors during early childhood for millennia Mechanistic explanations for the hygiene hypothesis have typically invoked the T-helper-type 1/2 (T(H)1/T(H)2) model Here, we discuss why we favour a broader 'counter-regulatory' model--one that might also explain the increasing incidence of autoimmune disease in westernized countries

The germless theory of allergic disease: revisiting the hygiene hypothesis

Aeroallergy results frommaladaptiveimmuneresponses toubiquitous, otherwise innocuous environmental proteins 1 . Although the proteinstargetedbyaeroallergicresponses representa tinyfraction of the airborne proteins humans are exposed to, allergenicity is a quite public phenomenon—the same proteins typically behave as aeroallergens across the human population. Why particular proteins tend to act as allergens in susceptible hosts is a fundamental mechanistic question that remains largely unanswered. The main house-dust-mite allergen, Derp2, has structural homology with MD-2 (also known as LY96), the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR) 4 signalling complex 2–4 . HereweshowthatDerp2alsohasfunctionalhomology,facilitating signalling through direct interactions with the TLR4 complex, and reconstituting LPS-driven TLR4 signalling in the absence of MD-2. Mirroring this, airway sensitization and challenge with Derp2 led to experimental allergic asthma in wild type and MD-2-deficient, butnotTLR4-deficient,mice.OurresultsindicatethatDerp2tends to be targeted by adaptive immune responses because of its autoadjuvant properties. The fact that other members of the MD-2-like lipid-binding family are allergens, and that most defined major allergens are thought to be lipid-binding proteins 5 ,s uggests that intrinsicadjuvantactivitybysuchproteinsandtheiraccompanying lipid cargo may have some generality as a mechanism underlying the phenomenon of allergenicity. Although the potential biological significance of several allergens having protease activity has received experimental attention 5,6 , cogent mechanistic hypotheses for why most aeroallergens have a propensitytogeneratemaladaptiveeffectorT-cellresponsesarelacking. TLRs, receptors for conserved microbial structures, have a critical role in the controlling initiation and class specification of adaptive immune responses by antigen-presenting cells (APCs) 7 . Exogenous antigen presentation by APCs in the absence of direct TLR stimulation generally leads to tolerance 8 . Moreover, efficient generation of effector T-cell responses by APCs is dependent on thepresence ofTLRligandsinthephagosomecontaining theantigen being presented 9 . House dust mites are a major source of aeroallergens for patients with allergic asthma 10 . Concentrated in mite faecal pellets 11 , the

/pdf/allergenicity-resulting-from-functional-mimicry-of-a-toll-4e6n691pyj.pdf

Marsha Wills-Karp

Papers

Interleukin-13: Central Mediator of Allergic Asthma

Interleukin-13: Central mediator of allergic asthma

Immunologic basis of antigen-induced airway hyperresponsiveness

The germless theory of allergic disease: revisiting the hygiene hypothesis

Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein