Rachana Agrawal

Oxidized phospholipid-induced inflammation is mediated by Toll-like receptor 2.

Oxidative tissue damage is a hallmark of many chronic inflammatory diseases. However, the precise mechanisms linking oxidative changes to inflammatory reactions remain unclear. Herein we show that Toll-like receptor 2 (TLR2) translates oxidative tissue damage into inflammatory responses by mediating the effects of oxidized phospholipids. Intraperitoneal injection of oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (OxPAPC) resulted in upregulation of inflammatory genes in wild-type, but not in TLR2(-/-) mice. In vitro, OxPAPC induced TLR2 (but not TLR4)-dependent inflammatory gene expression and JNK and p38 signaling in macrophages. Induction of TLR2-dependent gene expression required reducible functional groups on sn-2 acyl chains of oxidized phospholipids, as well as serum cofactors. Finally, TLR2(-/-) mice were protected against carbon tetrachloride-induced oxidative tissue damage and inflammation, which was accompanied by accumulation of oxidized phospholipids in livers. Together, our findings demonstrate that TLR2 mediates cellular responses to oxidative tissue damage and they provide new insights into how oxidative stress is linked to acute and chronic inflammation.

Skin barrier defects in atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology that is dependent upon interactions between the host and the environment. Acute skin lesions exhibit the features of a Th2-driven inflammatory disorder, and many patients are highly atopic. The skin barrier plays key roles in immune surveillance and homeostasis, and in preventing penetration of microbial products and allergens. Defects that compromise the structural integrity or else the immune function of the skin barrier play a pivotal role in the pathogenesis of AD. This article provides an overview of the array of molecular building blocks that are essential to maintaining healthy skin. The basis for structural defects in the skin is discussed in relation to AD, with an emphasis on filaggrin and its genetic underpinnings. Aspects of innate immunity, including the role of antimicrobial peptides and proteases, are also discussed.

Mechanisms of tolerance induction in allergic disease: integrating current and emerging concepts

The prevalence of atopy and allergic disease continues to escalate worldwide. Defining immune mechanisms that suppress the underlying Th2‐driven inflammatory process is critical for the rational design of new treatments to prevent or attenuate disease. Allergen immunotherapy has provided a useful framework for evaluating changes in the immune response that occur during the development of tolerance. Despite this, elucidating the phenotypic and functional properties of regulatory cells, has proven challenging in humans with allergic disease. This article provides an overview of our current understanding of the immune pathways that orchestrate allergen tolerance, with an emphasis on emerging concepts related to human disease. A variety of regulatory cell types, including IL‐10‐secreting T and B cells, play a pivotal role in suppressing allergic responses to inhaled, ingested and injected allergens. These cells may inhibit Th2 effectors directly, or else indirectly, through other cell types and mediators. Protective antibodies, including IgG4, Fc sialylated IgG, and IgA, have the capacity to modulate the response by preventing allergen binding to surface‐bound IgE, or inhibiting dendritic cell maturation. Immune cell plasticity may augment suppression of Th2 cells by T regulatory cells, through mechanisms that involve T cell conversion, or else unconventional roles of classical effector cells. These actions depend upon external cues provided by the in vivo milieu. As such, specific anatomical sites may preferentially favour tolerance induction. Recent scientific advances now allow a global analysis of immune parameters that capture novel markers of tolerance induction in allergic patients. Such markers could provide new molecular targets for assessing tolerance, and for designing treatments that confer long‐lasting protection in a safe and efficacious fashion.

Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis.

Atopic dermatitis (AD) is common in children; however, persistence of AD with or without asthma is less common. Longitudinal studies remain limited in their ability to characterize how IgE antibody responses evolve in AD, and their relationship with asthma.

A molecular perspective on TH2-promoting cytokine receptors in patients with allergic disease

The cytokines IL-4, IL-13, and thymic stromal lymphopoietin play a key role in allergic disease by virtue of their ability to initiate, maintain, and augment TH2 responses. These molecules mediate their effects through type 1 cytokine receptors, which bind cytokines with a characteristic structure. Receptors are expressed on a broad array of immune cell types and are integral to complex cytokine networks operating in health and disease. TH2-promoting cytokines bind different configurations of receptors. Receptor subunits can exist in surface-bound or soluble forms, as well as in isolation or in partnership with other subunits. Sharing of receptor subunits among different cytokine receptor complexes adds to the intricate landscape. This article describes the characteristics of receptors for IL-4, IL-13, and thymic stromal lymphopoietin and their respective ligands from a structure-function perspective. We detail the mechanisms of receptor complex assembly, the interrelated nature of these receptors, and the effect on allergic inflammation. The ability for novel and atypical types of receptors to modulate inflammatory processes is also discussed. We highlight current and emerging treatments that target TH2-promoting receptor complexes. Understanding the molecular features of these receptors provides insight into different disease phenotypes and the variable clinical outcomes arising from targeted therapies. These considerations can be used to inform future directions for research and creative strategies for treating individual patients.

The Role of Regulatory T Cells in Atopic Dermatitis

Regulatory T (T(reg)) cells play a pivotal role in immune suppression and are integral to the control of allergic responses. The chronic inflammatory skin condition atopic dermatitis (AD) is severest in patients who are sensitized to allergens from diverse sources including foods, pollens and animal danders, as well as skin-colonizing organisms. These individuals typically present with eczematous skin eruptions in early childhood, and evolution of the disease is thought to reflect an underlying dysregulated T-cell response to allergens that manifests as a Th2 response. Studying T(reg) cells in the context of AD from infancy into adulthood could yield insight into their role in disease pathogenesis and reveal new strategies for exploiting these cells for therapeutic purposes. Such studies are challenging in humans owing to the heterogeneous nature of T(reg) cells, lack of a reliable surface marker, and the paucity of knowledge surrounding the emergence of specialized T cells in early life. Moreover, the blurred distinction between activated effector T cells and T(reg) cells further complicates studies in the context of inflammatory disorders such as AD. There is emerging evidence to suggest that T(reg) cells can convert to Th2 cells and that this pathway is bidirectional. This phenomenon may be a double-edged sword with important implications not only for subverting T(reg) cells in disease, but also for potential treatments designed to amplify these cells in order to suppress the allergic inflammatory cascade in AD.

Analysis of Cytokine Production by Peanut-Reactive T Cells Identifies Residual Th2 Effectors in Highly Allergic Children Who Received Peanut Oral Immunotherapy

Only limited evidence is available regarding the cytokine repertoire of effector T cells associated with peanut allergy, and how these responses relate to IgE antibodies to peanut components.

Infection with human rhinovirus 16 promotes enhanced IgE responsiveness in basophils of atopic asthmatics

Rhinovirus and IgE act in concert to promote asthma exacerbations. While basophils are the principal cell type in the blood that is activated by IgE, their role in virus‐induced asthma episodes remains elusive.

Mast Cell-Activated Bone Marrow Mesenchymal Stromal Cells Regulate Proliferation and Lineage Commitment of CD34+ Progenitor Cells

Background: Shortly after allergen exposure, the number of bone marrow (BM) and circulating CD34+ progenitors increases. We aim to analyze the possible mechanism whereby the allergic reaction stimulates BM to release these effector cells in increased numbers. We hypothesize that mast cells (MCs) may play a predominant role in this process. Objective: To examine the effect of IgE-activated MCs on BM mesenchymal stromal cells which regulate proliferation and differentiation of CD34+ progenitors. Methods: Primary MCs were derived from CD34+ precursors and activated with IgE/anti-IgE. BM mesenchymal stromal cells were co-cultured with CD34+ progenitor cells and stimulated with IL-1/TNF or IgE/anti-IgE-activated MCs in Transwell system. Results: BM mesenchymal stromal cells produce low level of thymic stromal lymphopoietin (TSLP) under steady state conditions, which is markedly increased by stimulation with proinflammatory cytokines IL-1 and TNF or IgE-activated MCs. The latter also triggers bone marrow-derived mesenchymal stromal cells production of G-CSF, and GM-CSF while inhibiting SDF-1. MC-activated mesenchymal stromal cells stimulate CD34+ cells to proliferate and to regulate their expression of early allergy-associated genes. Conclusion and Clinical Relevance: This in vitro study indicates that IgE-activated MCs trigger BM mesenchymal stromal cells to release TSLP and hematopoietic growth factors and to regulate the proliferation and lineage commitment of CD34+ precursor cells. The data predict that the effective inhibition of MCs should impair mobilization and accumulation of allergic effector cells and thereby reduce the severity of allergic diseases.

TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status

Background: The pathogenesis of severe asthma in childhood remains poorly understood. Objective: We sought to construct the immunologic landscape in the airways of children with severe asthma. Methods: Comprehensive analysis of multiple cell types and mediators was performed by using flow cytometry and a multiplex assay with bronchoalveolar lavage (BAL) specimens (n = 68) from 52 highly characterized allergic and nonallergic children (0.5–17 years) with severe treatment‐refractory asthma. Multiple relationships were tested by using linear mixed‐effects modeling. Results: Memory CCR5+ TH1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN‐&ggr;+IL‐17+ and IFN‐&ggr;−IL‐17+ subsets constituted secondary TH types, and BAL fluid CD8+ T cells were almost exclusively IFN‐&ggr;+. The TH17‐associated mediators IL‐23 and macrophage inflammatory protein 3&agr;/CCL20 were highly expressed. Despite low TH2 numbers, TH2 cytokines were detected, and TH2 skewing correlated with total IgE levels. Type 2 innate lymphoid cells and basophils were scarce in BAL fluid. Levels of IL‐5, IL‐33, and IL‐28A/IFN‐&lgr;2 were increased in multisensitized children and correlated with IgE levels to dust mite, ryegrass, and fungi but not cat, ragweed, or food sources. Additionally, levels of IL‐5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE+Fc&egr;RI+ myeloid dendritic cells were present in BAL fluid. Conclusions: The lower airways of children with severe asthma display a dominant TH1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of TH1 cells in patients with severe asthma.