Asma Dan Alergi

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  Leading Edge Essay  Cell 140 , March 19, 2010 ©2010 Elsevier Inc. 777  Asthma is a syndrome characterized by intermittent attacks, often nocturnal, of breathlessness, wheezing, and cough. Onset of the disease is most common during childhood, when it can usually be controlled with inhaled medications.  Asthma runs a variable natural history, and as many as one in four patients may continue to have symptoms that persist or recur in adulthood. The childhood dis-ease is often associated with other aller-gic disorders, such as atopic dermatitis (eczema) and seasonal rhinitis (hayfever). The latter manifestations can precede the recognition of full-blown asthma, a processive sequence denoted the “atopic march.” Patients with persistent disease into adulthood, or those who have onset in adulthood, are more likely to include subgroups with more frequent and severe episodes that require intensi-fication of therapy. In general, however, the severity of the disease is usually established at or near the time of onset. A breakthrough in the understanding of asthma pathogenesis was made with the recognition that chronic inflammation of the conducting airways characterizes the disease, even during asymptomatic peri-ods. Inflammation includes the presence of CD4 T helper 2 (Th2) cells and Th2-associated cytokines, as well as eosino-phils, a finding that has greatly informed experimental animal studies seeking to understand the initiation and mainte-nance of allergic immunity (Robinson et al., 1992). More recent findings have suggested that IL-17-associated neu-trophil inflammation of the airways and even “pauci-granulocytic” subtypes with minimal inflammatory cell infiltrates can occur (Wenzel, 2006). Whether alternative forms of inflammation represent distinct subtypes of the disease or heterogene-ity in the response to currently available therapeutics, or both, is unknown. Per-sistent inflammation, possibly fueled by immune responses to repeated inhala-tions of environmental allergens, such as pollens, grasses, animal danders, molds, and excreta from urban-dwelling insects (particularly dust mites and cockroaches), results in compensatory structural airway alterations. These include epithelial mucus metaplasia, smooth muscle hypertrophy, and enhanced deposition of subepithe-lial matrix glycoproteins. These changes, collectively termed “airway remodeling,” are thought to lead to the persistent, poorly reversible airflow limitations and airway hyper-responsiveness found in some patients with chronic asthma. Air-way hyper-responsiveness is revealed by aerosolized agonist drugs, such as meth-acholine, that induce smooth muscle con-traction, by respiratory irritants, including pollutants (e.g., sulfur dioxide, diesel fuel particles), or by recurrent respiratory virus infections, such as those caused by rhi-noviruses or respiratory syncytial viruses. Despite many advances, it is clear that no animal model completely simulates the human disease. More access to human tissues will be required to gain a deeper understanding of the natural history, breadth, and pathogenesis of asthma. Scope of the Problem  Asthma and allergic inflammation, including food allergies, have increased over the past 50 years to become the most prevalent chronic illnesses of childhood in developed countries. The estimated worldwide prevalence of asthma is 300 million persons. In the United States, childhood asthma preva-lence more than doubled between 1980 and the mid-1990s, with 2007 estimates projecting 16.2 million adults and 6.7 mil-lion children with the disease, over 8% of the population (Moorman et al., 2007).  Although mortality is infrequent, asthma patients drive extensive use of the health care system, accounting for approxi-mately 10 million office visits, 400,000 hospitalizations, and 200,000 emer-gency room visits; in some communities, one in four emergency room patients are seen for asthma. Annual economic costs approach $20 billion in the United States alone. Over half of patients with asthma have additional allergic diseases, includ-ing food allergies. The latter has reached awareness levels such that peanut butter has been essentially banned from grade schools in many metropolitan areas of the United States.The increase in allergic diseases over relatively short time periods implicates environmental factors as overwhelming determinants of disease risk. Genetic pre-disposition to asthma is clear, however, with family and twin studies suggesting hereditary contributions approaching 60%. Genome-wide studies of asthma in carefully phenotyped populations remain few and, similar to other chronic complex human diseases, suggest relatively small contributions by many loci, few of which have been rigorously quantified (Rog-ers et al., 2009). Posited genome-envi-ronment interactions, as proposed for most complex human diseases, are only vaguely defined. Genetic disparities that drive ethnic differences in asthma risk, severity, or drug responsiveness also  Asthma and Allergic Inflammation Richard M. Locksley 1, * 1 Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94143, USA *Correspondence: locksley@medicine.ucsf.eduDOI 10.1016/j.cell.2010.03.004 Studies of the initiation and maintenance of asthma and allergic inflammation implicate dysregu-lated interactions between mucosal epithelia and innate immune cells as the underlying cause of these disorders. The similarities of these responses with mucosal responses to parasitic intes-tinal worms may reveal pathways relevant to the perplexing rise of these chronic inflammatory disorders.  778  Cell 140 , March 19, 2010 ©2010 Elsevier Inc. obscure analysis (Burchard et al., 2003). Replication against larger cohorts of well-defined populations will be needed. Intriguing links with genes involved in the pathway for the terminal differentiation of keratinocytes into barrier cells secret-ing the protein-lipid matrix that regulates skin permeability have suggested a con-nection with epithelial barrier dysfunc-tion. Common loss-of-function muta-tions in filaggrin, a cytoskeletal structural protein in keratinocytes, present in up to 10% of Western Europeans and their descendants have been associated with severe atopic dermatitis and, in some studies, with risk for asthma (Muller et al., 2009). Loss of barrier function may establish breaches for allergen entry and priming (Fallon et al., 2009) and/or lead to changes in the commensal microbial flora that alter the homeostatic regula-tion of immunity in ways that predispose to allergy, perhaps mediated by elabora-tion of the epithelial cell cytokine thymic stromal lymphopoietin (TSLP; Demehri et al., 2009). Epidemiologic studies have repeatedly identified more severe viral upper respiratory infections, most com-monly rhinoviruses, early in life as a major risk, particularly in families with a history of atopy. An urbanized lifestyle in early life also increases risk, suggesting that post-natal exposure to indoor antigens or urban pollutants affects the quality of subsequent mucosal immunity. Alter-natively, loss of exposure to microbes associated with rural environments may shape the infant immune system.Whatever underlies the rising preva-lence of asthma, it is recognized that some patients, although the exact pro-portion is unknown, progress to irre-versible lung changes characterized by the increased subepithelial fibrosis and structural hyperplasia of airway remod-eling. When severe, these patients can overlap the pathologic spectrum of patients with chronic bronchitis. The impact of primary and secondary smok-ing exposure has complicated analysis, although cases can occur in nonsmok-ers. Animal models have been very informative in increasing understand-ing of asthma, but these are imperfect, and lack of access to patient tissues has hampered the ability to delineate fully the natural history and full spectrum of human disease. Figure 1. Pathways of Allergic Immunity  Initiation of allergic immunity is mediated through interactions of allergens with epithelia that result in release of the cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25. TSLP mediates migration of dendritic cells (DCs) and their maturation, which primes the IL-4 competency of T helper (Th) cells. These competent Th cells move into follicular areas of lymph nodes and mature into IL-4-secreting T FH  cells. They mediate isotype switching in B cells in the germinal center reaction in lymph nodes. The B cells then produce IgE antibody (and IgG1 in the mouse). IgE, in turn, binds to mast cells and basophils, extending their survival and facilitating allergen-specific activation of these cells. IL-33 promotes IL-4 re-lease from basophils, and IL-33 and IL-25 promote IL-13 and IL-5 release from IL25R +  natural helper cells in tissues (these cells also release IL-6, which supports B cell maturation and impairs T regulatory cells). IL25R +  natural helper cells and basophils together produce IL-4, IL-5, and IL-13, which promote terminal differentiation and/or recruitment of T helper 2 (Th2) cells to tissues, as well as alternative activation of macrophages (AAM φ  ) and eosinophil recruitment. These effects are greatly augmented by activation of tissue Th2 cells, which contribute a diverse set of cytokines that feed back to facilitate the survival and activation of innate immune cells and the effects of Th2-associated cytokines on epithelia, smooth mus-cle, and the stromal matrix. Memory T and B cells are generated that can facilitate more rapid responses to repeated stimulation, particularly if the regulatory T cell response is impaired (not shown).  Cell 140 , March 19, 2010 ©2010 Elsevier Inc. 779 Pathogenesis: Current Status  Asthma and food allergies are initiated at mucosal sur-faces where environmental allergens contact epithelia. The physical properties that endow environmentally wide-spread entities with allergenic properties are of much inter-est but, in asthma, at least minimally involve the capacity to be sustained in aerosolized forms that reach conducting airways and evade muco-ciliary clearance. Allergens may share properties such as stability, protease activity, or molecular mimicry, which endows them with the capac-ity to penetrate mucus and epithelial barriers and induce cytokine release by engag-ing innate pattern recognition receptors on epithelia and resident lung myeloid cells, including macrophages, den-dritic cells, and mast cells. Natural allergens are typically complex biological mixtures of constituents that share many individual attributes, a fea-ture infrequently addressed in experi-mental models. Airway inflammation is sustained from these initial encounters through the interactions between epi-thelia of the airways and recruited anti-gen-processing cells, likely monocyte-derived dendritic cells, although recent studies suggest that basophils may subserve this function in allergic inflam-mation in some situations. In this way, adaptive immunity is engaged through the development of antigen-specific memory T cells and antibody-secret-ing plasma cells, thus establishing the potential for chronicity upon repeated exposures to allergens.The subsequent pathways are based on an amalgamation of mouse studies, often in the setting of overexpression or deletion of various genes, and human studies based largely on in situ analy-sis and studies of isolated cells and cell lines. Differences in cells, receptors, and anatomy of the airways between the spe-cies suggest caveats in creating a unify-ing hypothesis of current understanding. Of necessity oversimplified, the reader is referred to recent reviews (Barrett and  Austen, 2009; Lambrecht and Hammad, 2009; Saenz et al., 2008). Briefly, current models envision the release of epithelial cytokines, particularly IL-25, IL-33, and TSLP, and CC family chemokines as proximal events important in initiating allergic inflammation (Figure 1). Although few studies are available, IL-25, IL-33, and TSLP can be elicited from epithelia when activated by allergenic stimuli or by helminth parasitic worms and can induce IL-13-dependent allergic inflammation when administered individually to mice or when overexpressed as transgenes. In the lung, TSLP may be released from other sources as well, as epithelial pro-duction at this site is lower than in skin and bowel. These cytokines also target resident hematopoietic cells to induce the influx of inflammatory cells from the circulation and the activation and mobi-lization of dendritic cells. Although all of these cytokines can target multiple cell types, IL-33 potently activates mast cells to secrete vasoactive amines, lipid mediators, chemokines, and cytokines and as such may contribute to anaphy-laxis (Pushparaj et al., 2009). Basophils, initially fewer in number in parenchymal tissues, are also activated by IL-33 to secrete cytokines, particularly IL-4. IL-25 and IL-33 potently activate IL-25R +  lymphoid cells in tissues that remain incompletely charac-terized (Fort et al., 2001; Moro et al., 2009). When activated, these lymphoid cells respond by producing the key cytok-ines IL-5 and IL-13. IL-5 medi-ates the survival of eosino-phils, whereas IL-13 mediates the induction of chemokines, the differentiation of mucus-secreting goblet cells, a pro-fibrogenic stromal environ-ment, alternative macrophage activation, and smooth mus-cle alterations that contribute to enhanced airway hyper-responsiveness. IL-4, which shares use of the type II IL-4 receptor with IL-13, contrib-utes to these functions of IL-13, making this shared receptor an attractive phar-maceutical target. TSLP tar-gets dendritic cells and mediates mobi-lization, activation, and induction of the TNF superfamily member OX40L. In both mouse and human studies, OX40L-pos-itive dendritic cells activate naive CD4 T cells to an IL-4-competent state, consis-tent with an important priming step in Th2 cell differentiation.Once activated, IL-4-competent T cells in lymph nodes migrate to B cell zones and differentiate into T follicular helper (T FH  ) cells or exit into the drain-ing lymph and thence the circulation to complete maturation as Th2 cells (Figure 1). IL-4-secreting T FH  cells in parafolli-cular B cell areas mediate IgE switching and conjugate with B cells to drive IgG1 (and possibly IgG4 in human) switching and affinity maturation within germinal centers in lymph nodes (Reinhardt et al., 2009). The understanding of T FH  cells has been confusing due to the inabil-ity to distinguish these cells by surface phenotype, which is shared among most activated T cells in the lymph node. Most lymph node IL-4-secreting cells during allergic immunity are actually T FH  cells that mediate B cell help and not Th2 cells, which exit the lymph node and go to peripheral sites of inflammation. In Figure 2. Asthma and Helminth Infection The loss of universal helminth infections that occurred during human evolution may have altered the numbers or types of bacterial and fungal commensals and thus may have affected normal mucosal tissue homeostasis. In suscep-tible or highly exposed individuals, such alterations might alter the balance between immunotolerance, immunosurveillance, and nutrient extraction. This imbalance may contribute to the appearance of inflammatory systemic dys-regulation at mucosal surfaces, resulting in increases in asthma and allergic diseases, particularly in the setting of environmental changes that have in-creased exposure to indoor allergens and pollutants, and even in increases in obesity, which can be a risk factor for severe asthma.  780  Cell 140 , March 19, 2010 ©2010 Elsevier Inc. tissues, effector Th2 cells augment the survival of eosinophils and basophils by secretion of IL-5 and IL-3, respectively, facilitate mast cell survival via IL-9, and contribute antigen-specific elaboration of IL-4 and IL-13 required for epithelial and smooth muscle manifestations of the disease. Eosinophils, when sustained, mediate tissue remodeling and fibrosis. Macrophages assume an alternatively activated state in the setting of IL-4 and IL-13 stimulation and secrete pro-teases and enzymes involved in matrix remodeling; these cells also participate in restraining tissue inflammation. Many manifestations of the response resemble wound healing and likely target resolu-tion of the mucosal irritation. Over time, allergen-specific IgE (and, in the mouse, IgG1) antibodies occupy the high-affinity IgE Fc immunoglobulin receptor, Fc ε RI, expressed on mast cells and basophils (and, in the mouse, the respective IgG1-binding Fc γ RIII on these cells as well) to provide alternative mechanisms for cell activation by antibody crosslinking. With repeated allergen exposure, Fc ε RI activation leads to the rapid production of vasoactive amines and lipid media-tors that underlie the acute fall in respi-ratory function after allergen challenge, while also driving the elaboration of cytokines, chemokines, and lipid media-tors that regulate the delayed phase of the inflammatory process amplified by recruited cells. A common emergent theme is the role of adaptive immunity in providing cytokines and growth factors that sustain the recruitment, retention, and extended life span of a select group of myeloid cells, including eosinophils, basophils, and mast cells, in involved tissues. Occupancy of Fc ε RI by IgE can itself enhance the survival of mast cells and basophils, and serum IgE levels in humans correlate with Fc ε RI expression levels on dendritic cells, where, unlike in the mouse, components of the Fc ε RI are constitutively present on additional types of hematopoietic cells (Kraft and Kinet, 2007). Even relatively rare cell types, such as basophils, are increased in tis-sues from cases of fatal asthma (Kepley et al., 2001).Control of inflammation by regula-tory T cells (Treg) may also be compro-mised in asthma, although the precise pathways remain unclear. TGF- β  and IL-10 have been implicated in the reso-lution of allergic inflammation by Treg, but dysregulated expression of these cytokines has been connected with pro-gressive fibrosis and with a diminished capacity to restrain respiratory viruses, respectively. Further study of the natu-ral history of Treg and their specificity in allergic lung inflammation is needed (Lloyd and Hawrylowicz, 2009). With repeated allergen exposure, eosinophil and basophil infiltration become sus-tained, the mast cell pool enlarges, the epithelia undergo enhanced goblet cell differentiation with copious mucus pro-duction, thickening of the basal lamina reticularis is apparent, and increases in smooth muscle mass occur. The result is hyper-responsiveness to common air-way irritants. Although much insight has been gained in understanding the patho-genesis of asthma associated with Th2 cells and allergic pathology, very little is understood regarding the mechanisms that sustain airway inflammation among patients with neutrophilic or “pauci-granulocytic” presentations that make up a substantial number of adult-onset cases of asthma. New Directions and Needs Common environmental allergens are complex mixtures of bioactive entities. House dust mite allergens that elicit IgE reactivity include a papain-like cysteine protease; a lipid-binding MD-2 molecular mimetic capable of augmenting TLR4 sig-naling (Trompette et al., 2009); trypsin-like, chymotrypsin-like, and serine proteases; fatty acid- and lipid-binding proteins; chi-tinases; and at least ten other proteins (Thomas et al., 2002). Chitin and a variety of polymeric glycans are also present in mite and cockroach fecal pellets. Cock-roach allergens are similarly diverse and include active proteases and lipid-binding proteins involved in food digestion that are secreted in the fecal pellets. Fungi, a highly diverse spectrum of organisms, can con-tribute up to 10% of the particulate mass in air of sufficient size to be inhaled into the terminal airways and alveoli (Frohlich-Nowoisky et al., 2009). Fungi contain cell wall chitin and β -glucans that potently elicit eosinophil and neutrophil tissue infil-tration in experimental models and also secrete proteases implicated in allergic lung immunity (Porter et al., 2009).Chitinases and β -glucanases are present in plants and are induced in edible fruits and berries as part of evolu-tionarily ancient components of defense against invasive chitin-bearing fungi and insects. Like chitinases in insect excreta, these plant-derived proteins, together with a number of lipid-binding proteins, are common targets of IgE reactivity in atopic individuals. Cross-reactivity of IgE may occur among these shared group responses. Such cross-reactivity with chitin- and β -glucan-binding domain-like structures in natural latex rubber has been proposed to contribute to the prevalence of “latex-fruit syndrome”; similar cross-reactivity may underlie the emergence of “pollen-food allergy syn-drome.” Immunologists are only begin-ning to explore these complex antigen mixtures in experimental models of aller-gic lung disease, which, in humans, is sustained by “cocktails” of diverse natu-ral substances that intersect multiple innate immune pathways and contribute to allergenic priming and inflammation.Cell wall β -glucans in fungi are potent stimuli of dectin C-type lectin receptors on dendritic cells, macrophages, and neutrophils and initiate IL-17-driven neu-trophilic infiltration that may be relevant to the understanding of inflammatory subsets of asthma (Goodridge et al., 2009). Chitin, an insoluble polymer of N-acetyl- β -D-glucosamine, is a struc-tural element shared by fungi, crustacea, helminthes, and insects and constitutes, after cellulose, the most widespread natural biopolymer. When administered to the airways of mice, chitin induces a leukotriene-mediated infiltrate of eosino-phils and basophils and drives alternative macrophage activation in both resident and recruited macrophages (Reese et al., 2007). A conserved epithelial and mac-rophage chitinase, AMCase, is rapidly induced by a Stat6-dependent pathway and degrades chitin, thus solubilizing the particulate structure. Chitin is a compo-nent of the fungal cell wall and a constitu-ent of the insect peritrophic matrix (PM). The PM is a complex network of chitin, chitin-binding proteins, glycoproteins, and glycans that encloses the food bolus with a mix of intestinal digestive enzymes (Hegedus et al., 2009). Spatially com-partmentalizing the digestive process in the insect, the PM is ultimately excreted
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