The remarkable increase in asthma prevalence that has occurred over the last two decades is thought to be caused by changes in the environment due to improved hygiene and fewer childhood infections. However, the specific infections that limit T helper type 2 (TH2)-biased inflammation and asthma are not fully known. Infectious organisms, including commensal bacteria in the gastrointestinal tract and hepatitis A virus, may normally induce the development of regulatory T (TR) cells and protective immunity that limit airway inflammation and promote tolerance to respiratory allergens. In the absence of such infections, TH2 cells—which are developmentally related to TR cells—develop instead and coordinate the development of asthmatic inflammation.
Asthma is an immunological disease that has increased dramatically in prevalence over the past two decades. In industrialized countries, the incidence of asthma has nearly doubled since 1980; in the United States and other industrialized countries, one in five to ten individuals is affected. As a result, asthma has reached epidemic proportions, and current health care expenditure for asthma in industrialized countries is enormous.
Asthma is caused by environmental factors, such as allergen exposure and infection, in genetically predisposed individuals. It is estimated that at least a dozen polymorphic genes regulate asthma, controlling the inflammatory response, immunoglobulin E (IgE), cytokine and chemokine production1 as well as airway function and airway remodeling2,3. Although the genetic composition of the populations in industrialized countries has not changed significantly in the last 20 years, the environment in industrialized cultures has changed dramatically in a broad sense, in ways that appear to directly exaggerate the environmental effects on asthma pathogenesis. However, the specific conditions in industrialized societies that are responsible for driving development of the T helper type 2 (TH2)-biased immune responses and the overproduction of cytokines such as interleukin 4 (IL-4), IL-5, IL-9 and IL-13, which characterize asthma, are not yet clear. Nevertheless, we know that a dysregulated TH2 immune response is readily induced in the setting of the modern environment and that this dysregulated TH2 response overwhelms the protective mechanisms that normally prevent the development of asthma. The inappropriate TH2 response causes pulmonary inflammation, airway eosinophilia, mucus hypersecretion and airway hyperreactivity (AHR) to a variety of specific and nonspecific stimuli that result in the symptoms of asthma.
The Hygiene Hypothesis
The hypothesis that has received the greatest attention in explaining the increase in asthma prevalence is the Hygiene Hypothesis (Fig. 1)4. This hypothesis suggests that improved hygiene in industrialized societies, with improved public health measures and the use of vaccines and antibiotics, has reduced the incidence of infections that would normally stimulate the immune system in some way that mitigates against asthma5. The data that support this theory are imprecise, but they include several epidemiological studies showing an inverse relationship between family size and the risk of developing asthma6 as well as studies showing that early placement in day care settings, and presumed exposure to infectious agents, appears to protect against the development of asthma7. Other epidemiological studies that provide support for this hypothesis include observations demonstrating that exposure to farm animals and raw milk early in life reduces the likelihood of developing asthma, allergic rhinitis and atopic sensitization8. Several investigators suggest that exposure to bacterial endotoxin may be important in producing this protective effect, and others have shown that extensive exposure to cats or dogs and their epidermal allergens may replicate the protective effects of farm animal exposure9. Additional studies demonstrate that early childhood exposure to antibiotics, which may alter gastrointestinal flora and exposure to intestinal endotoxin, is associated with an increased incidence of allergy10. However, the specific infectious pathogens or the specific mechanisms that are responsible for these effects have not been identified, and thus, the link between asthma pathogenesis and infections remains nebulous.
Specific pathogens and the Hygiene Hypothesis
Infections with several pathogens—for example, Mycobacteria tuberculosis or respiratory viruses—may enhance TH1 responses and limit TH2-driven responses and, therefore, may be important in asthma. Thus, skin test reactivity to tuberculosis in children in Japan inversely correlated with the likelihood of having asthma, suggesting that exposure and response to M. tuberculosis inhibits the development of asthma11,12. However, this observation could be explained more directly by the fact that individuals who develop asthma and atopy genetically may have less robust cell-mediated immune responses to most antigens, including M. tuberculosis13, but have increased humoral (IgE-mediated) responses to allergens and helminths14.
A link between infection with specific respiratory viruses and asthma has been recognized for decades: respiratory viruses precipitate acute airway obstruction and wheezing in patients with asthma15. Although the Hygiene Hypothesis suggests that a reduced incidence of such infections may result in increased asthma prevalence, there are few data to suggest that infections with common respiratory viral pathogens are less frequent today than in the past. In addition, infection with respiratory syncytial virus (RSV) in young children appears to increase the risk of developing asthma, although this risk disappears by the age of 13 years16. Therefore, frequent respiratory viral infections appear to exacerbate, rather than prevent, the development of asthma, although it is possible that globally, multiple infections may in some way promote maturation of the immune system towards protection against asthma.
In contrast to respiratory viral infection, gastrointestinal exposure to bacteria and bacterial products may have a significant effect on maturation of the immune system and indeed protect against the development of asthma. Increased incidence of allergy is associated with reduced prevalence of colonization of the gastrointestinal tract in children with bifidobacteria and lactobacillus strains, two Gram-positive commensal bacteria17. In addition, exposure of infants to lactobacillus in the neonatal period appears to protect against the development of atopy18. The effect of gastrointestinal bacteria on the developing immune system may be mediated through Toll-like receptors (TLRs)—for example, TLR2, TLR4 and TLR9—which may inhibit the development of TH2-biased immune responses. “Improved” hygiene may eliminate exposure, but it may also eliminate the protective effects of these commensal gastrointestinal bacteria. The specific TLRs that may protect against asthma are not clear, although several investigators suggest that TLR4 and exposure to bacterial lipopolysaccharide (LPS)—based on epidemiological studies of farm environments as discussed above—may be protective against asthma19. However, examination of the specific effects of LPS and TLR4 on T cell differentiation and cytokine production indicates that LPS may in fact exacerbate, rather than limit, TH2 cell development20.
HAV and the Tim l asthma susceptibility gene
In addition to gastrointestinal bacteria, several other gastrointestinal pathogens appear to have potent effects on protection against the development of asthma. For example, evidence of infection with hepatitis A virus (HAV) is strongly associated with protection against the development of asthma21. Infection with other gastrointestinal pathogens, for example, Helicobacter pylori and Toxoplasma gondii, may protect against the development of asthma, although to a lesser extent22. However, because HAV, H. pylori and T. gondii are not respiratory pathogens and because HAV is transmitted through fecal-oral routes, clinical investigators have assumed that infection with these agents is merely a marker of poor hygiene and that other infectious pathogens, possibly involving the respiratory tract7, are more directly involved in protection against asthma.
The mechanisms by which HAV infection prevents the development of asthma may be more direct than previously suspected. The positional cloning of a newly identified asthma susceptibility gene, Tim1, provides evidence for a direct role of HAV in the prevention of atopic disease23. The human homolog of Tim1, which lies at human chromosome 5q33.2, a region that has been repeatedly linked to asthma, codes for the cellular receptor for HAV (hHAVcr-1)23. In addition, in mice, the Tim1 gene product is expressed on T cells and appears to regulate the production of IL-4 in T cells by affecting CD4+ T cell differentiation, the development of TH2 cells and the development of AHR23. Polymorphisms in Tim1 are associated with enhanced development of allergen-induced AHR in some strains of mice (for example, BALB/c), whereas other polymorphisms protect against the development of AHR (for example, in DBA/2 mice). By interacting with HAV, human TIM-1 may directly alter the TH cell balance of the infected individual. HAV persists in lymphoid tissues for weeks to months, and HAV infection of or interaction with certain lymphocyte subsets may have significant effects on TH2 differentiation and TH2 cell survival. Because Tim1 is associated with the development of TH2-biased immune responses and may be selectively expressed on TH2 cells, infection with HAV may selectively eliminate allergen-specific TH2 cells by clonal deletion and, thus, specifically protect against the development of atopy. Alternatively, HAV may alter T cell development and enhance the development of immune responses that protect against asthma. Therefore, HAV infection may have direct and specific effects on TH2 responses and AHR. The specific mechanisms, however, by which Tim1 alters T cell function and by which HAV limits TH2 cell development require further elucidation and are currently being studied.
Even in the absence of HAV infection, Tim1 may contribute to asthma susceptibility by affecting TH2 responses. Genetic variants of Tim1 may either enhance or prevent TH2-dependent inflammation in asthma and contrasts with another asthma susceptibility gene, ADAM332. This gene codes for a metalloprotease, which may regulate the response of the respiratory epithelium to damage and stress, rather than regulate immunological components of asthma. Epithelial and mesenchymal cell interactions (epithelial-mesenchymal trophic unit) coordinate the response of the respiratory epithelium to damage after repeated injury from the environment. Asthma-inducing alleles of ADAM33 may amplify these repair mechanisms, leading to greater inflammation, airway remodeling and to the development of asthma. The development of asthma, therefore, depends on immunological as well as intrinsic airway function abnormalities, which may explain why TH2-allergic responses are necessary but not sufficient for the development of asthma.
Do T H 1 responses protect against asthma?
Until recently, specific pathogens that were suspected of limiting the development of asthma were those that could induce TH1 responses. This is because the primary mechanism thought to protect against asthma involved TH1 cells, as predicted by the TH1-TH2 paradigm. TH1 responses were thought to protect against allergic disease by dampening the activity of TH2 responses, as has been shown in models of parasite infection24. In accordance with this idea, infection in infants has been proposed to stimulate the immune system nonspecifically to mature and convert the predominantly TH2 bias of infants towards a TH1 bias, by increasing the production of IFN-γ25. According to this hypothesis, however, in atopic infants this conversion towards TH1 fails to occur, perhaps because of infrequent infection. The TH2 bias therefore persists, resulting in asthma and allergy in the child.
The evidence that supports the hypothesis that TH1 cells render salutary effects in allergic disease and asthma is indirect. TH1 cells inhibit the proliferation and, therefore, the development of TH2 cells26, and interferon-γ (IFN-γ) inhibits IgE synthesis and eosinophilia27,28. In reality, however, TH1 cells may exacerbate asthma and allergy, as human asthma is associated with the production of IFN-γ that appears to contribute to disease pathogenesis29,30. Allergen-specific TH1 cells, when adoptively transferred into naïve recipients, migrate to the lungs but fail to counterbalance TH2 cell–induced AHR. Instead, allergen-specific TH1 cells caused severe airway inflammation31. Thus, although TH2 cells play a critical role in the pathogenesis of asthma, the binary TH1-TH2 paradigm—where TH1 cells balance TH2 cells—cannot explain all the immunological processes that occur in asthma. These processes in asthma may be much more complex than is predicted by the TH1-TH2 paradigm32,33,34, and “unhygienic” environments may protect against asthma by inducing additional non-TH1-TH2 immunological regulatory mechanisms. This is consistent with the fact that TH1-mediated autoimmune diseases—such as type 1 diabetes and inflammatory bowel disease—are also increasing in prevalence in industrialized cultures over the past 20 years. If improved hygiene in these cultures reduced TH1 responses, then the prevalence of autoimmune diseases should decrease rather than increase, suggesting that mechanisms other than pure TH1 responses must be involved in protection against asthma.
T cell tolerance and asthma
One immune mechanism that may protect against and regulate the development of asthma and could be significantly affected by changes in the environment in industrialized cultures is immune tolerance induced by mucosal (respiratory and gastrointestinal) exposure to antigen. In support of this possibility, peripheral CD4+ T cell tolerance, induced by respiratory exposure to allergen, prevents the development of TH2-biased responses and allergen-induced AHR35,36,37. In humans, the degree of allergen exposure appears to affect the induction of tolerance, with high exposure inducing greater tolerance9. The mechanisms by which respiratory antigens induce T cell tolerance include T cell clonal deletion, anergy or active suppression mediated by regulatory cells secreting IL-10 or transforming growth factor-β (TGF-β), as is thought to occur in oral tolerance38,39,40. The development of respiratory tolerance is initiated by uptake of antigen in the lungs by immature dendritic cells (DCs)41 that continuously sample the antigenic contents in the lung. Within 24 h after respiratory exposure to ovalbumin (OVA), pulmonary DCs migrate to the draining bronchial lymph nodes, where they mature, transiently produce IL-10 and express high amounts of B7-1 and B7-2 costimulatory molecules42. Even in the absence of inflammation, DCs migrate from the lungs to the bronchial lymph nodes. In the lymph nodes, DCs induce an initial phase of allergen-specific T cell activation, proliferation and expansion, followed by depletion of these T cells from the lymphoid organs, although a stable population of these cells survive but remain refractory (functionally disabled) to antigenic rechallenge36. The establishment of a tolerant state in allergen-specific T cells prevents the development of airway inflammation and airway AHR. Antigen-specific B cells also play a role in this process because in the absence of B cells, for example in JHD mice, respiratory tolerance cannot be induced43.
Allergen-specific CD4+ regulatory T (TR) cells mediate, in part, the T cell tolerance that inhibits airway inflammation and AHR44. These antigen-specific CD4+ TR cells produce IL-10, can potently inhibit the proliferation of OVA-specific T cells, inhibit the development of AHR when transferred to allergen-sensitized recipient mice and can be generated by activating CD4+ T cells with IL-10–producing bronchial lymph node DCs from tolerized mice44. Pulmonary DCs from tolerized mice express high amounts of costimulatory molecules, including inducible costimulatory molecule ligand (ICOSL) and possess a low capacity for phagocytosis, all of which are characteristics of mature DCs42. The production of IL-10 by these DCs plays a major role in the generation of TR cells, as IL-10 monoclonal antibody (mAb) blocks this process44. The in vivo and in vitro inhibitory capacity of the TR effector cells on AHR and inflammation can be abrogated by neutralization of IL-10 with an IL-10 mAb or by interrupting ICOS-ICOSL interactions with an ICOSL mAb. In addition, interference with the ICOS-ICOSL signaling pathway not only abrogates the inhibitory capacity of TR effector cells, but also blocks the development of IL-10 production and the induction of T cell tolerance after intranasal exposure to antigen44. Thus, TR cells may play an important role in mediating respiratory tolerance and protection against asthma via specific pathways that involve IL-10, ICOS-ICOSL costimulatory interactions and B7-2, which preferentially costimulates IL-10 production (Fig. 2)45,46.
Similar TR cells (TR1 cells) have been generated by other groups by the addition of large quantities of exogenous IL-10 to cultures of T cells or with immunosuppressive drugs47,48. In other systems, immature DCs expressing low amounts of costimulatory molecules induced T cell tolerance and the development of regulatory cells, often when the DCs were derived after extensive propagation in vitro in the presence of granulocyte–macrophage colony-stimulating factor (GM-CSF)49. These TR-like cells develop in the absence of costimulation and, therefore, may be related to anergic cells50,51. In addition, a variety of other mechanisms may be important for the development of other previously described regulatory cells—such as T helper type 3 (TH3)38, CD4+CD45RBloCD25+52,53 or TR1 cells47—or with CTLA-4–mediated suppression54. Heat-killed Mycobacterium vaccae can indeed induce CD4+CD45RBlo T cells that protect against airway inflammation55. However, although TGF-β–producing T cells may inhibit AHR40, TGF-β–producing TH3 cells may be more important in the gastrointestinal tract than in the lungs56, and CTLA-4–mediated suppression may not occur in the respiratory tract because inhibition of CTLA-4 signaling does not inhibit respiratory tolerance induction36. Nevertheless, TR cells producing anti-inflammatory cytokines such as IL-10 are more likely than pro-inflammatory TH1 cells to be involved in inhibiting airway inflammation in asthma.
The role of IL-10 in limiting AHR and inflammation has been controversial. IL-10 has been considered to be an essential TH2 cytokine24, particularly because IL-10 inhibits TH1 cytokine production by inhibiting IL-12 synthesis57, and IL-10−/− mice develop poor TH2 responses and resist the development of AHR58. However, IL-10 may have several roles in asthma, not only by playing a critical function in initiating the development of TH2-polarized responses, but also by playing an important regulatory role late during immune responses by down-modulating TH2-driven inflammation58,59,60,61. Administration of IL-10 inhibits AHR and TR cells that produce IL-10 prevent the development of AHR, even in allergen-sensitized mice. This suggests that TR cells producing IL-10 normally develop during respiratory exposure to allergen and protect against allergic asthma44.
ICOS and ICOSL in asthma and tolerance
The ICOS-ICOSL pathway is important in the activation and function of effector TH2 cells, and induces CD28-independent T cell proliferation and cytokine production45,62,63. This promotes preferential IL-10 production, along with the production of IL-4, IL-5 and GM-CSF64,65 but little IL-245,62,63. Mice deficient in ICOS show major reductions in IgE production45, TH2 cytokine production and in the development of AHR, which indicates a key role for ICOS in the development of allergic respiratory inflammatory responses66. In addition to its role in amplifying the development of TH2 responses, ICOS costimulation pathways are critically important in immune regulation and tolerance44. ICOS costimulates the induction of TR cells that inhibit the function of antigen-specific T cells and development of AHR44. Although the role played by ICOS in immune regulation was not expected, in retrospect, is not surprising because ICOS costimulation induces large quantities of T cell IL-10 production45,67 and ICOS−/− mice appear to be prone to the development of experimental allergic encephalomyelitis68,69.
The idea that ICOS-ICOSL interactions costimulate the development of both TH2-driven inflammation and TR cell–mediated tolerance suggests that these distinct processes are related. Both TH2 and TR cells are associated with respiratory mucosal responses, require costimulation through CD28 and ICOS for induction and produce both IL-4 and IL-10, although in different quantities. TH2 cells produce IL-4, IL-13 and IL-10 primarily, whereas TR cells produce IL-10 primarily and low amounts of IL-447, but not IL-1344. In addition, the functions of TR and TH2 cells in a mouse model of asthma were clearly distinct because TR cells, but not TH2 cells, blocked the development of AHR44. Pulmonary DCs from mice exposed to intranasal OVA induced T cell production of both IL-4 and IL-10 initially, but with subsequent stimulation, IL-4 production waned, whereas production of IL-10 was maintained. The specific signals that preferentially induce development of TR cells rather than TH2 cells are not entirely clear, but may involve IL-10 production by DCs. In the presence of IL-10–producing DCs (or in the presence of exogenously derived IL-10), TR cells develop47. In contrast, in the absence of IL-10, for example, when antigen is presented by DCs from IL-10−/− mice or from mice with allergic asthma42, TR cells fail to develop. The development of TH2 cells and of allergic diseases may represent an aberration of TR cell development, possibly due to inadequate production of IL-10 (Fig. 2)70. Thus, TH2 cells in allergic asthma may develop as a consequence of limited IL-10 and enhanced IL-4 and IL-13 production and from the failure to develop allergen-specific TR cells or “modified TH2 cells”, rather than a failure to develop TH1 cells. However, further study of the signals that differentially affect TH2 cell and TR cell development are required to fully understand the development of tolerance and its relationship to the pathogenesis of allergic asthma.
Loss of tolerance and the Hygiene Hypothesis
Based on the above studies, we propose that the natural environment in the past (prior to widespread industrialization) maintained the respiratory and gastrointestinal mucosal systems in a state that favored the development of T cell tolerance to nonreplicating antigens encountered at mucosal surfaces, for example, in food and inhaled material. The mechanisms at mucosal surfaces that favor the development of tolerance are not clear, but may involve epithelial cells, DCs, intraepithelial B cells and other cells in the mucosa and also involve the production of IL-10 and possibly TGF-β by DCs and by antigen-specific TR cells37,71,72. The TR cells that develop at these mucosal sites inhibit inflammatory responses in the lung and gut, inhibiting both the development of TH2-biased inflammation—for example, in allergic disease—preventing both respiratory diseases, such as allergic rhinitis, and gastrointestinal diseases, such as food allergy. Such mechanisms could also inhibit TH1-biased inflammation, for example, in autoimmune diseases such as diabetes mellitus, multiple sclerosis and inflammatory bowel disease. TH1 cells may, in some instances, be involved in inhibiting the development of TH2 cells, but this form of inhibition most likely occurs primarily in lymphoid organs such as the lymph nodes, where the proinflammatory effects of TH1 cells cause little tissue damage. In contrast, the major anti-inflammatory effector mechanisms in the mucosa involve TR cells, although cells producing IFN-γ and IL-10 together (for example, in CD4, CD8 cells or γδ T cells) may exert anti-inflammatory effects in the mucosa as well73. Finally, deletion of antigen-specific T cells, via activation-induced cell death, may also be involved as a mechanism to control inflammation in these organs.
The establishment of these tolerance mechanisms at mucosal surfaces may require the presence of commensal bacteria in the gastrointestinal and upper respiratory tracts74,75,76,77. Immune tolerance induced by mucosal exposure to antigen does not seem to occur in germ-free animals76,77, which indicates that normal microbial flora in the intestine, and perhaps in the upper respiratory tract, have significant effects on tolerance to allergens. Commensal bacteria may enhance production of IL-10 through mechanisms that involve the innate immune system and receptors such as nucleotide-binding oligomerization domain 2 (NOD2, which is encoded by CARD15).
CARD15 is a member of the NOD family of proteins, which are involved in the regulation of programmed cell death and host defense against pathogens78. CARD15 expression is restricted to monocytes and, when activated by LPS from a bacterium, it induces nuclear translocation of NF-κB in a manner that appears to down-modulate inflammation. Alterations in NOD2 function due to polymorphisms in CARD15 are associated with Crohn's disease, an inflammatory bowel disease79,80. The anti-inflammatory effects induced in the gastrointestinal tract by NOD2 may be related to the enteric “immunosuppressive” effects observed with nonvirulent Salmonella strains, which block NF-κB activation by inhibiting IκB degradation81. Infection with high numbers of helminths may also favor the development of tolerance to nonreplicating environmental antigens by enhancing IL-10 production82,83.
Therefore, some microorganisms may reduce inflammation at mucosal surfaces. Changes in the environment in industrialized societies limit exposure to these types of organisms and thereby diminish the normal tolerance-inducing state of mucosal surfaces, resulting in enhanced mucosal inflammation. These changes prevent the development of allergen-specific TR cells in some individuals, resulting in an aberrant form of TR cells developing in atopic individuals—TH2 cells—which induce the development of allergy. The responsible environmental changes may include frequent use of antibiotics or changes in diet84, which alter the normal gastrointestinal flora, resulting in reduced IL-10 and TGF-β production by epithelial cells, DCs and B cells in the mucosa and causing increased development of TH2 cells and allergy.
Immune-based therapies for asthma
If the significant increase in asthma is due to lack of tolerance to environmental allergens, then treatments that induce tolerance to these agents should be effective in treating and potentially curing asthma. Although the currently available pharmacotherapies for controlling the symptoms of asthma (such as inhaled corticosteroids and leukotriene antagonists) and the several that are being developed (IgE mAb, IL-5 mAb and IL-4 mAb) are effective, none of these therapies can cure established asthma. For example, corticosteroids are very effective at controlling symptoms, but are associated with side-effects and lose their beneficial effects soon after they are discontinued. Furthermore, therapies such as corticosteroids, although controlling the pathogenic TH2 responses, may limit protective tolerance responses.
Therapies that may enhance the tolerance process include the administration of probiotics, such as Lactobacillus, which improves and possibly prevents the development of atopic diseases18. Precisely how probiotics function is not clear, but may involve activation of the mucosal innate immune system—for example, NOD2 pathways—in a way that reduces inflammation. Oral allergen immunotherapy, which reduces symptoms of allergy85, may also utilize mucosal tolerance mechanisms. This allergen-specific therapy is a variant of conventional allergen immunotherapy, in which allergen is given in increasing amounts subcutaneously. Conventional allergen immunotherapy not only controls symptoms, but also reverses established disease and prevents progression from allergic rhinitis towards asthma86. Immunotherapy induces allergen-specific immune deviation and allergen-specific tolerance, which are associated with a reduction in IL-4 production87, increased IgG4 and, when bee venom is used as the antigen for bee venom allergy, increased IL-10 production60. This therapy is curative, particularly in children86 and in patients with bee venom allergy, and the beneficial effects are maintained for years after therapy has been discontinued88. However, the major problem with conventional allergen immunotherapy that decreases its appeal is that it is inefficient, requiring over 100 shots for successful completion. Therefore, modification of allergen immunotherapy, for example with the use of allergens conjugated with CpG motifs that bind to TLR9, are currently being studied and appear to be a promising form of allergen immunotherapy89. Perhaps even more effective therapies might be developed with specific subsets of allergen-pulsed DCs that induce tolerance or TR cells. Such therapies, however, await a more complete understanding of the immunobiology of tolerance and allergic disease and the mechanisms by which HAV prevents the development of asthma.
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Umetsu, D., McIntire, J., Akbari, O. et al. Asthma: an epidemic of dysregulated immunity. Nat Immunol 3, 715–720 (2002). https://doi.org/10.1038/ni0802-715
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