A New Strategy to Counter Allergy
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《新英格兰医药杂志》
Many features of cellular programs are tightly controlled by the balancing actions of activation and inhibitory signals. This principle applies in particular to the cells of the immune system, which are regulated by activating and inhibitory cell-surface receptors. Zhu and colleagues1 have recently described a clever strategy to repress specific allergic reactions by muting the activity of activation receptors.
The first step of the allergic response is the immunization phase, in which innocuous allergens trigger B cells to produce IgE and IgG that react specifically to these allergens. These IgE molecules then bind to high-affinity receptors for IgE (FcRI) on circulating basophils and mast cells in many tissues (Figure 1). The binding of IgE to FcRI does not itself induce allergic reactions. A second step is required. Allergens are multivalent: they express multiple epitopes that are recognized by specific IgEs and IgGs. Simultaneous multivalent binding of allergens to several membrane-bound IgEs induces receptor aggregation, which triggers a signaling cascade that leads to the production and release of allergic and inflammatory mediators (histamine, leukotrienes, chemokines, and cytokines) responsible for the symptoms of allergic diseases. This chain of events is central to many allergic diseases, including allergic rhinitis, allergic asthma, urticaria, and systemic anaphylaxis.
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Figure 1. A New Strategy to Counter Allergy.
Allergens induce the aggregation of membrane-bound IgEs that react specifically to them. The IgEs are bound to the membrane of basophils and mast cells by IgE receptors called FcRIs (Panel A). Thus, the aggregation of IgE induces the aggregation of FcRI and, hence, the triggering of activation signals that eventually lead to the release of the mediators (such as histamine) of allergic reactions (Panel B). In persons without allergies, membrane-bound IgG also forms immune complexes with allergens. IgG is tethered to the membrane by binding the Fc fragment of FcRIIb. When an allergen simultaneously binds IgE and IgG, the activating FcRI is brought together with the inhibitory FcRIIb, thereby silencing the FcRI-mediated activation pathway. Zhu and colleagues1 report a strategy that takes advantage of the natural capacity of FcRIIb to inhibit the allergenic activity of FcRI. They designed a chimeric molecule — a fusion of a cat allergen (Fel d1) and the Fc fragment of human IgG (Panel C) — that abolished allergic reactions to Fel d1 in vitro and in a mouse model. Similar fusion molecules could be designed to counter other types of allergy. Lyn, Fyn, and Syk are protein tyrosine kinases. P denotes phosphorylation.
How does the aggregation of FcRI generate this signaling cascade? FcRI is composed of an IgE-binding unit (the chain) and a signaling unit (one and two chains) (Figure 1). The aggregation of FcRI induces the activation of a tyrosine kinase bound to the chain; the tyrosine kinase then phosphorylates two tyrosine residues in the chains. These tyrosine residues are a central feature of the immunoreceptor tyrosine-based activation motif (ITAM), the canonical activation motif present on numerous receptors in the immune system. After phosphorylation, the ITAMs of the chains activate Syk tyrosine kinase, which, through the activation of downstream pathways, induces the release of allergic mediators (Figure 1).2,3
These FcRI-mediated activation pathways are modulated by inhibitory receptors — the IgG receptor FcRIIb in particular. The allergen-specific IgGs produced in response to immunization form complexes with allergens, which can, in turn, form a bridge between FcRI and FcRIIb. Both receptors are expressed on mast cells and basophils; the Fc fragment of IgG in the immune complex binds to FcRIIb, whereas the allergen binds to IgE, which is already bound to adjacent FcRI. The formation of this bridge induces the aggregation of activating FcRI with inhibitory FcRIIb, which inhibits the activation pathways activated by FcRI. This capacity of IgG to counteract IgE is probably the central mechanism behind successful allergen desensitization, although this has yet to be established. However, desensitization does not always work, as illustrated by dramatic failures involving life-threatening anaphylactic shock.
How does FcRIIb-mediated inhibition work? FcRIIb contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), a modified version of the activating ITAM present in FcRI. Like ITAM, ITIM must be phosphorylated by a tyrosine kinase to function. ITIM is phosphorylated when FcRIIb is brought into proximity to FcRI resulting in the aggregation of both receptors. Phosphorylated ITIM recruits phosphatases that inactivate key components in the activation pathway.4,5
To circumvent the uncertainties of classic allergen desensitization, Zhu and colleagues engineered a chimeric molecule in which the Fc fragment of human IgG1 is fused to the recombinant major cat allergen Fel d1. The fusion molecule thus binds both FcRIIb and the IgE specific for Fel d1. Because IgE is already bound to FcRI, the authors predicted that the complex would form a bridge between FcRIIb and FcRI, thereby inhibiting allergic reactions. And this is exactly what happened. The fusion protein inhibited allergen-mediated activation of basophils and mast cells in vitro. It also inhibited allergic responses after long-term immunization with Fel d1 in a relevant mouse model.
The potential of this novel approach is not limited to treating allergies to cats. Zhu et al. have provided proof of principle that this strategy may be effective in treating any type of allergy. For example, replacing Fel d1 with the major peanut allergen should help prevent the devastating anaphylactic responses to peanuts seen in many children. The fusion protein could also displace allergens already bound to IgE, in which case it would help terminate ongoing anaphylactic reactions. A potential problem, however, is that the fusion protein could actually induce or exacerbate an allergic reaction, because mast cells and basophils also express FcRIIa, an ITAM-containing and activating IgG receptor. Classic desensitization may fail in a subgroup of patients because activating FcRIIa prevails over inhibitory FcRIIb. If so, it will be essential to identify this subgroup of patients before they receive therapy with fusion molecules, because the fusion molecules could aggregate with the two activating receptors FcRI and FcRIIa, thus inducing allergic reactions.
The study by Zhu et al. focuses on the second step of the allergic response, after allergen-specific immunoglobulins have been produced. However, the fusion molecule may have an even stronger effect on countering allergy if it is used to ablate IgE-producing B cells — the source of such immunoglobulins — which also express FcRIIb. This approach would induce true desensitization.
Source Information
From the Beth Israel Deaconess Medical Center, Harvard University, Boston.
References
Zhu D, Kepley CL, Zhang K, Terada T, Yamada T, Saxon A. A chimeric human-cat fusion protein blocks cat-induced allergy. Nat Med 2005;11:446-449.
Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol 2003;15:639-646.
Rivera J. Molecular adapters in FcRI signaling and the allergic response. Curr Opin Immunol 2002;14:688-693.
Ravetch JV, Laniel LL. Immune inhibitory receptors. Science 2000;290:84-89.
Daeron M. Fc receptor biology. Annu Rev Immunol 1997;15:203-234.(Jean-Pierre Kinet, M.D.)
The first step of the allergic response is the immunization phase, in which innocuous allergens trigger B cells to produce IgE and IgG that react specifically to these allergens. These IgE molecules then bind to high-affinity receptors for IgE (FcRI) on circulating basophils and mast cells in many tissues (Figure 1). The binding of IgE to FcRI does not itself induce allergic reactions. A second step is required. Allergens are multivalent: they express multiple epitopes that are recognized by specific IgEs and IgGs. Simultaneous multivalent binding of allergens to several membrane-bound IgEs induces receptor aggregation, which triggers a signaling cascade that leads to the production and release of allergic and inflammatory mediators (histamine, leukotrienes, chemokines, and cytokines) responsible for the symptoms of allergic diseases. This chain of events is central to many allergic diseases, including allergic rhinitis, allergic asthma, urticaria, and systemic anaphylaxis.
View larger version (74K):
[in this window]
[in a new window]
Figure 1. A New Strategy to Counter Allergy.
Allergens induce the aggregation of membrane-bound IgEs that react specifically to them. The IgEs are bound to the membrane of basophils and mast cells by IgE receptors called FcRIs (Panel A). Thus, the aggregation of IgE induces the aggregation of FcRI and, hence, the triggering of activation signals that eventually lead to the release of the mediators (such as histamine) of allergic reactions (Panel B). In persons without allergies, membrane-bound IgG also forms immune complexes with allergens. IgG is tethered to the membrane by binding the Fc fragment of FcRIIb. When an allergen simultaneously binds IgE and IgG, the activating FcRI is brought together with the inhibitory FcRIIb, thereby silencing the FcRI-mediated activation pathway. Zhu and colleagues1 report a strategy that takes advantage of the natural capacity of FcRIIb to inhibit the allergenic activity of FcRI. They designed a chimeric molecule — a fusion of a cat allergen (Fel d1) and the Fc fragment of human IgG (Panel C) — that abolished allergic reactions to Fel d1 in vitro and in a mouse model. Similar fusion molecules could be designed to counter other types of allergy. Lyn, Fyn, and Syk are protein tyrosine kinases. P denotes phosphorylation.
How does the aggregation of FcRI generate this signaling cascade? FcRI is composed of an IgE-binding unit (the chain) and a signaling unit (one and two chains) (Figure 1). The aggregation of FcRI induces the activation of a tyrosine kinase bound to the chain; the tyrosine kinase then phosphorylates two tyrosine residues in the chains. These tyrosine residues are a central feature of the immunoreceptor tyrosine-based activation motif (ITAM), the canonical activation motif present on numerous receptors in the immune system. After phosphorylation, the ITAMs of the chains activate Syk tyrosine kinase, which, through the activation of downstream pathways, induces the release of allergic mediators (Figure 1).2,3
These FcRI-mediated activation pathways are modulated by inhibitory receptors — the IgG receptor FcRIIb in particular. The allergen-specific IgGs produced in response to immunization form complexes with allergens, which can, in turn, form a bridge between FcRI and FcRIIb. Both receptors are expressed on mast cells and basophils; the Fc fragment of IgG in the immune complex binds to FcRIIb, whereas the allergen binds to IgE, which is already bound to adjacent FcRI. The formation of this bridge induces the aggregation of activating FcRI with inhibitory FcRIIb, which inhibits the activation pathways activated by FcRI. This capacity of IgG to counteract IgE is probably the central mechanism behind successful allergen desensitization, although this has yet to be established. However, desensitization does not always work, as illustrated by dramatic failures involving life-threatening anaphylactic shock.
How does FcRIIb-mediated inhibition work? FcRIIb contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), a modified version of the activating ITAM present in FcRI. Like ITAM, ITIM must be phosphorylated by a tyrosine kinase to function. ITIM is phosphorylated when FcRIIb is brought into proximity to FcRI resulting in the aggregation of both receptors. Phosphorylated ITIM recruits phosphatases that inactivate key components in the activation pathway.4,5
To circumvent the uncertainties of classic allergen desensitization, Zhu and colleagues engineered a chimeric molecule in which the Fc fragment of human IgG1 is fused to the recombinant major cat allergen Fel d1. The fusion molecule thus binds both FcRIIb and the IgE specific for Fel d1. Because IgE is already bound to FcRI, the authors predicted that the complex would form a bridge between FcRIIb and FcRI, thereby inhibiting allergic reactions. And this is exactly what happened. The fusion protein inhibited allergen-mediated activation of basophils and mast cells in vitro. It also inhibited allergic responses after long-term immunization with Fel d1 in a relevant mouse model.
The potential of this novel approach is not limited to treating allergies to cats. Zhu et al. have provided proof of principle that this strategy may be effective in treating any type of allergy. For example, replacing Fel d1 with the major peanut allergen should help prevent the devastating anaphylactic responses to peanuts seen in many children. The fusion protein could also displace allergens already bound to IgE, in which case it would help terminate ongoing anaphylactic reactions. A potential problem, however, is that the fusion protein could actually induce or exacerbate an allergic reaction, because mast cells and basophils also express FcRIIa, an ITAM-containing and activating IgG receptor. Classic desensitization may fail in a subgroup of patients because activating FcRIIa prevails over inhibitory FcRIIb. If so, it will be essential to identify this subgroup of patients before they receive therapy with fusion molecules, because the fusion molecules could aggregate with the two activating receptors FcRI and FcRIIa, thus inducing allergic reactions.
The study by Zhu et al. focuses on the second step of the allergic response, after allergen-specific immunoglobulins have been produced. However, the fusion molecule may have an even stronger effect on countering allergy if it is used to ablate IgE-producing B cells — the source of such immunoglobulins — which also express FcRIIb. This approach would induce true desensitization.
Source Information
From the Beth Israel Deaconess Medical Center, Harvard University, Boston.
References
Zhu D, Kepley CL, Zhang K, Terada T, Yamada T, Saxon A. A chimeric human-cat fusion protein blocks cat-induced allergy. Nat Med 2005;11:446-449.
Siraganian RP. Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol 2003;15:639-646.
Rivera J. Molecular adapters in FcRI signaling and the allergic response. Curr Opin Immunol 2002;14:688-693.
Ravetch JV, Laniel LL. Immune inhibitory receptors. Science 2000;290:84-89.
Daeron M. Fc receptor biology. Annu Rev Immunol 1997;15:203-234.(Jean-Pierre Kinet, M.D.)