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Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment

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  • Authors: Sophia N. Karagiannis1, Panagiotis Karagiannis2, Debra H. Josephs3, Louise Saul4, Amy E. Gilbert5, Nadine Upton6, Hannah J. Gould7
  • Editor: Diana Boraschi8
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Cutaneous Medicine and Immunotherapy Unit, St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, King's College London School of Medicine, Guy's Hospital, King's College London, London SE1 9RT, United Kingdom; 2: Cutaneous Medicine and Immunotherapy Unit, St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, King's College London School of Medicine, Guy's Hospital, King's College London, London SE1 9RT, United Kingdom; 3: Cutaneous Medicine and Immunotherapy Unit, St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, King's College London School of Medicine, Guy's Hospital, King's College London, London SE1 9RT, United Kingdom; 4: Cutaneous Medicine and Immunotherapy Unit, St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, King's College London School of Medicine, Guy's Hospital, King's College London, London SE1 9RT, United Kingdom; 5: Cutaneous Medicine and Immunotherapy Unit, St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy's and St. Thomas's Hospitals and King's College London, King's College London School of Medicine, Guy's Hospital, King's College London, London SE1 9RT, United Kingdom; 6: Randall Division of Cell and Molecular Biophysics, Division of Asthma, Allergy, and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, United Kingdom; 7: Randall Division of Cell and Molecular Biophysics, Division of Asthma, Allergy, and Lung Biology, MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, United Kingdom; 8: National Research Council, Pisa, Italy
    • Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspec.AID-0006-2012
  • Received 24 October 2012 Accepted 21 March 2013 Published 25 October 2013
  • Sophia N. Karagiannis, [email protected]
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  • Abstract:

    The pathogenic role of immunoglobulin E (IgE) antibodies in triggering and maintaining allergic inflammation in response to allergens is due to the binding of multivalent allergens to allergen-specific IgEs on sensitized effector cells. These interactions trigger effector cell activation, resulting in release of potent inflammatory mediators, recruitment of inflammatory cells, antigen presentation, and production of allergen-specific antibody responses. Since its discovery in the 1960s, the central role of IgE in allergic disease has been intensively studied, placing IgE and its functions at the heart of therapeutic efforts for the treatment of allergies. Here, we provide an overview of the nature, roles, and significance of IgE antibodies in allergic diseases, infections, and inflammation and the utility of antibodies as therapies. We place special emphasis on allergen-IgE-Fcε receptor complexes in the context of allergic and inflammatory diseases and describe strategies, including monoclonal antibodies, aimed at interrupting these complexes. Of clinical significance, one antibody, omalizumab, is presently in clinical use and works by preventing formation of IgE-Fcε receptor interactions. Active immunotherapy approaches with allergens and allergen derivatives have also demonstrated clinical benefits for patients with allergic diseases. These treatments are strongly associated with serum increases of IgE-neutralizing antibodies and feature a notable redirection of humoral responses towards production of antibodies of the IgG4 subclass in patients receiving immunotherapies. Lastly, we provide a new perspective on the rise of recombinant antibodies of the IgE class recognizing tumor-associated antigens, and we discuss the potential utility of tumor antigen-specific IgE antibodies to direct potent IgE-driven immune responses against tumors.

  • Citation: Karagiannis S, Karagiannis P, Josephs D, Saul L, Gilbert A, Upton N, Gould H. 2013. Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment. Microbiol Spectrum 1(1):AID-0006-2012. doi:10.1128/microbiolspec.AID-0006-2012.

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/content/journal/microbiolspec/10.1128/microbiolspec.AID-0006-2012
2013-10-25
2020-07-07

Abstract:

The pathogenic role of immunoglobulin E (IgE) antibodies in triggering and maintaining allergic inflammation in response to allergens is due to the binding of multivalent allergens to allergen-specific IgEs on sensitized effector cells. These interactions trigger effector cell activation, resulting in release of potent inflammatory mediators, recruitment of inflammatory cells, antigen presentation, and production of allergen-specific antibody responses. Since its discovery in the 1960s, the central role of IgE in allergic disease has been intensively studied, placing IgE and its functions at the heart of therapeutic efforts for the treatment of allergies. Here, we provide an overview of the nature, roles, and significance of IgE antibodies in allergic diseases, infections, and inflammation and the utility of antibodies as therapies. We place special emphasis on allergen-IgE-Fcε receptor complexes in the context of allergic and inflammatory diseases and describe strategies, including monoclonal antibodies, aimed at interrupting these complexes. Of clinical significance, one antibody, omalizumab, is presently in clinical use and works by preventing formation of IgE-Fcε receptor interactions. Active immunotherapy approaches with allergens and allergen derivatives have also demonstrated clinical benefits for patients with allergic diseases. These treatments are strongly associated with serum increases of IgE-neutralizing antibodies and feature a notable redirection of humoral responses towards production of antibodies of the IgG4 subclass in patients receiving immunotherapies. Lastly, we provide a new perspective on the rise of recombinant antibodies of the IgE class recognizing tumor-associated antigens, and we discuss the potential utility of tumor antigen-specific IgE antibodies to direct potent IgE-driven immune responses against tumors.

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Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment
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Citation: Karagiannis S, Karagiannis P, Josephs D, Saul L, Gilbert A, Upton N, Gould H. 2013. Immunoglobulin e and allergy: antibodies in immune inflammation and treatment. microbiolspec 1(1): doi:10.1128/microbiolspec.AID-0006-2012
/content/microbiolspec/10.1128/microbiolspec.AID-0006-2012.fig1
FIGURE 1

Omalizumab blocks IgE-mediated mast cell activation. The allergic response mediated by multivalent allergen-IgE-FcεRI complex formation on the surface of mast cells triggers cross-linking of FcεRI, leading to downstream signaling events potentiated by the β and γ chains (left). These entail phosphorylation (P) by Src kinases and cellular activation through RhoGTPases and mitogen-activated protein kinase pathways, leading to mast cell degranulation and the rapid release of a range of vasoactive amines (e.g., histamine), prostaglandins, leukotrienes, cytokines, and chemokines, inducing and maintaining allergic inflammatory responses. Omalizumab, a humanized IgG1 monoclonal antibody that recognizes an epitope in the Cε3 region of IgE, can block the binding of circulating IgE to FcεRI, sequestering free and allergen-bound IgE (right). These interactions prevent allergen-IgE-FcεRI complex formation on the surface of mast cells and interfere with the signaling cascades that trigger degranulation and the onset of IgE-mediated allergic inflammatory cascades. Syk, spleen tyrosine kinase; AKT, Ak strain thymoma serine/threonine-specific protein kinase; ERK, extracellular signal-regulated kinase; JNK, Jun N-terminal protein kinase; P, phosphorylation. doi:10.1128/microbiolspec.AID-0006-2012.f1

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FIGURE 1

Omalizumab blocks IgE-mediated mast cell activation. The allergic response mediated by multivalent allergen-IgE-FcεRI complex formation on the surface of mast cells triggers cross-linking of FcεRI, leading to downstream signaling events potentiated by the β and γ chains (left). These entail phosphorylation (P) by Src kinases and cellular activation through RhoGTPases and mitogen-activated protein kinase pathways, leading to mast cell degranulation and the rapid release of a range of vasoactive amines (e.g., histamine), prostaglandins, leukotrienes, cytokines, and chemokines, inducing and maintaining allergic inflammatory responses. Omalizumab, a humanized IgG1 monoclonal antibody that recognizes an epitope in the Cε3 region of IgE, can block the binding of circulating IgE to FcεRI, sequestering free and allergen-bound IgE (right). These interactions prevent allergen-IgE-FcεRI complex formation on the surface of mast cells and interfere with the signaling cascades that trigger degranulation and the onset of IgE-mediated allergic inflammatory cascades. Syk, spleen tyrosine kinase; AKT, Ak strain thymoma serine/threonine-specific protein kinase; ERK, extracellular signal-regulated kinase; JNK, Jun N-terminal protein kinase; P, phosphorylation. doi:10.1128/microbiolspec.AID-0006-2012.f1

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspec.AID-0006-2012
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FIGURE 2

IgG4 antibodies induced by allergen immunotherapies modulate IgE-mediated activation of effector cells. The allergic response mediated by multivalent allergen-IgE FcεRI complex assembly and downstream signaling events leading to release of inflammatory mediators (left) may be blocked by adaptive immune responses triggered in response to SIT with recombinant antigens. IgG4 antibodies, induced following SIT, could compete with IgE for binding to allergens and prevent the formation of allergen-IgE-FcεRI complexes on the surface of effector cells, blocking effector functions such as degranulation (right). Syk, spleen tyrosine kinase; AKT, Ak strain thymoma serine/threonine-specific protein kinase; ERK, extracellular signal-regulated kinase; JNK, Jun N-terminal protein kinase; P, phosphorylation. doi:10.1128/microbiolspec.AID-0006-2012.f2

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FIGURE 2

IgG4 antibodies induced by allergen immunotherapies modulate IgE-mediated activation of effector cells. The allergic response mediated by multivalent allergen-IgE FcεRI complex assembly and downstream signaling events leading to release of inflammatory mediators (left) may be blocked by adaptive immune responses triggered in response to SIT with recombinant antigens. IgG4 antibodies, induced following SIT, could compete with IgE for binding to allergens and prevent the formation of allergen-IgE-FcεRI complexes on the surface of effector cells, blocking effector functions such as degranulation (right). Syk, spleen tyrosine kinase; AKT, Ak strain thymoma serine/threonine-specific protein kinase; ERK, extracellular signal-regulated kinase; JNK, Jun N-terminal protein kinase; P, phosphorylation. doi:10.1128/microbiolspec.AID-0006-2012.f2

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspec.AID-0006-2012
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Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment
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Citation: Karagiannis S, Karagiannis P, Josephs D, Saul L, Gilbert A, Upton N, Gould H. 2013. Immunoglobulin e and allergy: antibodies in immune inflammation and treatment. microbiolspec 1(1): doi:10.1128/microbiolspec.AID-0006-2012
/content/microbiolspec/10.1128/microbiolspec.AID-0006-2012.T1
TABLE 1

Interactions of omalizumab with IgE, the resulting mechanisms of action, and clinical effects of treatment in patients with allergies

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TABLE 1

Interactions of omalizumab with IgE, the resulting mechanisms of action, and clinical effects of treatment in patients with allergies

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspec.AID-0006-2012
/content/microbiolspec/10.1128/microbiolspec.AID-0006-2012.T2
TABLE 2

Active phase II, III, and IV interventional clinical studies for antibody immunotherapies of allergic diseases in 2012

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TABLE 2

Active phase II, III, and IV interventional clinical studies for antibody immunotherapies of allergic diseases in 2012

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspec.AID-0006-2012

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