Mucosal Immunol. 2015 Nov;8(6):1262-74.

Inhibition of CD23-mediated IgE transcytosis suppresses the initiation and development of allergic airway inflammation.

Palaniyandi S1,2, Liu X1, Periasamy S3, Ma A1, Tang J1, Jenkins M4, Tuo W4, Song W5,2, Keegan AD6, Conrad DH7, Zhu X1,2.

  • 1Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA.
  • 2Maryland Pathogen Research Institute, University of Maryland, College Park, MD, USA.
  • 3Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
  • 4Animal Parasitic Diseases Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD, USA.
  • 5Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA.
  • 6Center for Vascular and Inflammatory Diseases and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • 7Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.



The epithelial lining of the airway tract and allergen-specific IgE are considered essential controllers of inflammatory responses to allergens. The human low affinity IgE receptor, CD23 (FcɛRII), is capable of transporting IgE or IgE-allergen complexes across the polarized human airway epithelial cell (AEC) monolayer in vitro. However, it remains unknown whether the CD23-dependent IgE transfer pathway in AECs initiates and facilitates allergic inflammation in vivo, and whether inhibition of this pathway attenuates allergic inflammation. To this end, we show that in wild-type (WT) mice, epithelial CD23 transcytosed both IgE and ovalbumin (OVA)-IgE complexes across the airway epithelial barrier, whereas neither type of transcytosis was observed in CD23 knockout (KO) mice. In chimeric mice, OVA sensitization and aerosol challenge of WT/WT (bone-marrow transfer from the WT to WT) or CD23KO/WT (CD23KO to WT) chimeric mice, which express CD23 on radio-resistant airway structural cells (mainly epithelial cells), resulted in airway eosinophilia, including collagen deposition and a significant increase in goblet cells, and increased airway hyper-reactivity. In contrast, the absence of CD23 expression on airway structural or epithelial cells, but not on hematopoietic cells, in WT/CD23KO (the WT to CD23KO) chimeric mice significantly reduced OVA-driven allergic airway inflammation. In addition, inhalation of the CD23-blocking B3B4 antibody in sensitized WT mice before or during airway challenge suppressed the salient features of asthma, including bronchial hyper-reactivity. Taken together, these results identify a previously unproven mechanism in which epithelial CD23 plays a central role in the development of allergic inflammation. Further, our study suggests that functional inhibition of CD23 in the airway is a potential therapeutic approach to inhibit the development of asthma.

KEYWORDS: Asthma, sensitization, antibody, immune complex, transcytosis

PMID: 25783969; PMCID:PMC 4575230




An emerging role of epithelial CD23 in asthma development and therapy


Asthma is a highly prevalent chronic disease, affecting millions of people of all age groups in the world (1). The disease is characterized by bronchial inflammation with a hyper-responsiveness and intermittent airway obstruction, which is generally triggered by airway exposure to a variety of substances that are collectively referred to as allergens, such as mold, pollen, animal dander, house dust mite, cockroach product, etc. Sometimes, respiratory infections in early life, such as those caused by influenza, respiratory syncytial virus, and streptococcus pneumonia, facilitate and exacerbate development and progression of asthma. When asthmatic inflammation occurs, the airway wall is infiltrated with various inflammatory cells and becomes extremely narrow and obstructive with thick mucus, consequently causing clinical symptoms, such as sneezing, coughing, shortness of breath, and chest tightness.


The airway epithelium sitting at the interface between external environment and internal milieu of the lung is the first layer of cells to come into contact with inhaled allergens in the respiratory system. These special epithelial cells adhere tightly to each other and form an airway surface barrier, which functions to prevent allergens and infectious agents from diffusing freely across this barrier. To elicit allergic airway inflammation, allergens must cross the epithelium lining the airway tract and interact with underlying immune cells, such as dendritic cells, mast cells, and basophils in the airway mucosa/submucosa and trigger a cascade of inflammatory reactions. Hence, such a physical barrier plays a pivotal role in maintaining the health of the respiratory system (2).




Figure 1. CD23-mediated IgE transcytosis leads to initial sensitization and amplification of allergen specific inflammatory responses. IgE and allergen-IgE complexes can cross the epithelium by a bidirectional transport mediated by airway epithelial CD23. In the luminal mucosa, specific IgE captures the inhaled allergens and forms allergen–IgE complexes, which are in turn captured by CD23 expressed on the external side of the airway epithelium and transported into the inside of the airway tissue where they are released, bind to and activate high affinity IgE receptor, FcεRI, on dendritic cells and mast cells, etc. Allergen-IgE complex can bind to multiple cell types through CD23 receptor as well. IgE aggregated by allergen complexes bind to FcεRI and stimulates cell degranulation which leads to release of mediators such as histamine, prostaglandin D2 (PGD2) and tumor necrosis factor (TNF), promoting recruitment of Th2 cells, the migration, maturation and activation of dendritic cells and antigen presentation. These cellular and molecular changes result in asthmatic inflammation in the bronchioles. TSLP: Thymic stromal lymphopoietin; ILC2: type 2 innate lymphoid cell. Bronchial images are from Google Image.


IgE is commonly found in airway mucus and its level is elevated in human patients with allergic rhinitis or bronchial asthma. Allergen-specific IgE has been known to play a major role in asthma development and exacerbation (3). For many years, IgE in airway secretions has been simply attributed to its passive transport from the blood. It is also unknown whether and how the allergen–IgE complex from lumen crosses the airway epithelium to gain access to immune effector cells in the underneath epithelial tissue. Previous studies by Dr. Palaniyandi and his colleagues, for the first time, have demonstrated that human airway epithelial cells express CD23, and the level of CD23 can be enhanced by the asthma-relevant cytokine, interleukin-4 (IL-4). Most importantly, human CD23 is responsible for dual directional transport of both IgE and IgE-allergen complex across human airway epithelium (4). CD23-dependent transport of allergen-IgE complexes across the epithelial barrier results in greater activation of mast cells, leading to increased release of allergic mediators from the activated mast cells in human cell culture. These studies indicate that CD23-mediated IgE and allergen-IgE transport provides a pathway for the inhaled allergens in the airway lumen to get access to immune effector cells underneath the airway epithelial barrier at the earliest phase of asthmatic inflammation development (4, 5).


In an effort to further demonstrate the in vivo involvement of epithelial CD23 in airway allergy, the OVA allergen-based asthma model in mouse was used. Consistent with the results from the human cell model, mouse CD23 expressed on the epithelia of the nasal, tracheal and lung mucosa is required for transport of both IgE and allergen-IgE complexes across airway epithelial barrier, as mice lacking CD23 fail to do so. OVA allergen sensitization increases the expression level of CD23 in the mouse airway mucosa. Using bone marrow chimeric mice, this study has demonstrated that the role of CD23 in eliciting allergic inflammation is epithelial intrinsic, rather than being mediated by CD23 expression in hematopoietic origin cells. The chimeric mice were created by adoptive transfer of bone-marrow cells from normal mice to the CD23-deficient mice that were gamma irradiated to remove CD23-negative immune cells. In this model, CD23 is completely absent from airway epithelial cells, but is present on immune cells derived from the normal mice. The inflammation in the lung induced by OVA sensitization and aerosol challenge was significantly attenuated inflammation in the chimeric mice lacking epithelial CD23. In contrast, the chimeric mice expressing airway epithelial CD23 had increased eosinophilia, collagen deposition, the number of goblet cells, and the hyper-reactivity in the airway upon OVA treatment (6). Taken together, this study and the previous study clearly show that that airway epithelial CD23 plays a critical role in the development of asthmatic inflammation, by capturing and importing the allergens-IgE immune complex (Figure 1). It has been known that allergens can be captured by dendritic cells in the airway lumen or in the epithelium of the airway mucosa, or gain access to submucosal dendritic cells through disrupted epithelium or by breaching the airway epithelial cell barrier in some allergens with intrinsic protease activities (2, 3). Thus, it should be noted that findings by Palaniyandi et al. are a fundamental addition to the existing understanding of allergy development, in which patients can also efficiently acquire allergens from environment using an allergen-specific, receptor-mediated mechanism through an intact, seemingly healthy airway epithelium.


Conventionally, asthma treatments include inhaled corticosteroids, beta-2 adrenoceptor agonist, leukotriene modifiers, anti-IgE antibody and allergen specific immunotherapy, most of which do not eliminate the primary causes for the disorder (7). Based on the essential role of airway epithelial CD23 in development of asthmatic inflammation, this molecule is a potential drug target in treatment of allergy. For this purpose, Dr. Palaniyandi and his colleagues used CD23-specific antibody to specifically block IgE binding to CD23. Intranasal treatment with the CD23 antibody had significantly reduced transfer of OVA-IgE complexes across airway epithelial barrier, consequently suppressing allergic airway inflammation significantly (Figure 2). These results provide a proof of the concept for clinical application of targeting epithelial CD23 using antibody or an effective and safe compound as a therapy for asthma. Hence, this study has expanded the fundamental understanding of the function of epithelial CD23 in asthma and provides strong evidence that CD23 is a potential drug target for treating asthma.




Figure 2. A, Treatment of mice with anit-CD23 antibody alleviates airway inflammation. Mice intranasally received anti-CD23 antibody treatment had reduced airway allergic inflammation in the lung when compared to isotype-matched antibody-treated or PBS alone control mice. Insets (green squares) are shown in a higher amplification (40X).


Major Findings:

  1. CD23 plays a significant role in the initiation and development of airway allergic inflammation by transporting IgE or IgE-allergen complex across the airway epithelial barrier.
  2. Allergen-induced airway inflammation can be treated by antibodies blocking CD23-mediated transfer of allergen-IgE complexes, which represent a novel therapeutic strategy for reducing/inhibiting airway allergic inflammation by manipulating CD23 functions.


Acknowledgement: This work was supported by National Institutes of Health (NIH) grant AI101752.




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