Sensitizing and Th2 Adjuvant Activity of Cysteine Protease Allergens

Cunningham, Paula; Elliot, Claire E.; Lenzo, Jason C.; Jarnicki, Andrew G.; Larcombe, Alexander N.; Zosky, Graeme R.; Holt, Patrick G.; Thomas, Wayne R.

doi:10.1159/000334280

Cited by 32 publications

(43 citation statements)

References 70 publications

(53 reference statements)

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“…Interestingly, administration of proteolytically active rAmb a 11 in mice elicits a strong allergic inflammation (including AHR, eosinophil infiltrates in BALs, and Amb a 11-specific Th2 responses), whereas sensitization with pro-rAmb a 11 or E64-inhibited rAmb a 11 results in lower allergic responses. This observation is fully consistent with documented evidence that cysteine protease activities of Der p 1 and Der f 1 promote airway epithelium disruption (47,48), immune cell activation (49,50), and Th2 inflammation (51)(52)(53)(54).…”

Section: Discussionsupporting

confidence: 90%

Structural and Functional Characterization of the Major Allergen Amb a 11 from Short Ragweed Pollen

Groeme¹,

Airouche²,

Kopečný³

et al. 2016

Journal of Biological Chemistry

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Allergy to the short ragweed (Ambrosia artemisiifolia) pollen is a major health problem. The ragweed allergen repertoire has been recently expanded with the identification of Amb a 11, a new major allergen belonging to the cysteine protease family. To better characterize Amb a 11, a recombinant proform of the molecule with a preserved active site was produced in Escherichia coli, refolded, and processed in vitro into a mature enzyme. The enzymatic activity is revealed by maturation following an autocatalytic processing resulting in the cleavage of both N-and C-terminal propeptides. The 2.05-Å resolution crystal structure of pro-Amb a 11 shows an overall typical C1A cysteine protease fold with a network of molecular interactions between the N-terminal propeptide and the catalytic triad of the enzyme. The allergenicity of Amb a 11 was confirmed in a murine sensitization model, resulting in airway inflammation, production of serum IgEs, and induction of Th2 immune responses. Of note, inflammatory responses were higher with the mature form, demonstrating that the cysteine protease activity critically contributes to the allergenicity of the molecule. Collectively, our results clearly demonstrate that Amb a 11 is a bona fide cysteine protease exhibiting a strong allergenicity. As such, it should be considered as an important molecule for diagnosis and immunotherapy of ragweed pollen allergy.

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Section: Discussionsupporting

confidence: 90%

Structural and Functional Characterization of the Major Allergen Amb a 11 from Short Ragweed Pollen

Groeme¹,

Airouche²,

Kopečný³

et al. 2016

Journal of Biological Chemistry

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“…Inhaled papain is not only a potent allergen found in occupational settings [17], papain (if enzymatically active, as is the case in other cysteine proteinases) is also able to induce Th2 responses and to exert an adjuvant effect on the sensitizing potential of other allergens, independently of its own antigenicity [18,19]. In addition, its proteolytic properties can enhance its mode and route of transport across epithelial barriers, which may have an impact on the immune responses generated [20].…”

Section: Discussionmentioning

confidence: 99%

Anaphylaxis Induced by a Drug Containing Lysozyme and Papain: Influence of Papain on the IgE Response

Benedé

Pérez-Rangel

Lozano‐Ojalvo

et al. 2014

Int Arch Allergy Immunol

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Background: This paper reports the case of an egg-allergic pediatric patient who, once desensitized to egg following a successful rush oral immunotherapy protocol, could also tolerate Lizipaina®, a drug containing lysozyme (LYS) and papain, which had previously caused him a severe allergic reaction. Because the LYS amount that elicited the anaphylactic reaction (5 mg) was much lower than that tolerated during a double-blind placebo-controlled food challenge (corresponding to approximately 60 mg of LYS), the possibility that the presence of papain could increase the allergenic potential of LYS was investigated. Methods: Lizipaina, LYS and LYS hydrolyzed with papain were analyzed by SDS-PAGE under reducing and nonreducing conditions, and Western blotting of sera from egg-allergic patients was performed in order to detect IgE-binding fragments. Finally, sequence identification of the IgE-reactive bands was carried out by MALDI-TOF/TOF. Results: The SDS-PAGE pattern of LYS treated with papain under nonreducing conditions showed the presence of intact LYS that partially disappeared following reduction with β-mercaptoethanol, releasing IgE-reactive fragments as determined by Western blotting. MALDI-TOF/TOF revealed that papain degraded LYS, giving rise to three IgE-binding fragments: LYS (22-129), LYS (34-96) and LYS (62-128) that likely remained linked through the disulfide bonds present in the LYS molecule. Conclusion: The combined administration of LYS with proteolytic enzymes such as papain may have developed a severe allergic reaction in the patient studied, underlining the importance of considering all the components and their interactions when drugs are to be consumed by allergic persons.

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“…HDM group 1 allergens, Der f 1 and Der p 1, and papain, a papaya fruit-derived occupational allergen, belong to the same family of cysteine proteases, family C1 of clan CA (5,11,12). Protease activity of papain (10,13) and recombinant Der f 1 (rDer f 1) (10) is essential to airway eosinophilia and serum IgE/IgG1 responses induced by inhalation of the protease allergens. In recent studies, papain has been used as a model protease allergen mimicking those contained in allergen sources (10,(13)(14)(15)(16).…”

mentioning

confidence: 99%

“…Protease activity of papain (10,13) and recombinant Der f 1 (rDer f 1) (10) is essential to airway eosinophilia and serum IgE/IgG1 responses induced by inhalation of the protease allergens. In recent studies, papain has been used as a model protease allergen mimicking those contained in allergen sources (10,(13)(14)(15)(16).…”

mentioning

confidence: 99%

Subcutaneous Allergic Sensitization to Protease Allergen Is Dependent on Mast Cells but Not IL-33: Distinct Mechanisms between Subcutaneous and Intranasal Routes

Kamijo

Suzuki

Hara

et al. 2016

The Journal of Immunology

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Protease activity of papain, a plant-derived occupational allergen homologous to mite major allergens, is essential to IgE/IgG1 production and lung eosinophilia induced by intranasal papain administration in mice, and IL-33 contributes to these responses. In this work, we investigate skin and Ab responses induced by s.c. papain administration into ear lobes and responses induced by subsequent airway challenge with papain. Subcutaneous papain injection induced swelling associated with increased epidermal thickness, dermal inflammation, serum IgE/IgG1 responses, and Th2 cytokine production in draining lymph node cells restimulated in vitro. These responses were markedly less upon s.c. administration of protease inhibitor-treated papain. Results obtained by using mast cell–deficient mice and reconstitution of tissue mast cells suggested the contribution of mast cells to papain-specific IgE/IgG1 responses and eosinophil infiltration. The responses were equivalent between wild-type and IL-33−/− mice. After the subsequent airway challenge, the s.c. presensitized wild-type mice showed more severe lung eosinophilia than those without the presensitization. The presensitized IL-33−/− mice showed modest lung eosinophilia, which was absent without the presensitization, but its severity and IgE boost by the airway challenge were markedly less than the presensitized wild-type mice, in which protease activity of inhaled papain contributed to the responses. The results suggest that mechanisms for the protease-dependent sensitization differ between skin and airway and that cooperation of mast cell–dependent, IL-33–independent initial sensitization via skin and protease-induced, IL-33–mediated mechanism in re-exposure via airway to protease allergens maximizes the magnitude of the transition from skin inflammation to asthma in natural history of progression of allergic diseases.

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Sensitizing and Th2 Adjuvant Activity of Cysteine Protease Allergens

Cited by 32 publications

References 70 publications

Structural and Functional Characterization of the Major Allergen Amb a 11 from Short Ragweed Pollen

Structural and Functional Characterization of the Major Allergen Amb a 11 from Short Ragweed Pollen

Anaphylaxis Induced by a Drug Containing Lysozyme and Papain: Influence of Papain on the IgE Response

Subcutaneous Allergic Sensitization to Protease Allergen Is Dependent on Mast Cells but Not IL-33: Distinct Mechanisms between Subcutaneous and Intranasal Routes

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