API

Relationship: 1701

Title

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Activation/Proliferation, T-cells leads to Increase, Allergic Respiratory Hypersensitivity Response

Upstream event

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Activation/Proliferation, T-cells

Downstream event

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Increase, Allergic Respiratory Hypersensitivity Response

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse fish Histrio histrio High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages

Key Event Relationship Description

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In brief, once antigen has been processed and presented by DCs and Th2 cells activated (KEs 398 and 272), the differentiation and clonal expansion of Th2 cells lead to production of Th2 cytokines that induce immunoglobulin (Ig) class switching to production of antigen-specific allergic antibody (IgE) by B cells and clonal expansion of naive and memory B cell populations. (Dearman et al., 2003) These antibodies are then found throughout the body, in circulation and/or bound to Fce receptors on cells such as mast cells and basophils in tissues, including the respiratory tract. On subsequent re-exposure, antigen can crosslink IgE bound to the surface of the aforementioned cells and induce degranulation, releasing various mediators that lead to the clinical symptoms of asthma and rhinitis.

Evidence Supporting this KER

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Biological Plausibility

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The rapid onset of symptoms (within 1 hour and often within minutes of exposure) of respiratory allergic symptoms in sensitized individuals is indicative of an antibody-mediated (type I hypersensitivity) mechanism.

 

Antihapten antibodies have been found in mice treated epicutaneously with skin and respiratory sensitizers, although they produce qualitatively different immune responses, likely reflecting the different cytokine milieus (Th1 or Th2) produced by the activated T cells in each case. While IgG1 production occurred in response to both groups of chemicals, the skin sensitizers DNCB and oxazalone preferentially drove production of IgG2a, while the respiratory sensitizers TMA and PA preferentially drove production of IgG2b. In addition, only the respiratory sensitizers were associated with an increase in serum IgE. (Dearman and Kimber, 1992, Dearman and Kimber, 1991)

Empirical Evidence

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Uncertainties and Inconsistencies

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There is still remaining uncertainty regarding the role of IgE in chemical respiratory allergy, because specific IgE has not been demonstrated in all subjects sensitized to chemicals. (Kimber et al., 2014b, Kimber et al., 2014a, Quirce, 2014)

IgE production can occur both in the germinal centers of lymph nodes and locally in the airway mucosa, with the latter reported to be linked to nasal polyps associated with chronic rhinosinusitis and in response to inhaled protein allergens. (Baba et al., 2014, Hoddeson et al., 2010) The extent of germinal center involvement or local IgE production in respiratory sensitizers is currently unknown.

While there is considerable evidence that DCs are likely the most efficient APC for stimulating naive T cells, there is evidence that IgE at the surface of allergen-specific IgE-positive B cells and other APCs, such as alveolar macrophages, may also facilitate antigen presentation. (Zhong et al., 1997) A role for airway and alveolar epithelial cells in antigen presentation and induction and maintenance of adaptive responses is also becoming increasingly recognized. (Hasenberg et al., 2013)

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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BABA, S., KONDO, K., TOMA-HIRANO, M., KANAYA, K., SUZUKAWA, K., USHIO, M., SUZUKAWA, M., OHTA, K. & YAMASOBA, T. 2014. Local increase in IgE and class switch recombination to IgE in nasal polyps in chronic rhinosinusitis. Clin Exp Allergy, 44, 701-12.

DEARMAN, R. J. & KIMBER, I. 1991. Differential stimulation of immune function by respiratory and contact chemical allergens. Immunology, 72, 563-70.

DEARMAN, R. J. & KIMBER, I. 1992. Divergent immune responses to respiratory and contact chemical allergens: antibody elicited by phthalic anhydride and oxazolone. Clin Exp Allergy, 22, 241-50.

DEARMAN, R. J., STONE, S., CADDICK, H. T., BASKETTER, D. A. & KIMBER, I. 2003. Evaluation of protein allergenic potential in mice: dose-response analyses. Clin Exp Allergy, 33, 1586-94.

HASENBERG, M., STEGEMANN-KONISZEWSKI, S. & GUNZER, M. 2013. Cellular immune reactions in the lung. Immunol Rev, 251, 189-214.

HODDESON, E. K., PRATT, E., HARVEY, R. J. & WISE, S. K. 2010. Local and systemic IgE in the evaluation and treatment of allergy. Otolaryngol Clin North Am, 43, 503-20, viii.

KIMBER, I., DEARMAN, R. J. & BASKETTER, D. A. 2014a. Diisocyanates, occupational asthma and IgE antibody: implications for hazard characterization. J Appl Toxicol, 34, 1073-7.

KIMBER, I., DEARMAN, R. J., BASKETTER, D. A. & BOVERHOF, D. R. 2014b. Chemical respiratory allergy: reverse engineering an adverse outcome pathway. Toxicology, 318, 32-9.

QUIRCE, S. 2014. IgE antibodies in occupational asthma: are they causative or an associated phenomenon? Curr Opin Allergy Clin Immunol, 14, 100-5.

ZHONG, G., REIS E SOUSA, C. & GERMAIN, R. N. 1997. Antigen-unspecific B cells and lymphoid dendritic cells both show extensive surface expression of processed antigen-major histocompatibility complex class II complexes after soluble protein exposure in vivo or in vitro. J Exp Med, 186, 673-82.