API

Relationship: 1700

Title

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N/A, Covalent binding to protein, possibly lysine residue leads to Activation, Dendritic Cells

Upstream event

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N/A, Covalent binding to protein, possibly lysine residue

Downstream event

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Activation, Dendritic Cells

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 Mus musculus High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages Not Specified

Key Event Relationship Description

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Dendritic cells are activated directly by exposure to haptens in skin and respiratory sensitization.

Evidence Supporting this KER

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Biological Plausibility

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Monocyte-derived DCs (Mo-DCs) and THP-1 cells exposed to haptens with cysteine, lysine, or cysteine/lysine reactivity induced the expression of Nrf2 pathway-related genes when exposed to chemical sensitizers having cysteine and cysteine/ lysine affinities, while lysine-reactive chemicals (phthalic anhydride [PA] and TMA) were less efficient. (Migdal et al., 2013) Also, these chemicals did not prod the Mo-DCs to produce maturation markers CD86 and CD83, while PA was able to modify THP-1 cells to produce CD86 and CD54 markers.

(Toebak et al., 2006) used Mo-DCs to investigate the polarization potential of TMA compared to contact and protein allergens. In contrast to 2,4-dinitrochlorobenzene (DNCB) and similarly to protein allergen Der p1, TMA led to a decreased IL-12p70/IL-10 ratio and did not induce TNF-a or CXCL10 production, a demonstration of Th2-skewing. TMA was also found to increase the production of the cytokines IL-10 and IL-13, another hallmark of Th2 response, in DCs enriched from human blood. (Holden et al., 2008) Finally, TMA induced increased production of IL-10 when incubated with precision cut lung slices (PCLS) for 24 hours. (Lauenstein et al., 2014)

 

In BALB/c mice, TDI applied to the skin led to TDI-haptenated protein (TDI-hp) (skin keratins and albumin) localization in the stratum corneum, hair follicles, and sebaceous glands within 3 hours, with intensity of staining following a dose–response relationship. (Nayak et al., 2014) Subsequently, CD11b+, Langerin (CD207)-expressing DCs, and CD103+ cells migrated to regions of TDI-hp staining. These cells are involved in antigen uptake and stimulation of effector T cells.

Migration depends on the expression of chemokine receptors and their respective CCLs, as well as on adhesion molecules, such as integrins. DCs express receptors for, and respond to, constitutive and inflammatory chemokines and other chemoattractants, such as platelet-activating factor and formyl peptides.

Empirical Evidence

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In BALB/c mice, topical application of TMA induced rapid cytokine secretion in the skin—namely IL-4 and IL-10, which was not the case for the skin sensitizer DNCB. Increased IL-4 and IL-10 were also detected in the DLN after TMA exposure, and DC migration to the DLN was confirmed, although delayed behind DNCB-caused migration. Anti-IL-10 antibody ameliorated this response to TMA. (Cumberbatch et al., 2005)

Uncertainties and Inconsistencies

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Much investigation has gone into assessing the specific mechanistic events involved in skin sensitizer-caused DC migration. Ex vivo studies with intact human skin, epidermal sheets, and MUTZ-3-derived Langerhans cells (LC) show that fibroblasts mediate migration of cytokine-matured LC via chemokines, including CXCL12, CXCR4, and dermis-derived CCL2 and CCL5. (Ouwehand et al., 2008, 2011, 2012) The relevance of these studies for respiratory sensitization is not known. Some evidence indicates that IL-10, upregulated by TMA, may block the migration of LC for a short period of time to allow a Th2 phenotype to develop.(Holden et al., 2008, Cumberbatch et al., 2005)

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Mo-DCs express maturation factors in a few hours following exposure, similar in time-scale to the activation of inflammatory responses. In vivo, DC migration to lymph nodes is typically measured 18 hours after exposure.

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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CUMBERBATCH, M., CLELLAND, K., DEARMAN, R. J. & KIMBER, I. 2005. Impact of cutaneous IL-10 on resident epidermal Langerhans' cells and the development of polarized immune responses. J Immunol, 175, 43-50.

HOLDEN, N. J., BEDFORD, P. A., MCCARTHY, N. E., MARKS, N. A., IND, P. W., JOWSEY, I. R., BASKETTER, D. A. & KNIGHT, S. C. 2008. Dendritic cells from control but not atopic donors respond to contact and respiratory sensitizer treatment in vitro with differential cytokine production and altered stimulatory capacity. Clin Exp Allergy, 38, 1148-59.

MIGDAL, C., BOTTON, J., EL ALI, Z., AZOURY, M. E., GULDEMANN, J., GIMÉNEZ-ARNAU, E., LEPOITTEVIN, J. P., KERDINE-RÖMER, S. & PALLARDY, M. 2013. Reactivity of chemical sensitizers toward amino acids in cellulo plays a role in the activation of the Nrf2-ARE pathway in human monocyte dendritic cells and the THP-1 cell line. Toxicol Sci, 133, 259-74.

NAYAK, A. P., HETTICK, J. M., SIEGEL, P. D., ANDERSON, S. E., LONG, C. M., GREEN, B. J. & BEEZHOLD, D. H. 2014. Toluene diisocyanate (TDI) disposition and co-localization of immune cells in hair follicles. Toxicol Sci, 140, 327-37.

OUWEHAND, K., SANTEGOETS, S. J., BRUYNZEEL, D. P., SCHEPER, R. J., DE GRUIJL, T. D. & GIBBS, S. 2008. CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis. Eur J Immunol, 38, 3050-9.

OUWEHAND, K., SPIEKSTRA, S. W., WAAIJMAN, T., BREETVELD, M., SCHEPER, R. J., DE GRUIJL, T. D. & GIBBS, S. 2012. CCL5 and CCL20 mediate immigration of Langerhans cells into the epidermis of full thickness human skin equivalents. Eur J Cell Biol, 91, 765-73.

OUWEHAND, K., SPIEKSTRA, S. W., WAAIJMAN, T., SCHEPER, R. J., DE GRUIJL, T. D. & GIBBS, S. 2011. Technical advance: Langerhans cells derived from a human cell line in a full-thickness skin equivalent undergo allergen-induced maturation and migration. J Leukoc Biol, 90, 1027-33.

TOEBAK, M. J., MOED, H., VON BLOMBERG, M. B., BRUYNZEEL, D. P., GIBBS, S., SCHEPER, R. J. & RUSTEMEYER, T. 2006. Intrinsic characteristics of contact and respiratory allergens influence production of polarizing cytokines by dendritic cells. Contact Dermatitis, 55, 238-45.