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Subthreshold desensitization of human basophils re-capitulates the loss of Syk and FcεRI expression characterized by other methods of desensitization.
Clin Exp Allergy 2012; 42(7):1060-70CE

Abstract

BACKGROUND

Clinical desensitization of patients to drugs involves progressive exposure to escalating doses of drug over a period of 24 h. In prior studies, this method was re-capitulated in vitro to also demonstrate loss of mast cell or basophil responsiveness. However, most signalling studies of human basophils have identified changes in signalling by using other methods of inducing cellular desensitization.

OBJECTIVE

This study examined two well-described endpoints of basophil desensitization, loss of syk or FcεRI expression, under conditions of subthreshold desensitization.

METHODS

The loss of FcεRI and syk was examined in human basophils.

RESULTS

It was shown that both loss of syk and FcεRI/IgE occurred during an escalating series of stimulation (anti-IgE Ab) and that expression loss occurred despite the presence of little histamine release. If basophils were first cultured for 3 days in 10 ng/mL IL-3, the concentration-dependence of histamine release shifted to 100-fold lower concentrations of stimulus. However, loss of syk did not show any change in its EC50 while loss of FcεRI also shifted 100-fold. From the perspective of early signal element activation, the marked shift in the EC50 for histamine release was not accompanied by similar shifts in the EC50s for several signalling elements. The EC50s for phospho-Src, phospho-SHIP1, phospho-Syk, or phospho-Cbl did not change while the EC50s for phospho-Erk and the cytosolic calcium response did shift 100-fold.

CONCLUSIONS

These studies show that under normal conditions, subthreshold desensitization leads to loss of two critical signalling molecules (FcεRI and syk) but under at least one condition, treatment with IL-3, it is possible to markedly blunt the loss of syk, but not FcεRI, while executing a proper subthreshold titration. These data also suggest that IL-3 modifies only the sensitivity of signalling elements that are downstream of syk activation.

Authors+Show Affiliations

Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA. dmacglas@jhmi.edu

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22702505

Citation

MacGlashan, D. "Subthreshold Desensitization of Human Basophils Re-capitulates the Loss of Syk and FcεRI Expression Characterized By Other Methods of Desensitization." Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, vol. 42, no. 7, 2012, pp. 1060-70.
MacGlashan D. Subthreshold desensitization of human basophils re-capitulates the loss of Syk and FcεRI expression characterized by other methods of desensitization. Clin Exp Allergy. 2012;42(7):1060-70.
MacGlashan, D. (2012). Subthreshold desensitization of human basophils re-capitulates the loss of Syk and FcεRI expression characterized by other methods of desensitization. Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, 42(7), pp. 1060-70. doi:10.1111/j.1365-2222.2012.04013.x.
MacGlashan D. Subthreshold Desensitization of Human Basophils Re-capitulates the Loss of Syk and FcεRI Expression Characterized By Other Methods of Desensitization. Clin Exp Allergy. 2012;42(7):1060-70. PubMed PMID: 22702505.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subthreshold desensitization of human basophils re-capitulates the loss of Syk and FcεRI expression characterized by other methods of desensitization. A1 - MacGlashan,D,Jr PY - 2012/6/19/entrez PY - 2012/6/19/pubmed PY - 2012/10/19/medline SP - 1060 EP - 70 JF - Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology JO - Clin. Exp. Allergy VL - 42 IS - 7 N2 - BACKGROUND: Clinical desensitization of patients to drugs involves progressive exposure to escalating doses of drug over a period of 24 h. In prior studies, this method was re-capitulated in vitro to also demonstrate loss of mast cell or basophil responsiveness. However, most signalling studies of human basophils have identified changes in signalling by using other methods of inducing cellular desensitization. OBJECTIVE: This study examined two well-described endpoints of basophil desensitization, loss of syk or FcεRI expression, under conditions of subthreshold desensitization. METHODS: The loss of FcεRI and syk was examined in human basophils. RESULTS: It was shown that both loss of syk and FcεRI/IgE occurred during an escalating series of stimulation (anti-IgE Ab) and that expression loss occurred despite the presence of little histamine release. If basophils were first cultured for 3 days in 10 ng/mL IL-3, the concentration-dependence of histamine release shifted to 100-fold lower concentrations of stimulus. However, loss of syk did not show any change in its EC50 while loss of FcεRI also shifted 100-fold. From the perspective of early signal element activation, the marked shift in the EC50 for histamine release was not accompanied by similar shifts in the EC50s for several signalling elements. The EC50s for phospho-Src, phospho-SHIP1, phospho-Syk, or phospho-Cbl did not change while the EC50s for phospho-Erk and the cytosolic calcium response did shift 100-fold. CONCLUSIONS: These studies show that under normal conditions, subthreshold desensitization leads to loss of two critical signalling molecules (FcεRI and syk) but under at least one condition, treatment with IL-3, it is possible to markedly blunt the loss of syk, but not FcεRI, while executing a proper subthreshold titration. These data also suggest that IL-3 modifies only the sensitivity of signalling elements that are downstream of syk activation. SN - 1365-2222 UR - https://www.unboundmedicine.com/medline/citation/22702505/Subthreshold_desensitization_of_human_basophils_re_capitulates_the_loss_of_Syk_and_FcεRI_expression_characterized_by_other_methods_of_desensitization_ L2 - https://doi.org/10.1111/j.1365-2222.2012.04013.x DB - PRIME DP - Unbound Medicine ER -