Submitted March 15, 2006
Accepted May 24, 2006
Granzyme B, a novel mediator of allergic inflammation:
Its induction and release in blood basophils and human asthma
Cornelia M Tschopp, Nicole Spiegl, Svetlana Didichenko, Werner Lutmann, Peter Julius, J C Virchow, C E Hack, and Clemens A Dahinden*
Institute of Immunology, Inselspital, University of Bern, Switzerland
Department of Pneumology, University Medical Clinic, Rostock, Germany
Sanquin Research at the CLB, Amsterdam, the Netherlands
University Hospital
* Corresponding author; email: clemens.dahinden{at}iib.unibe.ch.
Histamine, leukotriene-C4, IL-4 and IL-13 are major mediators of allergy and asthma. They are all formed by basophils and are released in particularly large quantities after stimulation with IL-3. Here we show that supernatants of activated mast cells or IL-3 qualitatively change the make-up of granules of human basophils by inducing de-novo synthesis of granzyme B (GzmB), without induction of other granule proteins expressed by cytotoxic lymphocytes (granzyme A, perforin). This bioactivity of IL-3 is not shared by other cytokines known to regulate the function of basophils or lymphocytes. The IL-3 effect is restricted to basophil granulocytes as no constitutive or inducible expression of GzmB is detected in eosinophils or neutrophils. GzmB is induced within 6-24 hours, sorted into the granule compartment, and released by exocytosis upon IgE-dependent and - independent activation. In vitro, there is a close parallelism between GzmB, IL 13 and leukotriene-C4 production. In vivo, Granzyme B, but not the lymphoid granule marker granzyme A, is released 18 hours after allergen challenge of asthmatic patients in strong correlation with interleukin-13. Our study demonstrates an unexpected plasticity of the granule composition of mature basophils and suggests a role of granzyme B as a novel mediator of allergic diseases.
