THE ROLE OF BASOPHILS IN ALLERGIC DISEASE

During allergic disease, leucocytes infiltrate the affected tissues an d release their mediators and cytokines. In this way, the local inflam matory process is induced and maintained. Basophilic granulocytes have been demonstrated in lung and sputum of allergic asthmatics, in nasal mucosa and secretion of allergic rhinitis patients, and in skin lesio ns of atopic dermatitis patients. The number of basophils correlates w ith the severity of the disease. Analysis of mediator profiles and cel lular contents of lavages of nose, skin and lung during allergic late- phase reactions (LPR) have demonstrated histamine, but not tryptase or prostaglandin D-2. The histamine-containing cells have been character ized as basophilic granulocytes, This indicates that infiltrating baso phils but not mast cells are activated and release their inflammatory contents in the LPR. We are interested in the cellular mechanisms that determine the degranulation of basophils during LPR Basophil activato rs, such as allergens and activated complement, are not present at the se sites, However, cytokines that prime basophils but do not induce de granulation, such as interleukin-5 (IL-5) and granulocyte/macrophage c olony-stimulating factor (GM-CSF), have been detected at sites of LPR. We have now observed that after emptying intracellular Ca2+ stores by means of the Ca2+ adenosine triphosphatase (ATPase) inhibitor, thapsi gargin, basophils become extremely sensitive to stimuli that do not af fect the Ca2+ stores themselves but that induce degranulation, such as the phorbolester, phorbol myristate acetate (PMA). The most interesti ng finding was that although both thapsigargin and IL-3, IL-5 or GM-CS F do not induce basophil degranulation by themselves, a 2 min preincub ation of basophils with thapsigargin followed by addition of one of th ese cytokines resulted in extensive histamine release: IL-3 induced 71 +/-7% histamine release (conc1/2max 6 pM), IL-5 induced 43+/-8% histam ine release (conc1/2max 41 pM) and GM-CSF induced 57+/-10% histamine r elease (conc1/2max 140 pM). Interestingly, the effect of thapsigargin could be mimicked by platelet-activating factor (PAF) (range 10(-9) to 10(-6) M), although to a lesser extent. Our results indicate that bas ophil degranulation in tissues during late-phase reactions might be ca used by a combination of mediators or cytokines depleting Ca2+ stores, as platelet-activating factor or thapsigargin do, concurrent with act ivation by interleukin-3, interleukin-5 or granulocyte/macrophage colo ny-stimulating factor, The response of the basophils towards these cyt okines might also be influenced by cell adhesion events, such as bindi ng of basophils via integrins. This is the subject of further study.