Multiple defects in Fc epsilon RI signaling in Syk-deficient nonreleaser basophils and IL-3-induced recovery of Syk expression and secretion.
Human basophils respond to Ag-induced cross-linking of their high affinity IgE receptor, FcepsilonRI, by releasing histamine and other mediators from granules, producing IL-4 and other cytokines and, as shown in this study, by forming membrane ruffles and showing increased very late Ag-4 (VLA-4)-mediated adhesion to VCAM-1-expressing target cells. We have identified five blood donors whose basophils lack detectable levels of the FcepsilonRI-associated protein tyrosine kinase, Syk. Despite showing no obvious ultrastructural differences from normal basophils, nonreleaser basophils fail to form membrane ruffles, to show increased VLA-4-mediated adhesive activity, or to produce IL-4 in response to FcepsilonRI cross-linking. Although Syk protein levels are suppressed in basophils from all five donors, Syk mRNA is consistently present. Furthermore, culturing nonreleaser basophils for 4 days with IL-3 restores Syk protein expression and FcepsilonRI-mediated histamine release. Understanding the reversible suppression of Syk protein expression in nonreleaser basophils, and learning to replicate this property in patients with allergic inflammation could be a powerful and specific way to limit symptomatic disease.
Kepley
C L
CL
Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA. ckepley@thor.unm.edu
Youssef
L
L
Andrews
R P
RP
Wilson
B S
BS
Oliver
J M
JM
D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism; D001491:Basophils / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D002448:Cell Adhesion / Q000276:immunology; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D007377:Interleukin-3 / Q000502:physiology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D016029:Receptors, Very Late Antigen / Q000502:physiology; D000072377:Syk Kinase; D015854:Up-Regulation / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D004792:Enzyme Precursors; D039041:Integrin alpha4beta1; D016023:Integrins; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D017455:Receptors, IgE; D016201:Receptors, Lymphocyte Homing; D016029:Receptors, Very Late Antigen; C026408:anti-IgE antibodies; D015847:Interleukin-4; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase