IVIg-mediated amelioration of murine ITP via FcgammaRIIB is independent of SHIP1, SHP-1, and Btk activity.
It has been established that amelioration of murine immune thrombocytopenia purpura (ITP) by IVIg is dependent on the inhibitory receptor FcgammaRIIB. Co-cross-linking of the FcgammaRIIB with the B-cell receptor complex or with FcepsilonRI in mast cells results in cell inhibition, which is mediated by recruitment of the inositol phosphatase SHIP1 to the cytoplasmic tail of the FcgammaR. The FcgammaRIIB can also associate with protein tyrosine phosphatase SHP-1 as a potential secondary target of the receptor. Alternatively, homoaggregation of FcgammaRIIB can induce a proapoptotic state in B cells that is dependent on the presence of Bruton tyrosine kinase (Btk), a kinase also expressed in monocytes. We sought to determine if these signaling pathways may direct IVIg-mediated FcgammaRIIB-dependent regulation of in vivo monocyte function in a murine model of ITP in which IVIg functions in an FcgammaRIIB-dependent manner. We demonstrate that mice deficient in SHIP1, SHP-1, and Btk respond to the ameliorating effects of IVIg with the same kinetics as control mice. We conclude that IVIgmediated inhibitory pathways operating via monocyte FcgammaRIIB may involve a transmembrane signaling pathway different from that of B cells.
Crow
Andrew R
AR
Transfusion Medicine Research, St Michael's Hospital, Toronto, ON, Canada.
Song
Seng
S
Freedman
John
J
Helgason
Cheryl D
CD
Humphries
R Keith
RK
Siminovitch
Katherine A
KA
Lazarus
Alan H
AH
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D016756:Immunoglobulins, Intravenous; D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D010744:Phosphoric Monoester Hydrolases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases