title: B cell tolerance induction by cross-linking of membrane IgM, but not IgD, and synergy by cross-linking of both isotypes.
abstract: Previous studies in our laboratory demonstrated that overnight exposure of adult splenic B cells to anti-Ig resulted in an unresponsive state characterized by decreased antibody synthesis but normal mitogen-driven proliferation (i.e., energy). Because both anti-F(ab')2 and anti-mu were equally effective at inducing tolerance, it was important to determine whether cross-linking of IgD together with or separately from IgM influenced the induction of unresponsiveness. Although anti-mu induced significant unresponsiveness, treatment of adult splenic B cells with anti-delta alone generally failed to reduce the subsequent response to either LPS or fluoresceinated Brucella abortus. Interestingly, anti-delta synergized with suboptimal concentrations of anti-mu to induce tolerance. Synergy could be observed in this system when anti-delta was added either simultaneously with or before (but not after) anti-mu; moreover, anti-delta was effective in a pretreatment (wash-out) protocol. To investigate the role of protein tyrosine kinase (PTK) activity in tolerance induction, splenic B cells were treated with tyrphostin before treatment with either anti-mu or anti-delta. We found that pretreatment with tyrphostin for 2 h before the addition of anti-mu prevented the induction of unresponsiveness with this antibody, whereas this PTK inhibitor facilitated tolerance when used with anti-delta treatment only. We propose that cross-linking of surface IgM directly or indirectly invokes a tyrphostin-sensitive, PTK-dependent pathway leading to the early events in tolerance induction, which can be augmented under limiting conditions by anti-IgD. Because cross-linking of either receptor initiates several common pathways, simultaneous cross-linking can lead to synergy and a dominance of the IgM signal. In contrast, IgD alone may fail to elicit tolerance because this isotype may also be associated with different PTK that cause positive signaling.
authors.affiliation: Division of Immunology and Immunotherapy, University of Rochester Cancer Center, NY 14642.
authors.forename: A
authors.initials: A
authors.lastname: Gaur
authors.forename: X R
authors.initials: XR
authors.lastname: Yao
authors.forename: D W
authors.initials: DW
authors.lastname: Scott
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D007108:Immune Tolerance; D007072:Immunoglobulin D / Q000502:physiology*; D007132:Immunoglobulin Isotypes / Q000502:physiology*; D007075:Immunoglobulin M / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011961:Receptors, Fc / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D007072:Immunoglobulin D; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D011971:Receptors, Immunologic; C050855:immunoglobulin D receptor; C035311:immunoglobulin M receptor; D011505:Protein-Tyrosine Kinases