A selective defect in IgM antigen receptor synthesis and transport causes loss of cell surface IgM expression on tolerant B lymphocytes.
To explore the biochemical basis for maintaining immunological tolerance by functional inactivation of self-reactive B lymphocytes, transgenic mice carrying rearranged anti-lysozyme immunoglobulin transgenes and a lysozyme transgene were used as a source of large numbers of tolerant self-reactive B cells. Antigen receptors of the IgD isotype were expressed at normal levels on tolerant B cells, contained the heterodimeric MB1/B29 signalling component of the receptor complex and were structurally indistinguishable from IgD on nontolerant B cells. In contrast, cell surface expression of IgM receptor complexes on tolerant B cells was greatly reduced, despite normal expression of mRNA encoding the receptor components. Three-fold fewer immunoreactive mu heavy chains were detectable after a short period of biosynthetic labelling and the immunoreactive mu chains produced were paired with kappa light chains and assembled normally into intact receptor complexes containing the MB1/B29 heterodimer. Nascent IgM receptor complexes nevertheless failed to be processed into an endoglycosidase H-resistant form in the tolerant B cells and thus appeared to be selectively blocked in their transport from the endoplasmic reticulum to the medial Golgi. These findings demonstrate that intracellular trafficking of antigen receptor complexes is regulated by exposure to receptor stimuli at the cell surface causing a long-lasting decrease in surface receptor expression on tolerant B cells.
Bell
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Howard Hughes Medical Institute, Beckman Center, Stanford University Medical School, CA 94305-5428.
Goodnow
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D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001692:Biological Transport; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D007108:Immune Tolerance; D007072:Immunoglobulin D / Q000378:metabolism; D007075:Immunoglobulin M / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis*; D011961:Receptors, Fc / Q000096:biosynthesis* / Q000378:metabolism
D007072:Immunoglobulin D; D007075:Immunoglobulin M; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; C035311:immunoglobulin M receptor