Modifications of Igα and Igβ Expression as a Function of B Lineage Differentiation

Abstract

Membrane-bound immunoglobulin (Ig) molecules are noncovalently bound to the transmembrane Ig␣ (CD79a) and Ig␤ (CD79b) proteins, respectively the products of the mb1 and B29 genes, to form the B cell antigen receptor (BCR) 1 complex (1). Ig␣/Ig␤ heterodimers are also integral components of pre-BCR complexes composed of surrogate light chain (LC) and heavy chains (HC) on the surface of pre-B cells (2-8). Ligation of BCR and pre-BCR initiates cytoplasmic signals via the Ig␣ and Ig␤ molecules whose cytoplasmic domains contain immunoregulatory tyrosine-based activation motifs. BCR aggregation thereby promotes interaction with protein-tyrosine kinases and resultant immunoregulatory tyrosine-based activation motif phosphorylation, hydrolysis of phosphatidylinositol, sustained intracellular calcium elevation (9 -12), and the activation of multiple signaling pathways (13-15).Expression of Ig␣ and Ig␤ transcripts begins very early in B lineage differentiation prior to the onset of D H -J H rearrangements in the HC locus (16, 17), and Ig␤-deficient mice are unable to generate HC-producing pre-B cells (18). Surprisingly, B cell development in Ig␤ Ϫ/Ϫ mice appears to be compromised as early as the pro-B stage when V H -DJ H rearrangements are occurring, thereby suggesting an Ig␤ role in B lymphopoiesis even prior to HC synthesis. Although pro-B cell lines from humans also produce Ig␣ and Ig␤, expression of these as components of cell surface receptors has not been demonstrable (4). Correspondingly, the LC in human pro-B cells were found exclusively in the endoplasmic reticulum and early Golgi compartments, where they transiently associated with 40-, 60-, and 98-kDa proteins before undergoing intracellular degradation (7,8). In murine pro-B cells, however, Ig␣/Ig␤ heterodimers have recently been found on the cell surface, perhaps in association with calnexin (19,20).The physiological role of Ig␣ and Ig␤ during the earliest stages in B lineage differentiation thus remains unclear, and may differ in mice and humans. In this analysis of human B lineage cells, we have compared Ig␣ and Ig␤ expression, heterogeneity, and molecular association in pro-B cells versus their more mature pre-B and B cell offspring. The results reveal a remarkable progressive complexity of the Ig␣ and Ig␤ glycoproteins during B lineage differentiation, an unanticipated intracellular association with a Src family protein-tyrosine kinase in pro-B cells, and late stage Ig␣/Ig␤ union with assembled IgM molecules to form the BCR on B cells. EXPERIMENTAL PROCEDURESAntibodies-Mouse monoclonal antibodies (mAbs) included SA-DA 4;4 (␥1) anti-human H chain (21), CB3-1 (␥1), and CB3-2 (␥1) anti-human Ig␤ (4), HM57 (␥1) anti-human Ig␣ (22), SLC1 (␥1) anti-human LC (8), 4G10 (␥1) anti-phosphotyrosine (Upstate Biotechnology Inc., Lake Placid, NY), 4D10 (␥2a) anti-human Syk (Santa Cruz Biotechnology, Inc. CA), and Fyn (␥1) anti-human Fyn (Santa Cruz Biotechnology). The JH3 (␥1) anti-human Ig idiotype (23) and CT4 (␥1) anti-chicken CD4 (24) mAbs were used as controls. In ...

The alternative transcript of CD79b is overexpressed in B-CLL and inhibits signaling for apoptosis

“…Finally, we also used Western blotting experiments with a panel of anti-CD79b mAbs directed to the extracellular domain of CD79b to confirm the existence of truncated CD79b in transfected COS-7 cells, B-cell lines, and transfected EHRB cells. These experiments revealed that protein species are generated from the alternative transcripts of CD79 and confirm the work of Benlagha et al, 34 which has recently demonstrated the truncated form of CD79a in normal B cells by Western blotting. Intriguingly, all of the anti-CD79 mAbs available bound to both full-length and truncated forms of the CD79b molecule, despite the fact that the truncated molecule has lost the complete extracellular Ig-like domain and is left with only 25 amino acids to provide the Ab epitope.…”

Novel Roles for Lyn in B Cell Migration and Lipopolysaccharide Responsiveness Revealed Using Anti-Double-Stranded DNA Ig Transgenic Mice

“…Expressed throughout B cell development (3), Lyn participates in signaling from multiple cell surface receptors. Upon engagement of surface Ig, Lyn associates with the B cell Ag receptor (BCR) 3 complex and is rapidly tyrosine phosphorylated, with an associated increase in its enzymatic activity (4 -6). Lyn is also activated after engagement of the CD40 receptor (7), and in the absence of Lyn, CD40-induced Fas expression was reported to be substantially reduced, as was germinal center (GC) formation (8,9).…”

IgH DJ rearrangements within T-ALL correlate with cCD79a expression, an immature/TCRγδ phenotype and absence of IL7Rα/CD127 expression

“…While CD79b appears to be expressed as a single isoform, CD79a is expressed from two alternatively spliced transcripts, with the smaller one representing an immature form, whose protein is predicted not to form disulfide-linked dimers with CD79b but to maintain the transmembrane and cytoplasmic portions, thus permitting immunological detection. 2 Cytoplasmic (c)CD79a is expressed prior to CD19 during B lymphoid 3 development and is expressed by virtually all B-cell precursor ALLs (BCP-ALL). 4,5 It is considered to represent a B lineage restricted marker, 6 although weak cCD79a expression has been detected by immunohistochemistry or flow cytometry in 10-40% of a limited number of T-ALLs.…”