title: B-cell receptors and heavy chain diseases: guilty by association?
abstract: Heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by the production of monoclonal, incomplete, immunoglobulin (Ig) heavy chains (HCs) without associated light chains (LCs). These abnormal HCs are produced as a consequence of HC gene alterations in the neoplastic B cells. HC gene alterations will also impact on surface HC, which is part of the B-cell receptor (BCR), a crucial player in lymphocyte activation by antigen. The selective advantage conferred to mutant cells by abnormal BCR without an antigen-binding domain may be explained by activation of ligand-independent signaling, in analogy to what has been shown for mutated oncogenic growth factor receptors. Here we review data obtained from mouse models showing abnormal, constitutive activity of HCD-BCR, and we discuss the possible mechanism involved, namely, aberrant spontaneous self-aggregation. This self-aggregation might occur as a consequence of escape from the chaperone immunoglobulin binding protein (BiP) and from the anti-aggregation effect of LC association. The concept of misfolding-induced signaling elaborated here may extend to other pathologies termed conformational diseases.
authors.affiliation: Inserm Unité 955, Faculté de Médecine-Paris 12, Créteil, France. daniel.corcos@inserm.fr
authors.forename: Daniel
authors.initials: D
authors.lastname: Corcos
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Osborn
authors.forename: Louise S
authors.initials: LS
authors.lastname: Matheson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D052138:Genes, Neoplasm; D006362:Heavy Chain Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018832:Molecular Chaperones; D011947:Receptors, Antigen, B-Cell