title: Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain.
abstract: Russell bodies (RBs) are intracellular inclusions filled with protein aggregates. In diverse lymphoid disorders these occur as immunoglobulin (Ig) deposits, accumulating in abnormal plasma or Mott cells. In heavy-chain deposition disease truncated antibody heavy-chains (HCs) are found, which bear a resemblance to diverse polypeptides produced in Ig light-chain (LC)-deficient (L(-/-)) mice. In L(-/-) animals, the known functions of LC, providing part of the antigen-binding site of an antibody and securing progression of B-cell development, may not be required. Here, we show a novel function of LC in preventing antibody aggregation. L(-/-) mice produce truncated HC naturally, constant region (C)gamma and Calpha lack C(H)1, and Cmicro is without C(H)1 or C(H)1 and C(H)2. Most plasma cells found in these mice are CD138(+) Mott cells, filled with RBs, formed by aggregation of HCs of different isotypes. The importance of LC in preventing HC aggregation is evident in knock-in mice, expressing Cmicro without C(H)1 and C(H)2, which only develop an abundance of RBs when LC is absent. These results reveal that preventing antibody aggregation is a major function of LC, important for understanding the physiology of heavy-chain deposition disease, and in general recognizing the mechanisms, which initiate protein conformational diseases.
authors.affiliation: The Babraham Institute, Babraham, Cambridge, United Kingdom. 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
authors.forename: Fatima
authors.initials: F
authors.lastname: Santos
authors.forename: Xiangang
authors.initials: X
authors.lastname: Zou
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.forename: Geoff
authors.initials: G
authors.lastname: Morgan
authors.forename: Amanda
authors.initials: A
authors.lastname: Hutchings
authors.forename: Maureen
authors.initials: M
authors.lastname: Hamon
authors.forename: David
authors.initials: D
authors.lastname: Oxley
authors.forename: Marianne
authors.initials: M
authors.lastname: Brüggemann
mesh_terms: D000818:Animals; D055879:Gene Knock-In Techniques; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000378:metabolism*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism*; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; C508242:Sdc1 protein, mouse; D053668:Syndecan-1