Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain

Abstract

IntroductionIn the healthy organism, immunoglobulin (Ig) is present in membrane form, as part of the B-cell receptor (BCR), and in secreted form, as antibody. During B-cell development, V H DJ H rearrangement of a heavy chain (HC) precedes V L J L rearrangement of a light chain (LC). Nascent HC polypeptides are associated with the HC-binding protein (BiP, or GRP78) in the endoplasmic reticulum (ER) awaiting LC association, processing (eg, carbohydrate association), and export. [1][2][3] The key function of the BiP chaperone is to provide a scaffold to native or unfolded polypeptides, which prevents aggregation and establishes the appropriate conformation. Abnormal plasma cells called Mott cells, containing Ig aggregates, termed Russell bodies (RBs), have been found in nonsecretory myeloma, inflammatory diseases, and autoimmune disorders. 4,5 RB formation appears to indicate cellular indigestion due to a failure to eliminate misfolded or incorrectly assembled proteins. 6 An unsolved question is whether the inability to degrade or to export leads to Ig aggregation. It is possible that the production of large quantities of Ig as well as structural alterations may prevent appropriate processing.In the absence of LC, HC dissociation from chaperones and export is facilitated by deletions in the V H and/or C H 1 domain, a feature seen in pathology and also in cultured cell lines. [7][8][9] Shortened HC is produced in various lymphoid malignancies. In heavy-chain diseases (HCDs), HC is not associated with LC, lacks all or part of V H , and frequently shows deletion(s) in its C H domain(s). 7 In heavy-chain deposition disease (HCDD), a kidney disease secondary to plasma cell dyscrasia, deletions of C H 1 or of both C H 1 and C H 2 domains are found. 10,11 LCs are associated with HCs in HCDD serum antibodies but are missing from the deposits. 10,11 Expression studies showed that full-length HC cannot reach the cell surface in the absence of LC or surrogate LC, 12,13 although more recent experiments demonstrated that this is not always the case. 14-17 At the pre-B cell stage, HC pairing with surrogate LC results in surface expression and oligomerization of the pre-BCR, regarded as important for pre-BCR signaling. 18,19 HC-LC pairing permits a high level of surface IgM expression but appears to inhibit basal signaling, 20 possibly by preventing auto-aggregation.We previously found that ␥ and ␣ HCs lacking C H 1, similar to the proteins produced in HCDD, are present in the serum of LC-deficient (L Ϫ/Ϫ ) mice, which appear to be healthy. 21,22 HCs are encoded by mRNAs transcribed from somatically truncated HC genes with deletions extending from the switch region. Although membrane is required for these class-switch isotypes to be produced, no secreted HC could be detected.Here, we report that in L Ϫ/Ϫ mice, deletions in C result in the production of short HC transcripts and proteins by plasma cells; however, truncated proteins are only found in serum from older mice. In addition to this defect of secretion, a large majority ...

One siRNA pool targeting the λ constant region stops λ light-chain production and causes terminal endoplasmic reticulum stress

“…Of note, the loss of IgH production with manufacture of only IgL and the possible toxicity of IgH to plasma cells are fundamental themes in plasma cell biology. 7,[33][34][35][36] After passage in culture, hybridomas often lose IgH production and make IgL only, and the majority of human myeloma cell lines produce IgL without IgH partners. 33 IgL-deficient mice attain a complete block in B-cell development at the stage when lightchain rearrangement should occur, resulting in surface IgM deficiency, retention of unpaired IgH in the cytoplasm, and lack of plasma cells.…”

Serum free immunoglobulin light chain evaluation as a marker of impact from intraclonal heterogeneity on myeloma outcome

“…5 B cells and immunoglobulin-secreting plasma cells manufacture about twice as many light chains in their cytoplasm as heavy chains, which prevent toxicity to the cell from aggregation of free heavy chain. 6,7 Normal as well as neoplastic plasma cells secrete both whole immunoglobulin and free light chains (FLCs). In a series of 2709 Medical Research Council (MRC) myeloma trial patients, 85% secreted a whole paraprotein (56% IgG, 27% IgA, and 2% IgD).…”

Elevated serum free light chains predict cardiovascular risk in type 1 diabetes mellitus

“…12 It is proposed that this prevents toxicity from free heavy chain accumulation. 13 The serum cFLC reference range in healthy donors is approximately 3-19 mg/L for FLCκ and 6-26 mg/L FLCλ. 14 Serum polyclonal cFLC may be elevated above normal by two principal mechanisms: renal impairment and immune stimulation.…”