Light chain-deficient mice produce novel multimeric heavy-chain-only IgA by faulty class switching
The Babraham Institute, Babraham, Cambridge, UK. International Immunology
(Impact Factor: 2.54).
07/2009; 21(8):957-66. DOI: 10.1093/intimm/dxp062
Recently, we identified that diverse heavy chain (H-chain)-only IgG is spontaneously produced in light chain (L-chain)-deficient mice (L(-/-) with silenced kappa and lambda loci) despite a block in B cell development. In murine H-chain IgG, the first Cgamma exon, C(H)1, is removed after DNA rearrangement and secreted polypeptides are comparable with camelid-type H-chain IgG. Here we show that L(-/-) mice generate a novel class of H-chain Ig with covalently linked alpha chains, not identified in any other healthy mammal. Surprisingly, diverse H-chain-only IgA can be released from B cells at levels similar to conventional IgA and is found in serum and sometimes in milk and saliva. Surface IgA without L-chain is expressed in B220(+) spleen cells, which exhibited a novel B cell receptor, suggesting that associated conventional differentiation events occur. To facilitate the cellular transport and release of H-chain-only IgA, chaperoning via BiP association seems to be prevented as only alpha chains lacking C(H)1 are released from the cell. This appears to be accomplished by imprecise class-switch recombination (CSR) from Smu into the alpha constant region, which removes all or part of the Calpha1 exon at the genomic level.
Available from: Haruki Hasegawa
- "The first constant domain of the HC subunit (CH1) plays important roles in regulating Ig biosynthesis including the retention of free HCs by the BiP-mediated ER quality control mechanisms and the covalent assembly with the LC subunits. Despite such critical importance, the CH1 domain deletion can occur naturally via errors in gene recombination  . The deletion of CH1 domain is believed to circumvent the toxicity of full-length HC protein expression in the absence of LC synthesis in homologous systems . "
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ABSTRACT: Recombinant immunoglobulins comprise an important class of human therapeutics. Although specific immunoglobulins can be purposefully raised against desired antigen targets by various methods, identifying an immunoglobulin clone that simultaneously possesses potent therapeutic activities and desirable manufacturing-related attributes often turns out to be challenging. The variable domains of individual immunoglobulins primarily define the unique antigen specificities and binding affinities inherent to each clone. The primary sequence of the variable domains also specifies the unique physicochemical properties that modulate various aspects of individual immunoglobulin life cycle, starting from the biosynthetic steps in the endoplasmic reticulum, secretory pathway trafficking, secretion, and the fate in the extracellular space and in the endosome-lysosome system. Because of the diverse repertoire of immunoglobulin physicochemical properties, some immunoglobulin clones' intrinsic properties may manifest as intriguing cellular phenotypes, unusual solution behaviors, and serious pathologic outcomes that are of scientific and clinical importance. To gain renewed insights into identifying manufacturable therapeutic antibodies, this paper catalogs important intracellular and extracellular phenotypes induced by various subsets of immunoglobulin clones occupying different niches of diverse physicochemical repertoire space. Both intrinsic and extrinsic factors that make certain immunoglobulin clones desirable or undesirable for large-scale manufacturing and therapeutic use are summarized.
Available from: bloodjournal.org
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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.
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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.
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