Diversity and Diversification of Light Chains in Myeloma:The Specter of Amyloidogenesis by Proxy

Gu, M.; Wilton, Rosemarie; Stevens, Fred J.

doi:10.1159/000096766

Cited by 6 publications

(3 citation statements)

References 133 publications

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“…This set is composed of LCs from other PCDs, not only from MM ( n = 152) but also from LCDD ( n = 7) and WM ( n = 4). Although LCDD sequences by definition do not form fibrils [25], it is possible that some of the MM sequences could be amyloidogenic, as up to 10–20% of MM cases can develop fibrillar LC deposits [26–28]; thus, it is possible that some of the sequences classified as MM could actually be amyloidogenic. The final category, non-PCD, is a heterogeneous group that includes cDNA derived sequences from polyclonal healthy bone marrow, disease-related LCs and sequences of solved LC structures from the Protein Data Bank (www.rcsb.org/pdb).…”

Section: Discussionmentioning

confidence: 99%

AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences

Bodi

Prokaeva

Spencer

et al. 2009

Amyloid

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AL-Base, a curated database of human immunoglobulin (Ig) light chain (LC) sequences derived from patients with AL amyloidosis and controls, is described, along with a collection of analytical and graphic tools designed to facilitate their analysis. AL-Base is designed to compile and analyse amyloidogenic Ig LC sequences and to compare their predicted protein sequence and structure to non-amyloidogenic LC sequences. Currently, the database contains over 3000 de-identified LC nucleotide and amino acid sequences, of which 433 encode monoclonal proteins that were reported to form fibrillar deposits in AL patients. Each sequence is categorised according to germline gene usage, clinical status and sample source. Currently, tools are available to search for sequences by various criteria, to analyse the biochemical properties of the predicted amino acids at each position and to display the results in a graphical fashion. The likelihood that each sequence has evolved through somatic hypermutation can be predicted using an automated binomial or multinomial distribution model. AL-Base is available to the scientific community for research purposes.

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Section: Discussionmentioning

confidence: 99%

AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences

Bodi

Prokaeva

Spencer

et al. 2009

Amyloid

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“…Ig deposits are frequently associated with B cell malignancy (16). Autoantigens may be involved in the stimulation of B cell proliferative diseases, as suggested by the restricted use of particular V genes (17) and the accumulation of somatic mutations (18). Autoantigens may also participate in the formation of Ig deposits, such as in mixed cryoglobulinemia where precipitates reflect Ab-Ag interactions (19).…”

mentioning

confidence: 99%

Intra-Golgi Formation of IgM–Glycosaminoglycan Complexes Promotes Ig Deposition

Khan

Cox

Nishimoto

et al. 2011

The Journal of Immunology

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Immune complexes arise from interactions between secreted Ab and Ags in the surrounding milieu. However, it is not known whether intracellular Ag–Ab interactions also contribute to the formation of extracellular immune complexes. In this study, we report that certain murine B cell hybridomas accumulate intracellular IgM and release large, spherical IgM complexes. The complexes (termed “spherons”) reach 2 μm in diameter, detach from the cell surface, and settle out of solution. The spherons contain IgM multimers that incorporate the J chain and resist degradation by endoglycosidase H, arguing for IgM passage through the Golgi. Treatment of cells with inhibitors of proteoglycan synthesis, or incubation of spherons with chondroitinase ABC, degrades spherons, indicating that spheron formation and growth depend on interactions between IgM and glycosaminoglycans. This inference is supported by direct binding of IgM to heparin and hyaluronic acid. We conclude that, as a consequence of IgM binding to glycosaminoglycans, multivalent IgM–glycan complexes form in transit of IgM to the cell surface. Intra-Golgi formation of immune complexes could represent a new pathogenic mechanism for immune complex deposition disorders.

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“…To this end, we combined biochemical, spectroscopic, and bioinformatics methods with hydrogen-deuterium exchange (HDX) mass spectrometry (MS) to explore 14 patient-derived and engineered LCs and their domain fragments from two closely related κ1 sub-families. Patient-derived proteins were associated with either AL amyloidosis or multiple myeloma (MM), another monoclonal Ig disease wherein most patients do not develop AL [26]. In our study, MM LC was used as a naturally occurring non-AL control.…”

Section: Introductionmentioning

confidence: 99%

Role of Complementarity-Determining Regions 1 and 3 in Pathologic Amyloid Formation by Human Immunoglobulin κ1 Light Chains

Klimtchuk

Peterle

Bullitt

et al. 2023

Preprint

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Immunoglobulin light chain (LC) amyloidosis is a life-threatening disease whose understanding and treatment is complicated by vast numbers of patient-specific mutations. To address molecular origins of the disease, we explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01. Hydrogen-deuterium exchange mass spectrometry analysis of local conformational dynamics in full-length recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation, and amyloidogenic sequence propensities using spectroscopic, electron microscopic and bioinformatics tools. The results were mapped on the atomic structures of native and fibrillary proteins. Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower. These and other differences suggest different major factors influencing amyloid formation. In 33*01-related amyloid LC, these factors involved mutation-induced destabilization of the native structure and probable stabilization of amyloid. The atypical behaviour of 39*01-related amyloid LC tracked back to increased dynamics/exposure of amyloidogenic segments in βC′V and βEV that could initiate aggregation, combined with decreased dynamics/exposure near the Cys23-Cys88 disulfide whose rearrangement is rate-limiting to amyloidogenesis. The results suggest distinct amyloidogenic pathways for closely related LCs and point to the antigen-binding, complementarity-determining regions CDR1 and CDR3, which are linked via the conserved internal disulfide, as key factors in amyloid formation by various LCs.

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Diversity and Diversification of Light Chains in Myeloma:The Specter of Amyloidogenesis by Proxy

Cited by 6 publications

References 133 publications

AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences

AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences

Intra-Golgi Formation of IgM–Glycosaminoglycan Complexes Promotes Ig Deposition

Role of Complementarity-Determining Regions 1 and 3 in Pathologic Amyloid Formation by Human Immunoglobulin κ1 Light Chains

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