Antibodies gone bad – the molecular mechanism of light chain amyloidosis

Absmeier, Ramona M.; Rottenaicher, Georg J; Svilenov, Hristo; Kazman, Pamina; Büchner, Johannes

doi:10.1111/febs.16390

Cited by 18 publications

(39 citation statements)

References 231 publications

(296 reference statements)

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“…Survival of patients with systemic amyloidosis is extremely heterogeneous depending on the organs involved and the presence and extent of cardiac damage. Patients with localized amyloidosis have a considerably better prognosis than do those with systemic disease [5]. Hence, the early diagnosis of the amyloid process would provide the highest degree of therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

Primary Systemic Amyloidosis of Tongue: Pitfall and Challenges in the Diagnosis

Agarwal

Ermilov²,

Dorofeev³

et al. 2022

IJMPCR

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Amyloidosis is caused by the deposition of insoluble fibrillary protein in tissues and organs resulting in severe organ dysfunction. The clinical presentation for the diagnosis of amyloidosis is nonspecific, making it one of the most underdiagnosed conditions. Treatment is now available and is effective in improving patients’ survival and quality of life. We present a case of generalized amyloidosis in a 71-year-old patient admitted with a diagnosis of benign neoplasm of the root of the tongue. Subsequently, she underwent surgical treatment followed by purulent-septic complications developed leading to death. Microscopic examination of the biopsy tissue revealed deposits of amyloid and the patient was diagnosed to have primary generalized amyloidosis. These facts confirm the essential need to differentiate tumors from amyloidosis. Hence, this paper aims to provide physicians with knowledge about the clinical presentation that raises the suspicion of amyloidosis, bearing in mind the importance of early diagnosis.

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Section: Introductionmentioning

confidence: 99%

Primary Systemic Amyloidosis of Tongue: Pitfall and Challenges in the Diagnosis

Agarwal

Ermilov²,

Dorofeev³

et al. 2022

IJMPCR

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“…[2,[4][5][6][7][8][9][10] It is often observed that such fluid-like droplet phases undergo liquid-to-solid gel-like phase transitions over time, which upon maturation (or expedited by disease-associated mutations) lead to fibril formation and the development of pathological diseases, such as Parkinson's, Alzheimer's, cataract, and antibody light-chain (AL) amyloidosis. [11,12] In AL amyloidosis, fibrils are deposited in various organs, most often in the heart and kidney, and impair their function. [12] LLPS is generally driven by weak multivalent interactions, such as electrostatic, hydrophobic, π-π and cation-π interactions, [13,14] and strongly affected by external conditions including temperature, pH, ionic strength, and the types and concentrations of excipients.…”

Section: Introductionmentioning

confidence: 99%

“…[11,12] In AL amyloidosis, fibrils are deposited in various organs, most often in the heart and kidney, and impair their function. [12] LLPS is generally driven by weak multivalent interactions, such as electrostatic, hydrophobic, π-π and cation-π interactions, [13,14] and strongly affected by external conditions including temperature, pH, ionic strength, and the types and concentrations of excipients. Recently, we and others observed that protein systems undergoing LLPS can be very sensitive to pressure, [15][16][17][18][19][20][21][22] thus suggesting that pressure modulation may be used to suppress LLPS formation and subsequent irreversible aggregation and fibrilization.…”

Section: Introductionmentioning

confidence: 99%

“…At high concentrations, immunoglobulins undergo liquid‐liquid phase separation (LLPS) at low temperatures, that is, they phase separate into protein‐poor and protein‐rich liquid phases, in particular when formulated at low ionic strength and buffered at neutral pH near their isoelectric point [2,4–10] . It is often observed that such fluid‐like droplet phases undergo liquid‐to‐solid gel‐like phase transitions over time, which upon maturation (or expedited by disease‐associated mutations) lead to fibril formation and the development of pathological diseases, such as Parkinson's, Alzheimer's, cataract, and antibody light‐chain (AL) amyloidosis [11,12] . In AL amyloidosis, fibrils are deposited in various organs, most often in the heart and kidney, and impair their function [12] .…”

Section: Introductionmentioning

confidence: 99%

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Suppression of Liquid‐Liquid Phase Separation and Aggregation of Antibodies by Modest Pressure Application

Fetahaj

Jaworek

Oliva

et al. 2022

Chemistry A European J

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The high colloidal stability of antibody (immunoglobulin) solutions is important for pharmaceutical applications. Inert cosolutes, excipients, are generally used in therapeutic protein formulations to minimize physical instabilities, such as liquid–liquid phase separation (LLPS), aggregation and precipitation, which are often encountered during manufacturing and storage. Despite their widespread use, a detailed understanding of how excipients modulate the specific protein‐protein interactions responsible for these instabilities is still lacking. In this work, we demonstrate the high sensitivity to pressure of globulin condensates as a suitable means to suppress LLPS and subsequent aggregation of concentrated antibody solutions. The addition of excipients has only a minor effect. The high pressure sensitivity observed is due to the fact that these flexible Y‐shaped molecules create a considerable amount of void volume in the condensed phase, leading to an overall decrease in the volume of the system upon dissociation of the droplet phase by pressure already at a few tens of to hundred bar. Moreover, we show that immunoglobulin molecules themselves are highly resistant to unfolding under pressure, and can even sustain pressures up to about 6 kbar without conformational changes. This implies that immunoglobulins are resistant to the pressure treatment of foods, such as milk, in high‐pressure food‐processing technologies, thereby preserving their immunological activity.

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“…Of these patient variants, only a limited number has been analyzed on the protein level. These analyses have revealed the presence of "active", fibrilpromoting mutations, and "silent" ones which do not induce the fibril pathway 8 . One of the well-characterized AL variants is FOR005, which was derived from a patient with cardiac involvement.…”

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confidence: 99%

A constant domain mutation in a patient-derived antibody light chain reveals principles of AL amyloidosis

et al. 2023

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Light chain (AL) amyloidosis is a debilitating disease in which mutant antibody light chains (LC), secreted by aberrant plasma cell clones, misfold and form insoluble fibrils, which can be deposited in various organs. In the majority of cases, the fibrillar deposits consist of LC variable domains (VL) containing destabilizing mutations compared to their germline counterparts. This is also true for the patient LC FOR005. However, this pathogenic LC sequence contains an additional mutation in the constant domain (CL). The mechanistic impact of CL mutations is not yet understood in the context of AL amyloidosis. Our analysis reveals that the FOR005 CL mutation influences the amyloid pathway in specific ways: (1) folding and stability of the patient CL domain are strongly impaired; (2) the mutation disrupts the LC dimer interface and weakens dimerization; (3) the CL mutation promotes proteolytic cleavage of the LC monomers resulting in an isolated, amyloidogenic VL domain while dimeric LCs are not cleaved. The enhanced proteolysis rates and the inability of full-length LCs to form amyloid fibrils even in the presence of a destabilized CL domain support a model for AL amyloidosis in which the CL domain plays a protective role and in which proteolytic cleavage precedes amyloid formation.

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Antibodies gone bad – the molecular mechanism of light chain amyloidosis

Cited by 18 publications

References 231 publications

Primary Systemic Amyloidosis of Tongue: Pitfall and Challenges in the Diagnosis

Primary Systemic Amyloidosis of Tongue: Pitfall and Challenges in the Diagnosis

Suppression of Liquid‐Liquid Phase Separation and Aggregation of Antibodies by Modest Pressure Application

A constant domain mutation in a patient-derived antibody light chain reveals principles of AL amyloidosis

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