Primary amyloidosis pathophysiology: Difference between revisions
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* Both cytotoxicity and apoptosis have been implicated as mechanisms leading to tissue injury in primary amyloidosis.<ref name="RiekEisenberg2016">{{cite journal|last1=Riek|first1=Roland|last2=Eisenberg|first2=David S.|title=The activities of amyloids from a structural perspective|journal=Nature|volume=539|issue=7628|year=2016|pages=227–235|issn=0028-0836|doi=10.1038/nature20416}}</ref> | * Both cytotoxicity and apoptosis have been implicated as mechanisms leading to tissue injury in primary amyloidosis.<ref name="RiekEisenberg2016">{{cite journal|last1=Riek|first1=Roland|last2=Eisenberg|first2=David S.|title=The activities of amyloids from a structural perspective|journal=Nature|volume=539|issue=7628|year=2016|pages=227–235|issn=0028-0836|doi=10.1038/nature20416}}</ref> | ||
* Specificity for a particular organ in primary amyloidosis depends upon the light chain variable region gene and gene family of the clone. Germ line gene LV6-57 is more common in AL systemic amyloidosis and is associated with renal involvement, while LV1-44 preferentially leads to fibril deposition in the heart and KV1-33 is associated with hepatic involvement.<ref name="pmid22067386">{{cite journal |vauthors=Perfetti V, Palladini G, Casarini S, Navazza V, Rognoni P, Obici L, Invernizzi R, Perlini S, Klersy C, Merlini G |title=The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44 |journal=Blood |volume=119 |issue=1 |pages=144–50 |date=January 2012 |pmid=22067386 |doi=10.1182/blood-2011-05-355784 |url=}}</ref> | * Specificity for a particular organ in primary amyloidosis depends upon the light chain variable region gene and gene family of the clone. Germ line gene LV6-57 is more common in AL systemic amyloidosis and is associated with renal involvement, while LV1-44 preferentially leads to fibril deposition in the heart and KV1-33 is associated with hepatic involvement.<ref name="pmid22067386">{{cite journal |vauthors=Perfetti V, Palladini G, Casarini S, Navazza V, Rognoni P, Obici L, Invernizzi R, Perlini S, Klersy C, Merlini G |title=The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44 |journal=Blood |volume=119 |issue=1 |pages=144–50 |date=January 2012 |pmid=22067386 |doi=10.1182/blood-2011-05-355784 |url=}}</ref> | ||
==References== | |||
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Revision as of 00:08, 30 October 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Sabawoon Mirwais, M.B.B.S, M.D.[3]
Overview
Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), blood vessel walls, and in the different connective tissues. Primary (AL) amyloidosis) is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that usually produced by plasma cell clones.
Pathophysiology
Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), blood vessel walls, and in the different connective tissues.
Pathogenesis
Amyloids
- Amyloids consist of aggregated proteins that accumulate extracellularly as insoluble fibrils of misfolded proteins. Pathogenic amyloids are the consequence of previously normal proteins that lose their physiological properties and assume a beta-pleated quaternary configuration with a characteristic appearance on electron microscopy. The axis of the fiber (5-15nm in width) in these deposits is perpendicular to antiparallel chains of beta peptides.
- These misfolded proteins are seen in various diseases such as Alzheimer's disease (beta-amyloid), diabetes mellitus type 2 (amylin), Parkinson's disease (alpha-synuclein), fatal familial insomnia (PrPsc), Huntington's disease (Huntingtin), medullary carcinoma of the thyroid (calcitonin), atherosclerosis (apolipiprotein A-I), rheumatoid arthritis (serm amyloid A), Lattice corneal dystrophy (keratoepithelin) and trasnmissible spongiform encephalopathy (PrP).
- Amyloid fibrils are composed of smaller amyloid oligomers, which are toxic. Amyloid fibrils, once formed, catalyze the formation of these toxic oligomers.
Light chain amyloid or AL amyloid
- Primary amyloidosis is characterized by multi-organ deposition of immunoglobulin light chains of lambda variety. These light chains are normal components of antibodies produced by plasma cells (fully differentiated B cells). The plasma cells are involved in antibody production under physiological conditions via reorganization of immunoglobulin heavy and light chains.
- Since primary amyloidosis occurs in patients suffering from plasma cell dyscrasias, the inciting event for primary or AL amyloidosis is formation of an unstable misfolded secondary or tertiary structure of a monoclonal plasma cell-derived immunoglobulin light chain.
Role of plasma cells in primary (AL) amyloidosis
- In primary amyloidosis, the marrow plasma cell burden is < 10% therefore, primary amyloidosis is not considered a neoplasm. Due to monoclonal proliferation of these mature B cells, only one type of a unique protein sequence is synthesized.
- The mutational pattern of primary amyloidosis is intermediate between those of monoclonal gammopathy of undetermined significance and multiple myeloma.
- Studies have shown that in immunoglobulins produced by monoclonal plasma cell proliferation, there is alteration in the dimer interface formed between the variable domain of the light chains and the variable domain of the heavy chains. Mutations that disrupt immunoglobulin folds (structural domain) of beta strands lead to abnormal folding (N- and C-terminals oriented in opposite directions) and decreased thermodynamic stability.
- Therefore, destabilizing somatic mutations are present in both the complementarity-determining regions and structural regions of light chains and are thought to increase the propensity to develop insoluble aggregates.
- Because of somatic hypermutations, the amino acid sequence of the pathogenic AL protein differs in each patient
Interaction of amyloid fibrils with microenvironment
- Accumulation of insoluble amyloid fibrils in tissues leads to activation proteosomes that lead to their endoproteolysis and release of amyloidogenic light chain fragments.
- Interaction of these deposits with extracellular chaperones, matrix components including glycosaminoglycans (GAGs) and collagen, shear forces, endoproteases, and metals modulate aggregation and oligomer formation.
Tissue damage
- The deposition of amyloid aggregates leads to architectural disruptions in tissues.
- Amyloid fibrils may also produce organ dysfunction via interation with ligands and disruption of cell membranes.
- Both cytotoxicity and apoptosis have been implicated as mechanisms leading to tissue injury in primary amyloidosis.[1]
- Specificity for a particular organ in primary amyloidosis depends upon the light chain variable region gene and gene family of the clone. Germ line gene LV6-57 is more common in AL systemic amyloidosis and is associated with renal involvement, while LV1-44 preferentially leads to fibril deposition in the heart and KV1-33 is associated with hepatic involvement.[2]
References
- ↑ Riek, Roland; Eisenberg, David S. (2016). "The activities of amyloids from a structural perspective". Nature. 539 (7628): 227–235. doi:10.1038/nature20416. ISSN 0028-0836.
- ↑ Perfetti V, Palladini G, Casarini S, Navazza V, Rognoni P, Obici L, Invernizzi R, Perlini S, Klersy C, Merlini G (January 2012). "The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44". Blood. 119 (1): 144–50. doi:10.1182/blood-2011-05-355784. PMID 22067386.