Amyloidosis Flashcards
What is amyloidosis?
a condition in which extracellular deposits of fibrillar proteins are responsible for tissue damage and functional compromise.
What is amyloid made by?
These abnormal fibrils are produced by the aggregation of misfolded proteins (which are soluble in their normal folded configuration) or protein fragments.
T or F. Amyloidosis is fundamentally a disorder of protein misfolding
T.
What is the composition of amyloid?
Regardless of their derivation, all amyloid deposits are composed of nonbranching fibrils, 7.5 to 10 nm in diameter, each formed of β-sheet polypeptide chains that are wound together
How is amyloid identified?
The dye Congo red binds to these fibrils and produces a red–green dichroism (birefringence), which is commonly used to identify amyloid deposits in tissues.
Normally, misfolded proteins are degraded intracellularly in proteasomes, or extracellularly by macrophages. Why not with amyloid?
In amyloidosis, these quality control mechanisms fail, allowing the misfolded protein to accumulate outside cells.
Misfolded proteins often are unstable and self-associate, ultimately leading to the formation of oligomers and fibrils that are deposited in tissues.
What are the three most common forms of amyloid?
1) AL (amyloid light chain) protein
2) AA (amyloid-associated) fibril
3) AB amyloid
What is AL amyloid produced by? Composition?
produced by plasma cells and is made up of complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both. For unknown reasons, only a few types of immunoglobulin light chains are prone to forming aggregates.
The deposition of amyloid fibril protein of the AL type is associated with ______.
some form of monoclonal B cell proliferation.
Defective degradation has also been invoked as the basis for fibril formation, and perhaps particular light chains are resistant to complete proteolysis. However, there are no sequence motifs peculiar to the immunoglobulin light chains found in amyloid deposits.
What is AA amyloid?
immunoglobulin protein derived from a serum precursor called SAA (serum amyloid-associated) protein that is synthesized in the liver.
What leads to SAA production in the liver?
cytokines such as IL-6 and IL-1 that are produced during inflammation
thus, long-standing inflammation leads to elevated SAA levels, and ultimately the AA form of amyloid deposits.
Does increased SAA always lead to AA deposit? Why?
Elevation of serum SAA levels is common to inflammatory states but in most instances does not lead to amyloidosis.
There are two possible explanations for this. According to one view, SAA normally is degraded to soluble end products by the action of monocyte-derived enzymes. Conceivably, people who develop amyloidosis have an enzyme defect that results in incomplete breakdown of SAA, thus generating insoluble AA molecules.
Alternatively, a genetically determined structural abnormality in the SAA molecule itself renders it resistant to degradation by macrophages.
What is AB amyloid common in?
found in the cerebral lesions of Alzheimer disease.
Aβ is a 4-kDa peptide that constitutes the core of cerebral plaques and the amyloid deposits in cerebral blood vessels in this disease.
What is AB amyloid derived from?
The Aβ protein is derived from a much larger transmembrane glycoprotein called amyloid precursor protein (APP)
What is Transthyretin (TTR)?
a normal serum protein that
binds and transports thyroxine and retinol (vitamin A), hence the name.
What do mutations in TTR lead to?
Mutations in the gene encoding TTR may alter its structure, making the protein prone to misfolding and aggregation, and resistant to proteolysis. This leads to the formation of aggregates that deposit as amyloid.
The resultant diseases are called familial amyloid polyneuropathies.
Where is TRR also deposited?
TTR is also deposited in the heart of aged persons (senile systemic amyloidosis); in such cases the protein is structurally normal, but it accumulates at high concentrations. Some cases of familial amyloidosis are associated with deposits of mutant lysozyme.
How is B2-microglobulin related to amyloidosis?
a component of MHC class I molecules and a normal serum protein, has been identified as the amyloid fibril subunit (Aβ2m) in amyloidosis that complicates the course of patients on long-term hemodialysis.
What are AB2m fibers? When are they common?
Aβ2m fibers are structurally similar to normal β2m protein.
Present in high concentrations in the serum of patients with renal disease and is retained in the circulation because it is not efficiently filtered through dialysis membranes. In some series, as many as 60% to 80% of patients on long-term dialysis developed amyloid deposits in the synovium, joints, and tendon sheaths.
• Amyloid deposits derived from diverse precursors such as hormones (procalcitonin) and keratin also have been reported.
T or F. Amyloid may be systemic (generalized), involving several organ systems, or it may be localized, when deposits are limited to a single organ, such as the heart.
T.
What are the main classes of amyloidosis clinically?
On clinical grounds, the systemic, or generalized, pattern is subclassified into primary amyloidosis when associated with a monoclonal plasma cell proliferation and secondary amyloidosis when it occurs as a complication of an underlying chronic inflammatory or tissue destructive process.
Hereditary or familial amyloidosis constitutes a separate, albeit heterogeneous group, with several distinctive patterns of organ involvement.
T or F. Primary amyloidosis is typically localized and is of the AL type.
Primary amyloidosis is typically systemic and is of the AL type.
This is the most common form of amyloidosis
common with multiple myeloma
Almost all patients with myeloma who develop amyloidosis have ____ proteins in the serum or urine, or both.
Bence Jones proteins - λ or κ light chain synthesized by plasma cells
However, amyloidosis develops in only 6% to 15% of patients with myeloma who have free light chains. Clearly, the presence of Bence Jones proteins, although necessary, is by itself not sufficient to produce amyloidosis.
The great majority of patients with AL amyloid do not have classic multiple myeloma or any other overt B cell neoplasm. Then why are they classified as primary amyloidosis?
because their clinical features derive from the effects of amyloid deposition without any other associated disease.
In virtually all such cases, patients have a modest increase in the number of plasma cells in the bone marrow, and monoclonal immunoglobulins or free light chains can be found in the serum or urine. Clearly, these patients have an underlying monoclonal plasma cell proliferation in which production of an abnormal protein, rather than production of tumor masses, is the predomi- nant manifestation.
What is Reactive Systemic Amyloidosis? Common amyloid type?
The amyloid deposits in this pattern are systemic in distribution and are composed of AA protein.
Reactive Systemic Amyloidosis was previously referred to as secondary amyloidosis. Why?
Because it is secondary to an associated inflammatory condition. In fact, the feature common to most cases of reactive systemic amyloidosis is chronic inflammation.
