Page 99 - Textbook of Pathology, 6th Edition

and part of C region. AL fibril protein is more frequently 5. Amyloid from hormone precursor proteins. It includes 83
derived from the lambda (λ) light chain than kappa (κ), the examples such as amyloid derived from pro-calcitonin
former being twice more common. However, in any given (ACal), islet amyloid polypeptide (AIAPP, Amylin), pro-
case, there is amino acid sequence homology. insulin (AIns), prolactin (APro), atrial natriuretic factor
AL type of fibril protein is produced by immunoglobulin- (AANF), and lactoferrin (ALac).
secreting cells and is therefore seen in association with plasma 6. Amyloid of prion protein (APrP). It is derived from CHAPTER 4
cell dyscrasias and is included in primary systemic precursor prion protein which is a plasma membrane
amyloidosis. glycoprotein. Prion proteins are proteinaceous infectious
AA PROTEIN. AA fibril protein is composed of protein with particles lacking in RNA or DNA. Amyloid in prionosis
molecular weight of 8.5-kD which is derived from larger occurs due to abnormally folded isoform of the PrP.
precursor protein in the serum called SAA (serum amyloid- 7. Miscellaneous heredofamilial forms of amyloid. This
associated protein) with a molecular weight of 12.5-kD. group includes a variety of amyloid proteins reported
Unlike AL amyloid, the deposits of AA amyloid do not have recently. These are amyloid derived from: apolipoprotein I
sequence homology. In the plasma, SAA circulates in (AApoAI), gelsolin (AGel), lysozyme (ALys), fibrinogen α-
association with HDL (high-density lipoprotein). SAA is an chain (AFib), lysozyme (ALys), cystatin C (ACys) and
3
acute phase reactant protein synthesised in the liver, its level amyloid of familial dementia etc.
being high in chronic inflammatory and traumatic conditions.
SAA fibril protein is found in secondary amyloidosis II. Non-fibrillar Components
which includes the largest group of diseases associated with Non-fibrillar components comprise about 5% of the amyloid
amyloidosis.
material. These include the following: Immunopathology Including Amyloidosis
OTHER PROTEINS. Apart from the two major forms of 1. Amyloid P (AP)-component. It is synthesised in the liver
amyloid fibril proteins, a few other forms of proteins are and is present in all types of amyloid. It is derived from
found in different clinical states:
circulating serum amyloid P-component, a glycoprotein
1. Transthyretin (TTR). It is a serum protein synthesised resembling the normal serum α -glycoprotein and is PAS-
1
in the liver and transports thyroxine and retinol normally positive. It is structurally related to C-reactive protein, an
(trans-thy-retin). It was earlier called AFp (amyloid familial acute phase reactant, but is not similar to it. By electron
prealbumin) since it precedes albumin (pre-albumin) on microscopy, it has a pentagonal profile (P-component) or
serum electrophoresis but is not related to serum albumin. doughnut-shape with an external diameter of 9 nm and
Single amino acid substitution mutations in the structure of internal diameter of 4 nm.
TTR results in variant form of protein which is responsible 2. Apolipoprotein-E (apoE). It is a regulator of lipoprotein
for this form of amyloidosis termed as ATTR. About 60 such metabolism and is found in all types of amyloid. One allele,
mutations have been described. apoE4, increases the risk of Alzheimer precursor protein
ATTR is the most common form of heredofamilial (APP) deposition in Alzheimer’s disease but not in all other
amyloidosis e.g. in familial amyloid polyneuropathies. types of amyloid deposits.
However, the deposits of ATTR in the elderly primarily
involving the heart (senile cardiac amyloidosis) consists of 3. Sulfated glycosaminoglycans(GAGs). These are
normal TTR without any mutation. Another interesting constituents of matrix proteins; particularly associated is
aspect in ATTR is that despite being inherited, the disease heparan sulfate in all types of tissue amyloid.
appears in middle age or elderly. 4. αα αα α-1 anti-chymotrypsin. It is seen in cases of AA deposits
2. Aββ ββ β -microglobulin (Aββ ββ β M). This form of amyloid is seen only but not seen in primary amyloidosis.
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in cases of long-term haemodialysis (for 8-10 years). As the 5. Protein X. This protein has been shown to be present in
name suggests, β M is a small protein which is a normal cases of prionoses.
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component of major histocompatibility complex (MHC) and 6. Other components. Besides above, components of
has β -pleated sheet structure. β M is not effectively filtered complement, proteases, and membrane constituents may be
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during haemodialysis and thus there is high serum seen.
concentration of β M protein in these patients. Although
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the deposit due to Aβ M may be systemic in distribution, it PATHOGENESIS OF AMYLOIDOSIS
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has predilection for bones and joints.
The earliest observation that amyloidosis developed in
3. ββ ββ β-amyloid protein (Aββ ββ β). Aβ is distinct from Aβ M and is experimental animals who were injected repeatedly with
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seen in cerebral plaques as well as cerebral blood vessels in antigen to raise antisera for human use led to the concept
Alzheimer’s disease. Aβ is derived from amyloid beta that amyloidogenesis was the result of immunologic
precursor protein (AβPP) which is a transmembrane mechanisms. AL variety of amyloid protein was thus first to
glycoprotein. The normal function of βPP is probably cell- be isolated. It is now appreciated that amyloidosis or
to-matrix signalling. fibrillogenesis is multifactorial and that different mechanisms
4. Immunoglobulin heavy chain amyloid (AH). AH is are involved in different types of amyloid.
derived from truncated heavy chain of immunoglobulin and Irrespective of the type of amyloid, amyloidogenesis in
is an uncommon form of systemic amyloidosis. general in vivo, occurs in the following sequence (Fig. 4.10):