REvIEW

review
Adv Clin Exp Med 2011, 20, 5, 647–652
ISSN 1230-025X
© Copyright by Wroclaw Medical University
Lidia Usnarska-Zubkiewicz1, Jadwiga Hołojda2, Kazimierz Kuliczkowski1
AL Amyloidosis (Amyloidosis Antibody Light).
Part 1. Definition, Classification, Amyloid Structure,
Development and Etiopathogenesis of AL Amyloidosis
Amyloidoza AL (amyloidosis antibody light). Część I. Definicja,
podział, budowa i rozwój amyloidu, etiopatogeneza amyloidozy AL
Departament of Hematology, Blood Neoplasms and Bone Marrow Transplantation,
Wroclaw Medical University, Poland
2
Hematology Department of District Specialist Hospital of Legnica, Poland
1
Abstract
Amyloidosis is an inherited or acquired systemic storage disease in which a pathologic, amorphous substance produced as a result of abnormal protein metabolism and resistant to proteolysis is deposited in the extracellular space
of various tissues (intracellular deposits occur rarely). This leads to the destruction of normal tissue architecture
and disturbs its function. The development of amyloidosis is associated with the transformation of the α-spiral conformation of fibrous protein into a stratified, parallel, folded spatial β-conformation. The transition of the fibrous
proteins conformation and their tissue localization causes resistance of the fibers to proteolytic processes as a result
of a limited access of the protein converting enzymes. In this paper we show the actual classification of amyloidosis
and up-to-date knowledge about the amyloid structure, development and etiopathogenesis of AL amyloidosis (Adv
Clin Exp Med 2011, 20, 5, 647–652).
Key words: amyloidosis AL, classification, amyloid structure, etiopathogenesis.
Streszczenie
Amyloidoza (skrobiawica) jest wrodzoną lub nabytą układową chorobą spichrzeniową, w przebiegu której dochodzi
do gromadzenia się w przestrzeni pozakomórkowej różnych tkanek (rzadko wewnątrzkomórkowo), patologicznej,
amorficznej substancji, która powstaje na skutek nieprawidłowego metabolizmu białek i jest oporna na proteolizę.
Prowadzi to do zniszczenia normalnej architektoniki tkanek i zakłócenia ich funkcji. Rozwój amyloidozy jest
związany z przekształceniem α-spiralnej konformacji włókien białkowych w warstwową, równoległą, pofałdowaną,
przestrzenną β-konformację. Zmiana konformacji włókien białkowych i ich tkankowe umiejscowienie powoduje
oporność włókien na procesy proteolityczne w wyniku ograniczonego dostępu enzymów rozkładających białka.
W pracy przedstawiono aktualny podział amyloidozy oraz obecny stan wiedzy na temat rozwoju, budowy i etiopatogenezy amyloidozy z łańcuchów lekkich (Adv Clin Exp Med 2011, 20, 5, 647–652).
Słowa kluczowe: amyloidoza AL, klasyfikacja, struktura amyloidu, etiopatogeneza.
Amyloidosis is an inherited or acquired systemic storage disease in which a pathologic, amorphous substance produced as a result of abnormal
protein metabolism and resistant to proteolysis is
deposited in the extracellular space of various tissues (intracellular deposits occur rarely), which
leads to the destruction of normal tissue architecture and disturbs its function. The disease may
affect one organ or several organs simultaneously
and is always fatal [1–3].
So far, 27 proteins which may initiate the process of formation of abnormal forms of amyloidosis have been identified. The proteins are heterogeneous and unrelated, they are characterized by the
ability to assume more than one conformation and
forming amyloid deposits of a typical, common
648
structure. The kind of protein deposit determines
the type of amyloidosis [3, 4].
Classification of
Amyloidosis
The names of the individual types of amyloidosis start with the letter A (symbolic term for amyloid
fibrils), followed by an abbreviation of the protein
forming the deposits [5]. The first classification of
amyloidosis, which distinguished primary and secondary amyloidosis, was presented in 1971.
In AL amyloidosis (amyloidosis antibody
light), the amyloid deposits consist of monoclonal immunoglobulin light chains, most commonly
of the λ class, VI subclass, which are a product of
a neoplastic plasma cell clone. Depending on the
number of plasma cells in the bone marrow, the
level of monoclonal protein in the serum and/or
urine and the presence of osteolytic changes, we
can diagnose AL, or AL in the course of multiple
myeloma and other monoclonal gammapathies.
Kyle et al. demonstrated that 85% of patients diagnosed with AL amyloidosis meet the criteria of
various forms of plasma cell dyscrasia, while the
remaining 15% lack clinical symptoms of plasma
cell clonal growth [3]. According to Abraham et
al., all patients with AL amyloidosis reveal monoclonal gammapathy on the basis of a serum free
light chain evaluation [6]. AL amyloidosis affects
organs originating from the mesoderm tissue (the
heart, digestive tract, peripheral nervous system,
skin and tongue).
Secondary amyloidosis (AA) is associated with
chronic inflammatory diseases. In this reactive form
of amyloidosis, amyloid A protein deposits form in
the organs originating from the parenchymal tissue
(the kidneys, spleen and adrenal glands) [7].
In 1998, Saeger and Röcken divided amyloidosis into 27 types depending on the kind of protein
precursors. In 2002, Wastermark and colleagues
presented a classification of amyloidosis including the inheritance type and disease syndromes
or organ involvement which occur in its course
(Table 1) [4, 5, 8, 9].
Structure of Amyloid
and Development of
Amyloidosis AL
In normal conditions, plasma cells and B lymphocytes produce one of five types of heavy chains
together with κ or λ light chains, with the number of light chains exceeding the number of heavy
L. Usnarska-Zubkiewicz, J. Hołojda, K. Kuliczkowski
chains by about 40%. Moreover, the synthesis of
kappa chains, which are monomers with a mass of
25 kDa, is twice as big as that of lambda chains,
which are chain dimers with a mass of 50 kDa,
but kappa monomers are 2–3 times more quickly
filtered by the kidneys than lambda chain dimers
[10]. In healthy individuals, the number of plasmocytes producing light chains does not exceed
4%, and the λ to κ ratio is 2 : 3. In patients suffering
from AL amyloidosis, about 5–10% of plasma cells
in the bone marrow produce excessive amounts of
immunoglobulin light chains, and in the amyloid
fibril, the λ to κ or κ to λ ratios are 2 : 1 and 3 : 1,
respectively [11, 12].
AL amyloidosis from λ light chains is the most
common type, the next most prevalent being AL
from kappa chains, while heavy chain AH amyloidosis is extremely rare and only a few cases have
been reported worldwide.
The development of amyloidosis is associated
with the transformation of the α-spiral conformation of fibrous protein into a stratified, parallel,
folded spatial β-conformation. The transition of
the fibrous proteins conformation and their tissue
localization causes resistance of the fibers to proteolytic processes as a result of a limited access of the
protein converting enzymes. Amyloid fibrils are of
various lengths and widths and do not break readily. Amyloid fibrils precursor monomers contain N-terminal fragments of proteins, they join together
hydrostatically and form filaments, coil in 4–6 element bundles and form amyloid fibrils [13].
Immunoglobulin germ line genes have been
demonstrated to play an important role in the
development of amyloidosis in specific organs.
Comenzo et al. proved that λ chain overproduction, which is associated with a significant Vλ6a
gene overexpression, predisposes a person to the
development of renal amyloidosis, while excessive
expression of the Vλ3r, Vλ1c and Vλ2a2 genes promotes the development of multi-organ amyloidosis, and especially cardiac amyloidosis [14]. Moreover, it was demonstrated that the λVI subtype
of a light chain forms amyloid more readily than
other chains [15]. A similar relationship concerns
kappa light chains, for which the rearrangement of
the VκI and VκIV genes more often conditions the
development of AL amyloidosis [12, 15, 16].
Amyloid fibrils constitute about 90% of amyloid, the remaining 10% being occupied by the
components of the extracellular matrix [17]. They
include heparan sulfate proteoglycans (HSPG),
glycosaminoglycans molecules (Gags), which are
components of the basal membrane, serum amyloid P component (SAP) and co-factor E and J apolipoproteins. These molecules play a specific role
in fibrinogenesis, as they modulate the formation
649
AL Amyloidosis (Amyloidosis Antibody Light). Part 1
Table 1. Classification of amyloidosis according to Wastermark, Saeger, Schonland, Skotnicki [4, 5, 8, 9]
Tabela 1. Podział amyloidozy wg Wastermark, Saeger, Schonland, Skotnickiego [4, 5, 8, 9]
Amyloid
proteins
(Białko amyloidowe)
Precursor
(Prekursor)
Distribution
(Umiejscowienie)
Type
(Typ)
Syndrome or involved tissues
(Zespół lub zajęte tkanki)
β
Aβ protein precursor
local
acquired
sporadic Alzheimer disease, ageing
local
inherited
prototype inherited cerebral angiopathy
– Dutch type amyloidosis
local
acquired
sporadic (iatrogenic) CJD, new-variant CJD
(alimentary?)
local
inherited
familial CJD, GSSD, FFI
AprP
prion protein
Abri
Abpi protein precursor
local or systemic?
inherited
British dementia family
Acys
C cystatin
systemic
inherited
Island inherited cerebral amyloid angiopathy
Aβ2M
beta2-microglobulin
systemic
acquired
chronic hemodialysis
AL
immunoglobulin light
chains
systemic or local
acquired
myeloma-associated primary amyloidosis
AA
serum A amyloid
systemic
acquired
secondary amyloidosis in reaction to
chronic infection or inflammation, including inherited periodic fever syndrome (FMF,
TRAPS, HIDS, FCU and MWS)
ATTR
transthyretin
systemic
inherited
prototype FAP
systemic
acquired
senile heart, vessels
AapoAI
A-I Apolipoprotein
systemic
inherited
liver, kidneys, heart
AApoAII
A-II Apolipoprotein
systemic
inherited
kidneys, heart
Agel
gelsolin
systemic
inherited
inherited systemic amyloidosis finnish type
Alys
lysozyme
systemic
inherited
kidneys, liver, spleen
Afib
Aα fibrynogen chain
systemic
inherited
kidneys
CJD – Creutzfeldt-Jakob disease; GSSD – Gerstmann-Sträussler-Scheinker disease; FFI – fatal familial insomnia; FMF –
fatal familial fever; TRAPS – tumor necrosis factor receptor associated periodic syndrome; HIDS – tumor necrosis factor
receptor-associated periodic syndrome; FCU – familial cold urticaria; MWS – Muckle-Wells syndrome; FAP – familial amyloidotic polyneuropathy.
CJD – choroba Creutzfeldta-Jacoba; GSSD – choroba Gerstmanna-Sträusslera-Scheinkera; FFI – rodzinna śmiertelna
bezsenność; FMF – rodzinna gorączka śródziemnomorska; TRAPS – okresowy zespół związany z receptorem dla czynnika
martwicy nowotworów; HIDS – zespół hiper IgD; FCU – rodzinna pokrzywka z zimna; MWS – zespół Muckle’a-Wellsa;
FAP – rodzinna polineuropatia amyloidowa.
of amyloidogenic fibrils, combining immediately
with specific domains or their precursor proteins,
as well as protect and stabilize the fibrils against
degradation [18, 19].
The SAP, also referred to as P-pentraxine, is
a globular protein with a pentagonal structure, constant sedimentation 9.5S and molecular mass 254 Da,
and it occurs in all types of amyloid. The protein is
synthesized and catabolized in the liver, and its halflife is 24 hours [3]. The primary function of SAP is to
bind amyloid fibrils (the process is calcium-dependent), which may constitute additional protection
for the fibrils against proteolysis. The glycoprotein
character of SAP is probably responsible for a positive PAS reaction of amyloid deposits [20].
Etiopathogenesis
of Amyloidosis and
Amyloidogenic Mechanisms
The most important factor in the development of amyloidosis is the formation of amyloid
fibrils mainly in the extracellular matrix, and very
rarely, intracellularly, e.g. in pathological plasma
650
cells. The process in which the precursor proteins
are transformed into fibrils has a multi-factorial
character and differs with different amyloid types.
Buxbaum presented 4 basic mechanisms of amyloidogenesis [21].
1. Overproduction and disturbed elimination
of unchanged molecules, which, having achieved
high concentration, reveal a tendency to abnormal
breaking and formation of higher order spatial
conformations, as in the case of b2-microglobulin, atrial natriuretic factor (ANF) and islet amyloid polypeptides (AIPP) [22]. The molecules do
not require supporting processes to form fibrils,
although partial proteolysis may increase their
capability of fibrilogenesis. It is probably a basic
mechanism in the development of amyloidosis in
plasma cell dyscrasias.
2. A normal molecule does not have amyloidogenic properties, however abnormal proteolysis
leads to transformation of a protein precursor,
e.g. amyloid β-AP and release of amyloidogenic
protein fragments, as in the case of Alzheimer
disease [23].
3. Insufficient proteolysis leads to the formation of amyloidogenic fragments, e.g. in the case
of increased production and insufficient degradation of a specific protein. This type of production
is responsible for the development of AA amyloidosis and participates in the development of AL
amyloidosis.
4. It occurs in prion infections, which constitute a template for abnormal breaking of a protein
molecule. This type amyloidosis develops in infections.
The tendency to fibrilogenesis and development of amyloidosis is a derivative of the genetic
predispositions and factors affecting micro-environment and protein precursors.
Genetic predispositions include: 1) gene mutations, which lead to the production of “wild”
analogues of proteins, 2) the polymorphism of
co-factors (e.g. E apolipoproteins) and proteins
(e.g. serum A protein), 3) the inheritance of diseases which lead to the accumulation of precursor
proteins, e.g. presanilin – a mutation in familial
Alzheimer disease, 4) inborn diseases, which are
associated with chronic inflammation and deposition of precursor proteins.
Contrarily to other plasma cell dyscrasias, the
light chain lambda isotope is more common in AL
amyloidosis, which points to the presence of the
Vλ germ line gene, with excessive expression of
Vλ 6a and Vλ 3r [16, 24]. Moreover, it has been
demonstrated that the rearrangement of the VκI
and VκIV genes occurs more often in AL amyloi-
L. Usnarska-Zubkiewicz, J. Hołojda, K. Kuliczkowski
dosis [15]. Perhaps the presence of the germ line
genes increases the tendency of the light chains to
assume various molecular conformations. It has
been shown that amino acid exchange occurs in
the light chains that were formed as a result of gene
mutations, which decreases their thermostability and promotes fibril formation [25]. Common
chromosome aberrations in AL amyloidosis include: chromosome 18 monosomy, trisomy of numerous chromosomes, t(11;14)(q13;q23) and deletion (13q14) [26, 27]. Bryce reported that, among
56 patients with light chain amyloidosis, 70% had
abnormal cIg-FISH, with the most common abnormalities being t(11;14) [39%], t(14;16) [2%].
and del13/del13q [30%]. [28]. The risk of death
for patients with the t(11;14) translocation was the
highest, 2.1 (CI 1.04-6.4), independent of therapy.
It is important to note that patients with t(11;14)
had the lowest levels of clonal plasma cells, and
those with del13 had the highest. The levels of circulating immunoglobulin free light chains among
patients with AL vary greatly too, but even patients
with very low levels can have very advanced amyloidosis. According to Poshusta et al., the location
of mutations rather than the amount of free light
chains in circulation determines its amyloidogenic
propensity, as in patients with different levels of
secreted light chains there are significant differences in the location of mutations. This is especially true for patients with very low levels of light
chains and advanced amyloid deposition [29]. On
the other hand, the data gathered by Solomon et al.
has shown that the spleens of 12/26 patients with
amyloidosis also contain plasma cells, producing
a monoclonal light chain identical to the amyloid,
which indicated that the spleen may be another
source of amyloidogenic light chains [30].
Environmental conditions promoting amyloid
formation include factors that disturb the tridimensional structure of proteins: low pH, elevated
temperature, insufficient proteolysis, metal ions,
and high local levels of amyloidogenic protein precursors. Molecular mechanisms leading to tissue
damage by amyloid fibrils are still being investigated. Among others, it has been demonstrated
that lambda light chains encoded by the Vλ6a gene
mainly damage the kidneys probably through their
reaction with mesangial cell receptors [31]. Also,
specific reactions between amyloid fibrils and tissue glycosaminoglycans or glycation end-product
receptors – RAGE (receptor for advanced glycation end-products) may play a significant role [18,
32]. Regardless of the toxic effect of amyloid fibrils
on tissues, soluble light chain oligomers may also
contribute to organ damage [33].
AL Amyloidosis (Amyloidosis Antibody Light). Part 1
Conclusions
Most cases of AL amyloidosis are associated
with a mature plasma cell clone, but part of them
have “dangerous small” clones and do not meet the
criteria for multiple myeloma. The clonal plasma
cells produce abnormal monoclonal immunoglobulin light chains, the precursor proteins for amyloid
fibrils. The tendency to fibrilogenesis and the development of amyloidosis is a derivative of a genetic
predisposition and factors affecting the micro-environment and protein precursors. In AL amyloidosis, the light chain lambda isotope is more com-
651
mon, which points to the presence of the Vλ germ
line gene, with excessive expression of Vλ 6a and
Vλ 3r. Moreover, it has been demonstrated that the
rearrangement of the VκI and VκIV genes occurs
more often in AL amyloidosis. Patients with different levels of secreted light chains have distinct differences in the location of mutations, which rather
than the amount of free light chains in circulation,
may determine its amyloidogenic propensity. Environmental conditions promoting amyloid formation include: low pH, elevated temperature, insufficient proteolysis, metal ions, and high local levels
of amyloidogenic protein precursors.
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Address for correspondence:
Lidia Usnarska-Zubkiewicz
Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation
Wroclaw Medical University
Pasteura 4
50-367 Wrocław
Poland
E-mail: [email protected]
Tel. +48 71 784 25 96, +48 600 642 881
Conflict of interest: None declared
Received: 2.08.2011
Revised: 21.09.2011
Accepted: 5.10.2011