Amyloid arthropathy in chickens - Biochemistry and Molecular Biology

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Amyloid arthropathy in chickens
W.J.M. Landman a
a Animal Health Service, Poultry Health Centre, Arnsbergstraat 7, Deventer, 7418 EZ,
the Netherlands
Version of record first published: 01 Nov 2011.
To cite this article: W.J.M. Landman (1999): Amyloid arthropathy in chickens, Veterinary Quarterly, 21:3, 78-82
To link to this article: http://dx.doi.org/10.1080/01652176.1999.9694998
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AMYLOID ARTHROPATHY IN CHICKENS
(SUMMARY OF THESIS, UTRECHT UNIVERSITY, FACULTY OF VETERINARY MEDICINE, 1998)
W.J.M. Landman1
Vet Quart 1999; 21: 78-82
Accepted for publication: January 20, 1999.
Downloaded by [University of Georgia] at 10:38 19 October 2012
SUMMARY
The present paper presents an overview of current knowledge
of amyloid arthropathy in chickens, and covers the
pathogenesis of amyloidosis in general and in birds, field
cases reported, and the studies performed to assess the
amyloidogenicity of various agents compared to that of
Enterococcus faecalis. An animal model of amyloid
arthropathy is presented, as are studies on the pathogenesis
of arthropathic and amyloidogenic E. faecalis infections
in brown layers. The review concludes with a description
of the pathology of amyloid arthropathy, the
biochemical characterization of the chicken joint amyloid
protein as being of the AA type, investigation of the
serum amyloid A (SAA) gene involved, and local SAA
mRNA expression in joint and liver.
INTRODUCTION
Amyloidosis is a well-recognized pathological disorder
especially in waterfowl, and although extensive studies have
been performed on its pathomorphology and epidemiology,
knowledge of the pathogenesis of avian amyloidosis, and
amyloidosis in general, is still incomplete.
The highest incidence in captive wild birds is seen in
Anseriformes, Gruiformes, and Phoenicopteriformes (67).
Within the Anseriformes, the Anatidae are especially prone
to develop amyloidosis (47, 8, 19, 48). As in wild Anatinae,
in domestic ducks systemic amyloid A (AA) protein amyloidosis
is a common pathological disorder (43, 44, 45, 46, 14,
31, 32, 16) that has been found to be associated with chronic
inflammatory disease (13). Differences between species
have been reported in both caged wild fowl (9, 67) and domestic
ducks (33). There were few reports describing the occurrence
of systemic amyloidosis in chickens (64, 61, 52)
before our description of amyloid arthropathy in chickens
(24). The articular localization seems characteristic for
Galliformes (34, 51, 28). Amyloidosis is becoming.a clinical
problem of increasing importance in several European countries
(3, 29), with up to 20-30% of commercial flocks being
affected. In most cases brown layers are involved.
This article summarizes our knowledge of (avian) amyloidosis,
the occurrence, the nature, the pathogenesis, and possible
aetiological factors of amyloid arthropathy in chickens, and
the identification and characterization of the amyloid protein
and the gene. Studies were conducted at the Poultry Health
Centre of the Animal Health Service in Deventer and the
Department of Veterinary Pathology of the Utrecht
University, the Netherlands (27).
(AVIAN) AMYLOIDOSIS IN GENERAL
Amyloidosis has been defined as the extracellular deposition
of normally autologous soluble proteins or fragments thereof
Animal Health Service, Poultry Health Centre, Arnsbergstraat 7, 7418 EZ Deventer,
the Netherlands.
(the precursor proteins) in various tissues and organs in a
characteristic fibrillar form. Although amyloid deposits have
been described for more than a century and a half, their fibrillar
nature was not revealed until after 1950. The molecular
structure of amyloid (13-pleated sheet) was identified much
later by using X-ray and infra-red spectroscopy (11). Both
the primary amino acid sequence and the secondary molecular
structure (13-sheets) of amyloid proteins are thought to be
responsible for their congophilia and low solubility (7, 23).
The low solubility and the relative resistance to proteolytic
digestion of amyloid fibrils under physiological conditions
are thought to be the cause of the irreversible course of amyloidosis.
The disease is often fatal in mammals within
months or a few years after diagnosis (17).
The biochemical characterization of amyloids has shown
that several non-related proteins can re-organize into amyloid
fibrils. At present, more than 17 amyloid proteins of human
and animal origin have been characterized which differ
in their primary amino acid sequence. While in humans localized
cerebral amyloid associated with senescence and mental
retardation is most prevalent, in animals most amyloid deposits
are of the reactive or AA type, made of the acute phase
(precursor) protein serum amyloid A (SAA). To date, in
caged wild and domestic birds only systemic AA amyloidosis
has been described, although theoretically other not yet
recognized forms might exist.
It is noteworthy that the pathogenesis of this interesting but
complex disorder is still not well understood, especially at
the molecular level. Multiple factors acting in concert are
thought to play a role in amyloid fibril formation. Because it
is a two-phase process (62, 53), an increased pool of precursor
protein SAA is required before AA amyloid fibril formation
or AA activation occurs. The up-regulation of SAA genes
is in fact a normal physiological response to inflammatory
stimuli and provides the required pool of SAA for
amyloidogenesis, but will only lead to amyloid formation in
a small subset of individuals with a prolonged acute phase
response. Therefore, additional factors must be necessary for
AA amyloidogenesis.
In some cases certain amino acid substitutions of the precursor
protein may favour the, amyloidogenicity of the isotypes
(50, 5, 54, 63), facilitating the occurrence of unstable intermediate
protein conformations that easily adapt into 13-
pleated sheets (4) or, as more recently proposed, into 13-
helixes (30). Alternatively, some substitutions may confer
resistance to fibrillogenesis (6). Although an amyloidogenic
amino acid sequence is necessary for a precursor protein to
cause amyloid formation, it is not the sole determinant because
amyloid formation does not occur in all patients with
such sequences. Thus, the action of other factors seems
necessary to initiate fibrillogenesis, e.g. the presence of
amyloid-enhancing factor, which may act as a nidus for 13-
pleated nucleation (38). Also, the presence of certain inorganic
ions such as calcium (35, 1), proteoglycans, and their
-
.
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glycosaminoglycans (55, 56, 57, 58), pentraxines such as
serum amyloid P (SAP) (41), apolipoprotein E (42, 22), and
an altered metabolism of basement membrane proteins (2)
are thought to contribute to amyloidogenesis. They act as
stabilizers inducers or inductors of13-pleated sheet formation
(35), facilitating amyloid deposition and inhibiting clearance
mechanisms (58, 63). Proteolysis, represents a step in the
maturation of amyloid deposits rather than in their formation,
because the precursor protein SAA is deposited in its
intact form in amyloid deposits of duck (12), cow (39),
mouse, and other species (59, 60, 66). In chickens, indications
for SAA fibril deposition have been found in amyloid
precipitates (25).
AMYLOID ARTHROPATHY AND POSSIBLE AETIO-
LOGY
The first description of amyloid arthropathy in chickens indicated
that affected birds show a characteristic stiff gait and
marked growth retardation (24). The condition occurred
mainly during the rearing period, with clinical signs being
observed from 5 to 6 weeks of age onwards. The morbidity in
most flocks was 1 to 4%, but in some cases it was as high as
20%. In 35% of necropsied birds articular amyloid deposits
were found and classified as being of the AA type because of
the positive reaction with anti-duck and anti-bovine AA antisera
on peroxidase-antiperoxidase (PAP) staining. An association
with Enterococcus faecalis was proposed because
this bacterium was isolated in 2 out of 6 flocks (from joints of
10% of affected birds). Reovirus was isolated in 1 out of 6
flocks.
Review of additional field cases and routine post-mortem
examination of samples sent to the Poultry Health Centre of
the Animal Health Service in Deventer in 1996-1997 revealed
that amyloid arthropathy occurred in 12.9% of necropsied
brown layers, but in only 2.9% of broiler breeders
(29). The condition was never encountered in white layers
and broiler chickens. The absence of amyloid arthropathy in
the latter group was not unexpected as these birds have a life
span of approximately 7 weeks maximally. In brown layers,
E. faecalis was the major pathogen isolated (46/60) from
amyloidotic joints positive on bacteriology (60/303), while
Staphylococcus aureus (47/64) was mainly isolated from the
amyloidotic joints of broiler breeders (64/86). When
necropsy data were analysed per year, the prevalence of
amyloid arthropathy was found to have increased in both
brown layers and broiler parent birds. Of necropsied brown
layers, 11% (118/1070) suffered from amyloid arthropathy
in 1996 and 15.2% (131/860) in 1997. For broiler parent
birds the proportions were 0.9% (11/1190) and 6.5%
(42/625), respectively. Affected flocks were housed in cages
as well as on litter, and no season variability was observed in
the occurrence of amyloid arthropathy.
While investigating the role of various agents in chicken
amyloid arthropathy (29), it was shown that primarily E.
faecalis and Freund's adjuvans were able to elicit extensive
amyloid arthropathy in brown layer pullets, with there being
marked differences between E. faecalis isolates. Of the other
micro-organisms studied, S. aureus, Salmonella enteritidis,
and Escherichia coli were also able to cause joint amyloidosis;
however, the amount of amyloid deposited was
very small and clinical symptoms were minimal.
Mycoplasma synoviae, inactivated E. faecalis, chicken
anaemia virus, and reovirus did not cause amyloid arthropathy
after intra-articular inoculation. These results are in line
with data from an inventory of additional field cases where
E. faecalis was isolated from joints in 12% of affected
brown layers, which suggests that this bacterium has a role
in the pathogenesis of joint amyloidosis in chickens. The
importance of E. faecalis as an aetiological agent for amyloid
arthropathy in the field may have been overlooked because
the bacteria may be confined to articular pouches in
chronic arthritis which makes their isolation difficult. This
could lead to a number of false negative results. Studies
comparing sampling techniques as well as growth media
need to be performed to address this issue.
Indications for clonal spread of amyloidogenic and amyloidassociated
E. faecalis isolates were found after strain typing
by restriction endonuclease fragment analysis of chromosomal
DNA by pulsed-field gel electrophoresis (PFGE) after
Sma I digestion (29). The observation of identical restriction
endonuclease digestion (RED) patterns in E. faecalis isolates
collected from field cases over a 4-year period and from
several European countries indicates that they can be stable
in nature over a number of years. This is in agreement with
the results of other studies where E. faecalis strains were
found to have stable RED patterns over even longer periods
of 7 (49) and 8 years (37). The persistence and spread of a
single arthropathic and amyloidogenic clone for at least 4
years justifies further investigation of its epidemiology and
pathogenicity. This will help investigators to develop and
promote measures that will reduce the transmission of these
strains.
INDUCTION OF AMYLOID ARTHROPATHY WITH
ENTEROCOCCUS FAECALIS AND TRANSMISSION
STUDIES
AA joint amyloidosis in chickens can be induced by a single
injection of E. faecalis isolated from field outbreaks of reactive
amyloid arthropathy in brown layers (26). All 6-weekold
brown layer pullets injected intravenously with 108 or
109 colony-forming units (cfu) developed reactive amyloid
arthropathy. Amyloid masses were . also present in the internal
organs. The first articular amyloid deposits were observed
5 days after injection whereas such depositswere encountered
in the internal organs from day 13 onwards. On
intra-articular injection, amyloidosis developed particularly
in the target joint and in the internal organs, suggesting local
SAA production and fibrillogenesis. The results obtained
with this novel animal model for amyloid arthropathy are
consistent with those of other major animal models for AA
(15) and fit with the current hypothesis for the role of acutephase
protein serum amyloid A in the pathogenesis of AA
(18, 60).
The pathogenesis of arthropathic and amyloidogenic E. faecalls
infections in brown layers was studied using our animal
model as a positive control. Amyloid arthropathy was elicited
in 6-week-old pullets after intravenous, intra-articular,
and intraperitoneal inoculation of high doses (109 cfu), but it
was not after intramuscular, oral, and intratracheal inoculation.
Similarly, oral inoculation of 1-day-old chicks with 108
cfu did not cause any pathology; however, intramuscular inoculation
with 106 cfu resulted in severe growth retardation
and arthritis in 60% of the birds, and joint amyloidosis in approximately
40%, reflecting the existence ofage resistance
for this route. Transmission of arthropathic and amyloidogenic
E. faecalis to 1-day-old chicks might occur as a result
of intramuscular vaccination with Marek's disease vaccine
because samples of hatchery air (hatcher and processing
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room), Marek's disease vaccine suspensions, and injection
needles were found to be contaminated with varying and
sometimes high levels (< 10 to 106 cfu/ml vaccine suspension
and approximately 104 cfu/injection needle) of E. faecalis.
If vaccine suspensions and injection needles were contaminated
with arthropathic and amyloidogenic strains, then
amyloid arthropathy could have been induced in those birds
injected with = 106 cfu. Arthritis had already developed in
some birds injected with lower doses (165 cfu). PFGE of
hatchery strains showed that dominant RED patterns can occur
in a particular hatchery. One of the isolates showed a
banding pattern (1 fragment difference) that was similar to
that of a known arthropathic and amyloidogenic isolate.
In egg transmission studies neither egg dipping nor inoculation
of the air chamber with E. faecalis reproduced the condition,
although E. faecalis caused septicaemia in a few chicks.
Yolk sac inoculation of embryonated eggs incubated for 6
days caused embryonic death within a few days, which suggests
that transovaric transmission is unlikely. In contrast, inoculation
of egg albumen with lower doses of the isolate led
to later embryo mortality, some hatching chicks, and E. faecalls
arthritis transmission to 1 out of 6 hatched chicks, which
indicates the possibility of transoviductal transmission.
Indications for vertical transmission of arthropathic and
amyloidogenic E. faecalis on a small scale were found after
brown layer parent birds were intravenously inoculated with
high doses (109 cfu) of E. faecalis. The inoculated birds
developed chronic bacteraemia and arthritis, and in several
cases amyloid arthropathy (2/6): egg production was decreased.
E. faecalis was isolated from the ovaries and
oviducts of all birds that died due to septicaemia, and from
the egg content of 76% (13/17) of candled and 100% (6/6) of
non-hatching eggs of the first 2 (out of 6) production weeks
after inoculation. It was also cultured from arthritic joints of
3% (2/66) of the hatched chicks of the same batch at 8 weeks
of age. However, the chicks did not develop joint amyloidosis.
The mortality pattern of embryos (E. faecalis- positive
deaths in shell) is in line with that found after egg albumen
inoculation of embryonated eggs with lower doses, suggesting
again that transoviductal transmission occurs. Although
ovaric transmission may occur, it will probably result in an
early embryo mortality similar to that of high-dose contamination
of egg albumen.
During these studies natural infection routes were not found.
However, intramuscular vaccination against Marek's disease
of 1-day-old chicks might result in amyloid arthropathy
depending on the presence of AA inducing pathotypes. This
could be favoured by vertical transmission of the pathogenic
bacterium, as suggested by the experimental data and field
findings. Infected eggs and chicks represent a source of
arthropathic and amyloidogenic E. faecalis that could contaminate
hatchery air and Marek's disease vaccine suspensions
after colonization and replication of the bacterium in
the intestines of newborns (20, 21, 10). Chicks inoculated
with sufficiently high doses would develop the condition and
show the typical clinical and pathological lesions.
This scenario is in line with the clinical problems of amyloid
arthropathy described in the field. These problems are encountered
mostly during the early rearing period and are said
to resolve once affected birds are culled, indicating that
transmission by natural routes is inefficient. In some field
cases, however, clinical amyloid arthropathy developed during
the production period in well-developed hens, which
suggests the existence of additional infection routes that may
enable intestinal E. faecalis in sufficient numbers to gain access
to the blood stream before the joint is colonized.
PATHOLOGY OF AMYLOID ARTHROPATHY IN
CHICKENS
The light microscopic, immunohistochemical, and electron
microscopic features of amyloid arthropathy in chickens
have been documented (40). Predominantly, femoro-tibial
and tarso-metatarsal joints are affected, showing (peri)articular
orange amyloid deposits. Immunohischemical evaluation
reveals the amyloid to be of the reactive type. In the
naturally occurring disease and in induced disease, amyloid
deposits are found in the hypertrophic synovial villi and in
the articular cartilage, particularly in the superficial layer
and in the nutritional blood vessel walls. Highly sulphated
glycosaminoglycans (GAGs), which supposedly play an important
role in amyloid fibrillogenesis because they stabilize
or induce B-sheeting of SAA (55, 56, 35), are also found to
co-localize with chicken joint amyloid. Ultrastructurally,
bundles of amyloid fibrils are seen in invaginations ofsynoviocytes
and chondrocytes. Immunogold electron microscopy,
however, has failed to reveal signs of intracellular
amyloid formation.
CHARACTERIZATION OF CHICKEN AA, SAA, AND
THE GENE INVOLVED
The amyloid fibrils extracted from deposits in joint tissue of
brown layers with spontaneous amyloid arthropathy were
characterized by amino acid sequencing as being of the AA
type (25). The amino acid pattern found was quite similar to
that of duck AA. Acute-phase sera of chicken experimentally
injected with E. faecalis showed a SAA protein-like
band that cross-reacted with polyclonal anti-chicken AA on
immunoblotting. This band occurred approximately at the
same level as the major band ( 14 kDa) of the major retarded
peak of distilled water-extracted and guanidine-HC1 dissolved
amyloid fibrils after Sephacryl S-200 chromatography,
while a second smaller peak ( 9 kDa) appeared to
be AA, as evidenced by amino acid sequencing. This finding
indicates that SAA deposition occurs in chicken joint amyloid
as has been described in other species (12, 39, 66),
where SAA is transformed into amyloid fibrils prior to C-terminal
proteolytic cleavage and transformation into mature
AA fibrils.
Post-mortem data from commercial chickens collected over
a 2-year period showed that amyloid arthropathy occurred
regularly in brown layers, whereas the white layerswere free
of this disease. The susceptibility of brown layers was confirmed
experimentally by injection of arthropathic and amyloidogenic
E. faecalis from a spontaneous case. As both
breeds, brown and white layers, are bred and kept under similar
management conditions, a genetic basis for this difference
is likely. The enhanced susceptibility of organisms to
develop systemic AA type amyloidosis has often been attributed
to the expression of an amyloidogenic SAA protein.
Characterization of the chicken SAA gene has revealed that
it is a single copy gene containing 4 exons,.of which the first
is not expressed. Unexpectedly, SAA cDNA sequences of
brown and white layers indicate that the primary translation
products are identical in the two breeds. Thus the difference
in susceptibility between these two breeds might be caused
by differential expression of the SAA gene, or by factors
which influence amyloid protein deposition.
Finally, in situ hybridization studies have revealed SAA
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mRNA expression in both, the liver and the altered synovial
membrane of amyloidotic birds, which suggests that the synovial
production of SAA is important in the development of
Joint amyloidosis. The synthesis of SAA by the synovial fibroblasts
of rabbits has been reported (36), but not in relation
to local amyloid deposition, which makes this finding of particular
interest.
CONCLUDING OVERVIEW
Amyloid arthropathy in chickens is, in a number of cases, a
complication of bacteraemia derived chronic (poly)arthritis,
where E. faecalis is considered to be a causative agent, especially
in brown layers. Its primary aetiological importance in
the field might have been overlooked due to the chronic nature
of the disorder and because of shortcomings in the isolation
systems used. The persistent acute-phase response induced
by E. faecalis will provide an adequate pool of the
precursor protein SAA necessary for SAA and AA fibril formation.
The specific articular localization of amyloid deposits
in Galliformes may be explained by in situ SAA mRNA
production, as shown by hybridization in brown layers.
Haematogenous spread of E. faecalis is necessary to penetrate
and infect the joints. In this respect, the intramuscular
Marek's disease vaccination of day-old chicks at the
hatchery may represent a possible infection route, leading to
. clinical problems during the rearing period. Small-scale
transoviductal transmission could represent a pathway for
arthropathic and amyloidogenic E. faecalis contamination of
chicks. After horizontal spread and multiplication in flockmates,
hatchery air, Marek's disease vaccine suspensions,
and injection needles could become contaminated. However,
a role for faecal-egg shell contamination in transmission to
chicks cannot be excluded, because small-scale transmission
ofE. faecalis to offspring was achieved after egg dipping and
air chamber inoculation.
Although natural infection routes have not been found, their
existence is speculated upon because amyloid arthropathy is
sometimes recorded in older well-developed birds after diseased
birds in affected flocks have been culled. Also, the presence
of antibodies to E. faecalis in intratracheally and orally infected
birds suggests their existence. Investigations to evaluate
the effect of a number of factors on E. faecalis translocation,
dual infections with other pathogens that affect the integrity of
the intestines, combined infections with immunosuppressive
agents, aerosol transmission, etcetera, may contribute to our
understanding of the pathogenesis of invasive E. faecalis infections
and related amyloid arthropathy in chickens.
The clonal spread of arthropathic and amyloidogenic E. faecalls
justifies further research on the epidemiology and
pathogenesis of this micro-organism. On the basis of the information
obtained, programmes for the screening of flocks
for the occurrence of pathogenic E. faecalis can be set up and
strategies to reduce its transmission and the subsequent amyloid
arthropathy can be introduced.
With regard to the pathogenesis of AA fibrillogenesis itself,
our animal model may provide unique opportunities to further
study factors that are of importance in inducing protein
conformational changes in situ, by comparing E. faecalis
isolates with a different amyloidogenic potential.
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