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Pathogenesis of chronic inflammation in experimental ferritin-induced arthritis.

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The earliest and most severe changes in articular
collagenous tissues (ACT) occur within 24 hours of antigen challenge and are associated with and are possibly
secondary to maximal immune complex deposition in
ACT surfaces. The immuno-electron microscopic
(immuno-em) staining characterizes the ferritin as aggregates with antibody and suggests its occurrence and deposition as a preformed immune complex. These data indicate a direct interaction between immune complexes and
collagenous matrix which could relate to both antigen
From the Division of Orthopaedics, Department of Surgery,
Queen's University, Kingston, Ontario, Canada.
Work presented in part at the scientific sessions of the 23rd
meeting of the Orthopaedic Research Society, February I , 1977; the
Canadian Orthopaedic Research Society Meeting, June 13, 1977; and
the 14th International Congress of Rheumatology. June 30, 1977.
Work supported by the Canadian Arthritis and Rheumatism
Society Grant No. 14-168-(72)and the Canadian Orthopaedic Foundation.
Osamu Ohno. Ph.D., M.D.: Research Fellow, currently Lecturer in Orthopaedics, Department of Orthopaedics, University of
Kobe, Kobe, Japan; Hiroomi Tateishi, Ph.D., M.D.: Lecturer in
Orthopaedics, Department of Orthopaedics, Hyogo Medical School,
Hyogo, Japan; T. Derek Cooke, M.A.. M.B., B.Chir., FRCS(C):
Associate Professor of Surgery, Division of Orthopaedics, Department of Surgery, Queen's University, Kingston, Ontario, Canada.
Address reprint requests to T. Derek Cooke, M.A., Division
of Orthopaedics, Department of Surgery, Queen's University, Kingston, Ontario, Canada.
Submitted for publication May 31, 1977; accepted in revised form August 2, 1977.
Arthritis and Rheumatism, Vol. 21, No. 1 (January-February 1978)
persistence and chronicity of the immune response. The
changes described in this model have features in common
with rheumatoid disease and suggest the potential for
similar mechanisms of cartilage degradation.
In this model for rheumatoid arthritis (RA) ( I ,2)
persistence of the inducing antigen (Ag) in association
with rabbit immunoglobulin (Ig) and complement components (p,,) has been demonstrated in a surface relationship of the articular collagenous tissues (ACT), i.e.
hyaline cartilage, intra-articular ligaments, and the menisci of the knee (3). The specificity of antibody synthesis
in synovial cultures suggested that the local immune
response was directed at and maintained by the complexed Ag in ACT (2). The fact that detailed information of the nature, form, and site of these complexes, as
well as knowledge of changes in ACT matrix, was not
known prompted this study using immuno-em techniques. Ferritin was chosen as the antigen as it contains
more than 20%of iron by weight, is easily detected by its
characteristic em appearance (4), and was shown in a
preliminary study to be a suitable protein antigen (5,6).
Animals. New Zealand white rabbits of either sex
weighing 2-3 kg were used. They were fed regular Purina
Chow and water ad libitum.
Table 1. Study Protocol of Ferritin-Induced Arthritis
Number of Animals Studied
Pure Ferritin Crude Ferritin
Times of sacrifice
30 minutes-6 hours
I day- I0 days
2-6 weeks
3-6 months
1-9 months
5 (3)
7 (3)
4 (2)
4 (2)
6 (3)
Numbers in parentheses indicate animals studied for rabbit IgG.
Materials. Ferritin (Fn), 6X crystallized without cadmium (pure Fn), Fn 2X crystallized and containing 3 pg/ml of
cadmium (crude Fn), and horseradish peroxidase (HRP) as a
salt-free, freeze-dried powder were obtained from Miles Laboratories, Inc., Kankakee, Illinois. CNBr-activated Sepharose
4B was obtained from Pharmacia Fine Chemicals, Uppsala,
Sweden. Complete Freund's adjuvant (CFA), containing I
mg/ml of tubercle bacilli H 37 Ra, was obtained from
D l F C O Laboratories, Detroit, Michigan.
Antibody Preparation and Conjugation with Horseradish Peroxidase. Anti-rabbit IgG (anti-lgG) was obtained
from guinea pigs immunized with 1.5 mg of rabbit IgG in CFA
and bled on the twenty-first day after immunization. The
gammaglobulin was precipitated with saturated ammonium
sulfate and chromatographed on a column of CNBr-activated
sepharose 4B coupled with rabbit IgG (7). The purified anti-
IgG was then eluted with glycine-HCI buffer at pH 2-3. Coupling of the antisera to H R P was undertaken with glutaraldehyde as described by Avrameas (8), and Avrameas and
Ternynck (9). After conjugation the preparation was dialyzed
at 4°C against phosphate buffered saline (PBS). The labeled
antiserum (HRP-anti-lgG) was precipitated with an equal volume of saturated neutral solution o f ammonium sulfate and
dialyzed again. It was then stored frozen at -30°C.
lmmunization of Rabbits and Induction of Arthritis.
Two groups, totaling 48 animals, were studied (Table 1 ). The
first group of 22 was immunized with 10 mg of pure Fn in CFA
and 3-4 weeks later was challenged with 5 mg of this Ag in I
ml PBS injected in the right knee. The left control received an
equal volume of PBS. The animals were sacrificed at intervals
from I day to 9 months after joint injection.
A second group of 26 rabbits was immunized and
challenged with crude Fn. Both knees were injected and uninjected elbows used as controls. The animals were sacrificed at
intervals from 30 minutes to 9 months. Shown in Table I i n
parentheses is the number of animals used for immuno-em
identification of rabbit IgG.
Tissue Preparation for EM Study and Immuno-EM Examination. At sacrifice, ACT were obtained by careful joint
dissection as previously outlined (10) and washed in PBS. For
direct em study, the specimens were fixed in 3% glutaraldehyde
and osmicated in 2% OsO,, dehydrated, and embedded i n
EPON in the usual manner ( 1 I ) . Blocks were trimmed and cut
to permit examination of the surface at right angles. The
tissues for the immuno-em studies were frozen and stored a t
-30°C. Frozen specimens were sectioned at 40 p and fixed for
1 hour at 4°C in 10% buffered formalin. The sections were
washed in PBS overnight and then reacted with the HRP-antiIgG for 24 hours at 4OC. They were then washed extensively
Figure 1. Electron micrograph of hyaline cartilage under high magnification 30 minutes post challenge showing a single isolated deposit of aggregated Fn (arrow) in the tangential collagenous zone. Surrounding tissue
has a normal appearance. With heavy metal staining (original magnijkation X 51,6001. JS = joint space.
Figure 2 . Iittttruiio-i,lecrro,i micrograph of hyaline cartilage under inlermediate ttiagnification I .5 hours post
challengi~showinz tiutnerous deposits of Fn. densely stainedfor IgG (Fn-lgG = arrows) concentrated in the
superjcial layers (original magniJcation X 33,750).JS = joint space; N = nucleus.
overnight again. The control specimens were incubated in
unconjugated anti-lgG for 24 hours and then stained with
HRP-anti-lgC. These sections were washed and all tissues
were then fixed with 3% glutaraldehyde for I hour, washed
overnight, and stained for peroxidase by the method of Graham and Karnovsky (12). They were washed in distilled water
three times, osmicated, dehydrated, and embedded so that the
brown-stained surfaces were vertical in the EPON blocks.
Ultra-thin sections were cut on a Porter-Blum MT2-B Ultramicrotome, always including the surface. They were examined
in a Hitachi HSI I-C microscope, with or without heavy metal
staining (uranyl acetate and lead citrate).
The most striking findings were observed within
weeks of articular challenge during the Arthus phase.
The data are presented for convenience in three sections,
dividing the most prominent acute and early chronic
phases of the reactions into initial-from 30 minutes to
6 hours; intermediate-from
2 to 10 days; and latefrom 1 month or more. Subsequently, these events are
correlated with the inflammatory phases in the joint
over the time course of up to 1 week to permit a more
dynamic interpretation of them. The long-term changes
are the subject of another report (13).
Influence of Immunization Protocol on the Severity of Arthritis. Rabbits immunized with highly purified
Fn had a mild chronic arthritis. In general, acute synovitis disappeared rapidly, and a diminishing chronic response was seen at 2 weeks. This correlated with an
absence of detectable antigen in joint ACT beyond 2
days by em. Because the changes in the crude Fn group
were similar in kind but more severe, our data reflect the
findings in the crude Fn group.
The Initial Changes Observed Half to 6 Hours
Following Articular Challenge. At 30 minutes tiny aggregates of Fn were observed in the tangential collagenous
zone in isolated areas surrounded by normal-looking
cartilage. Such an area with an Ag deposit is shown in
Figure 1 . Small amounts of free Fn were also seen in the
amorphous debris scattered on the articular surfaces. A t
this time the synovial membrane histology showed perivascular polymorphonuclear (PMN) cell infiltration, indicating the earliest phase of the acute inflammatory
The articular cartilage, 1.5 hours following challenge, showed patchy areas of surface irregularity with
deposits of aggregated Fn in considerable concentration. Figure 2, an illustration of the same hyaline cartilage stained with HRP-anti-IgG, shows that the Fn
aggregates stained strongly for antibody. Neither the
matrix nor the debris showed positive staining.
At 6 hours large quantities of surface debris were
Figure 3. Electron micrograph of hyaline cartilage under low magni’jication 6 hours post challenge showing a
highly irregular surface, with fragmentation of superficial collagen becoming part of a pleomorphic inJammatory detritus (original magniJcation X 24.000). JS = joint space: Sur = surface: Co = collagen
Figure 4. High magnification of Figure 3, showing fragmented collagen in detail, breaking away from a surface rich in Fn deposits (arrows) (original magnification X 51,600). Co = collagen.
Figure 5. Wrctron micrograph o/’h.valine cartilage under intermediate magnificarion at 6 hours post chalIcwge. .xhoiiing a P M N cell in direct relationship to a surface rich in Fn deposirs. The aggregated Fn (arrows)
i.r i ~ a s i liclc.nti/Ii~d
the endocytotic vacuoles (original magnification X 31.200). JS = .joint space.
found to be associated with fragmentation of the superficial collagenous matrix: in Figure 3 this debris can be
seen breaking free from the surface. The dense Fn deposits underlying and adjacent to the disrupted collagen
are apparent in Figure 4. The deposition of Fn a t the
surface and in superficial layers was a most prominent
finding at this time. A surface PMN cell (Figure 5 )
actively phagocytosed Fn, which can be seen within its
cytoplasmic vacuoles. Such cells occurred frequently at
these damaged surfaces during this initial phase as the
Art hus reaction intensified.
Intermediate Changes from 1 to 14 Days after
Challenge. By 24 hours widespread loss of the tangentially arranged collagen had occurred with Fn in
varying and often heavy concentrations in the superficial layers of ACT, as illustrated in Figure 6 . Figure 7
shows a meniscus at 2 days post-challenge stained for
IgG. The Fn aggregates are evident in quite high concentration, but in a more diffuse pattern and staining
strongly for antibody. Figure 8 is a control specimen of
the same meniscus preincubated with unconjugated
anti-IgG. The marked decrease in density of the Fn
aggregate staining indicates the specificity of the
HRP-anti-IgG reaction.
The distribution of aggregates in the matrix appeared to relate to their size, so that the largest remained
superficial and the smallest occurred deeply (Figure 9).
At this high magnification the complexes are shown as
elliptically shaped bodies, measuring from 0.04 to 0.06 p
long or as irregular masses. Their maximal penetration
was found to a depth of about 4 p in menisci. Figure 9
also shows the Fn aggregates in lacuna-like spaces surrounded by partially disrupted collagen fibers. Collagen
could not be visualized crossing these lacunae.
By 1 week, loss of Ag occurred associated with
the progressive breakdown of ACT surfaces. Deposits of
complexes in high concentration, but focally distributed
and penetrating more deeply, were readily found by em
in ACT up to the second week but not beyond that time.
Inflammatory cells were not seen at denuded surfaces
lacking superficial complexes.
The histology of the synovium illustrated the
peak of the Arthus response, its decline, and a developing active chronic synovitis over this period of observation.
During the first week after challenge a change in
cell type at the surfaces occurred. Macrophage-like cells,
which appear at damaged regions and coincided with
antigen-rich deposits, seemed to be phagocytosing debris and probably immune complexes (Figure 10).
Another new feature became evident during this
phase. Electron-dense matrix material ( E D M M ) in and
Figure 6 . Electron tnicrograph of hyaline cartilage under intermediate magnification I day post challenge
showing complete erosion of the tangential collagenous layers with diguse loss of matrix density. Scattered
deposits of Fn aggregates (arrows) are seen penetrating deeply into the superficial zone (original magniJication X 48.000). JS =joint space.
among the superficial collagen fibers was seen initially at
2 days. Its concentration was greatest at the surface; it
became sparse deeper. It was not associated with antibody staining. It continued to be evident in specimens
sporadically, but in a less concentrated form, for up to 6
The Late Changes Observed from 1 to 6 Months
from Challenge. U p to 6 months after challenge the
specimens showed evidence of focally severe cartilage
damage. Most often this was a loss of the upper layers of
the superficial cartilage zone, with varying amounts of
EDMM evident. Figure I 1 shows hyaline cartilage at 1
month post challenge. Dense collections of EDMM are
seen in an irregular pattern, most concentrated at the
dam aged surface.
Synovitis diminished progressively in intensity as
time went on. The damaged eroded surfaces in many
cases became covered with a noncollagenous fibrin-like
Incidence and Severity of Immunologically Induced Changes in ACT and Their Relationship to Joint
Inflammation. The surface changes, ferritin deposition,
and polymorphonuclear (PMNs) and macrophage-like
cell localization, with EDMM deposition and superficial
chondrocyte changes, are outlined in Table 2, which
indicates their onset and severity in relation to the immune synovitis. As previously mentioned, the changes
occurred in a random, somewhat patchy, distribution in
ACT and in this regard they were consistently and maximally observed in regions where Fn had been deposited.
The deposition of complexed Fn in almost normal appearing matrix surfaces continued up to 3 hours; a dramatic change occurring at 6 hours was associated with
massive PMN cell interaction. This coincided with an
intense Arthus reaction and in the continuing presence
of immune complexes at a phase of Ag excess (10). At
the Arthus peak, after 24 hours, severe damage has
occurred with the surfaces stripped of their tangential
layers, Fn, and cells. Macrophage-like cell interactions
coincided with the influx of lymphocytes and plasma
cells in the membrane, at the onset of the chronic local
immune response.
Of note is the very early finding of chondrocyte
damage seen in cells of the superficial zone after 1.5
hours. EDMM appears a t the peak of the Arthus reactions and during maximal autolysis of the PMN cells.
The involved matrix has no surface protection and its
density and collagen network are disorganized.
Figures 7 and X. It~ri~runo-c,lrcrron
micrograph and conrrol stained /or rabbir IgG using H R P anti-IgG (Figure 7 )and blocking trchniyues wiih unconjugatrd anti-IgC (Figure 8). Figure 7 shows a meniscus under inrermediate magnification 2 days post-challenge with dense staining of Fn aggregates for IgG (arrows) (original
magnification X 40,000).Figure X shows a marked decrease in density of this staining indicative of a specific
reaction Jbr rabbit IgG (original magnification X 67,500). JS = joinr space.
In previous studies of this model the inducing
antigen on the surfaces of ACT from arthritic joints was
identified by radioautography and immunofluorescence
(IF)(2,3) with evidence for its long-term persistence in
the form of immune complexes (3,14).The immunoelectron microscopic techniques described used to study
the antigen Fn in this model have permitted a detailed
approach to the ultramicroscopic morphology of immune complexes in these tissues and the related matrix
changes from less than 1 hour to more than 6 months
following challenge.
The initial findings at 30 minutes occurred before
a significant Arthus reaction had developed. At this
time, the first deposits of Fn in low concentration but
Figure 9. Electroti uiirrograph ofmeniscus 2 days post challenge showitig
at high rtiagnificarion the siwdependetit penetration of Fti in aggregates
that varied iti length frorri 0.04 to 0.06 p . The aggregates are seen within
lucent zones (arrows) with dismption of adjacent collagen fibers at their
periphery (original magnification X 81.600). JS = joint space.
Cellular Changes in Cartilage and Findings in
Controls. Chondrocytes at various phases of degeneration and death were invariably observed in the damaged
regions both early and late. The earliest findings occurred by 1.5 hours post challenge. If erosions had occurred, these cells related to the upper regions of the
middle cartilage zone. Degenerate but probably viable
cells appeared more deeply. Proliferative cell changes
were not found.
The control joints obtained at varying time inter-
were identified.
tiou X 7.XfN~J.JS = joint space
Figure 1 I . Elrcrroii itricrograpli n/ livaline cartilage I niorith post challenge at low magnification showing
dcri.w irrcyular co1lwrioii.s o/'EI)MM.rtiost conceiitrated at the .surJace. which in turn is eroded oJiis super,/Ii,ial l q l w s forigiriul riiugiii/icariori X 10.000~.JS = ,joint space.
widely dispersed were found in otherwise normal-looking surfaces of ACT. Tiny deposits in the form of aggregates appeared in isolated defects of the tangential collagenous layers. Free Fn occurred in debris on the surface
but was not seen in the matrix. These and subsequent
observations suggested that the Fn entered the superficial layers of ACT from the joint space as a preformed
aggregate. The superficial distribution of large aggregates and the deep distribution of small suggested that
penetration of the matrix occurred in relationship to
size; this finding also supports the deposition of Ag as a
formed complex. The specific staining of the aggregates
for rabbit IgG, but lack of free staining for IgG in the
matrix or joint space, suggests an initial local state of
antigen excess without free antibody in either the tissue
matrix or joint space (10). The aggregated form of Fn
and its intense and highly specific staining for antibody
add strong support to previous data for antigen locaiization in ACT as an immune complex (2.3,10,14,15).
These data do not support the idea that antigen is
trapped in the matrix by preexisting antibody (14,16). I f
one accepts this interpretation, a mechanism of how
Table 2 . Tiniing and Severit), of Irnmuno-EM Changes in ACT* arid the Associated Synouial Histology up to I Week Following Articular Challenge
Surface Change
Fn Deposition
PMN Cell
Chondrocyte Change
Time Course
Synovial Inflammation
30 minutes
3 hours
6 hours
Massive PMN reaction
Fibrinous exudate and debris
Edema and hemorrhage
24 hours
Arthus peak
Early mononuclear cell
48 hours
Decay Arthus
Earliest lymphocytes
7 days
Lining proliferation
Lymphocyte and plasma
cell infiltration
*These data represent studies in both knees of each animal. including hyaline cartilage and menisci, one animal at 0.5. 1.5. and 6 hours, and two
animals at 3 , 24. 48 hours, and 1 week.
these large complexes permeate the densely collagenous
tangential zones and matrix network of collagen and
proteoglycan is required. The observation of electron
lucent regions around the Fn complexes with absence or
disruption of adjacent collagen fibers suggests a direct
interaction between them. One might speculate that a
competitive interaction between the complex, perhaps
its likely Clq component, and the inhibitor counterpart
of an intrinsic cartilage collagenase (1 7,18), already in
the matrix, occurs which permits collagenolysis immediately around the immune complex-and hence its penetration. Such an occurrence may have important bearings on its binding and persistence in ACT (3,14,15).
At 6 hours, severe destructive changes in the
surfaces occurred; collagen broke free and contributed
to the inflammatory detritus. This change was accompanied by the continuing deposition of immune complexes in large amounts, in part relating to the destruction of the superficial matrix and paralleling the
increasing amounts o f Fn complexes in the joint space
(10). Many PMN cells at these surfaces actively phagocytosed complexes and probably surface debris, and
their influx was followed by severe surface erosions.
Their focusing at ACT surfaces may be due to the production of chemotactic factors resulting from complement fixation by the depositing immune complexes
(3), as has been demonstrated t o occur in vitro (21).
Although not essential to the process of antigen deposition ( 1 5), their activities may enhance its occurrence (10)
and provide the major source of enzymes for the severe
matrix degradation that was observed ( l9,20).
By 1 or 2 days after challenge, regions of complete superficial loss of matrix layers were observed and
the concentration of immune complexes decreased progressively. By em, Fn could not be found beyond 2
weeks, but light microscopic observations showed positive patchy staining on ACT surfaces with HRP-antiIgG more than 9 months after challenge (13). Furthermore, previous experiments have indicated an extended
half-life for radio-labeled antigen persisting in ACT
The origin of the EDMM evident in the superficial matrix and following the initial surface damage is
unexplained. I t may represent aggregated matrix proteoglycan, deposited material from synovial fluid, or
possibly enzymes released by PMN and/or other cells.
The changes that occurred at the eroded surfaces in a
rather irregular fashion from a month onward suggested
some kind of repair process, as a pseudomembrane of
noncollagenous material appeared to be filling the sur-
face erosions. Grossly, these same surfaces appeared
quite smooth and functional.
The synovial histologic changes followed the pattern previously described of an acute Arthus reaction
developing into chronic synovitis (1.2). However, as
time passed, a slowly diminishing chronic response occurred, associated with the loss of antigen and “healing”
of the articular surfaces. Chronic arthritis induced with
pure Fn was short-lived. Its brevity may relate to the
rapid loss of Fn that could not be found by em beyond 2
days. A n explanation for the lack of complex persistence
was not forthcoming from these observations, but may
relate to the highly purified nature of the Ag used,
providing some form of immune suppression, and/or to
the class and affinity of antibody with which it could
interact. These features and data on the long-term specificity of synovial antibody synthesis are the subject of a
further communication (13).
Numerous aspects of this model have been
shown to resemble rheumatoid disease, including in
both the immunofluorescent demonstration of immunoglobulins and complement components in ACT surfaces
(2,3,15,22). Immuno-em studies of rheumatoid ACT
have suggested the presence of IgG and IgM (23). Our
preliminary observations (24) include 12 ACT biopsies in
RA which have shown intense and extensive concentrations of aggregated IgG and IgA with a specific form
and pattern and similarities to complexes described in
this communication. These data are still in a preliminary
phase of collection.
One might speculate that cyclic events involving
immune complex deposition, PMN cell attraction, and
ACT matrix degradation, suggested by these data in the
rabbit model. may be occurring continuously in RA.
The authors acknowledge the expert technical assistance of Mr. E. Winker and Ms. L. Wright and the diligent
secretarial work o f Ms. J . Pringle and Ms. J . Cooke.
They also extend their thanks to the Department of
Pathology at Queen’s University. especially Drs. D. M.Robertson and s. A . Bencosme and the em laboratory staff, without whose interest and cooperation this study would not have
been possible.
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experimentov, inflammation, induced, ferritic, arthritis, pathogenesis, chronic
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