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How important are t cells in chronic rheumatoid synovitis.

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HOW IMPORTANT ARE T CELLS IN CHRONIC
RHEUMATOID SYNOVITIS?
GARY S. FIRESTEIN and NATHAN J. ZVAIFLER
The role of immunologic processes in the pathogenesis of rheumatoid arthritis (RA) is indisputable.
Histopathologic and ultrastructural studies of rheumatoid synovium show synovial lining cell hyperplasia,
along with subintimal chronic inflammatory cell
infiltrates that include T cells, B cells. and macrophages. Rheumatoid factor, anti-collagen and other
locally produced antibodies, and a number of soluble
mediators that contribute to joint destruction, such as
prostaglandins and collagenase, are produced in large
amounts by synovial tissue cells.
In most models of RA synovitis it is theorized
that T cells orchestrate the local inflammatory response. In these paradigms, an arthrotropic agent,
such as a virus or bacterial cell wall fragments, or an
“autoantigen,” such as type I1 collagen, proteoglycan,
or Ia molecules, serves as a stimulus for T cell
activation. The antigen-specific T cells preferentially
expand in the synovium and recruit and/or influence
other cells (including macrophages, B cells, and fibroblasts) through the elaboration of lymphokines. Although this might be true in the initial phases of RA,
the evidence of T cell primacy in established, chronic
synovitis is not definitive.
In this report, we challenge the “T cellcentric” paradigm of established RA based on analysis
of some predictions that flow from this model: 1) T
cells should proliferate and express high levels of
From the Division of Rheumatology. University of California San Diego Medical Center.
Supported in p;ut by NIH grants AR-39576 and AR-14196.
Gary S. Firestein. MD: Nathan J . Zvaifler. MD.
Address reprint requests to Gary S. Firestein, MD. Division of Rheumatology. H-81 IG, UCSD Medical Center, 225 Dickinson Street, San Diego, C h 92103.
Arthritls and Rheumatism, Vol. 33, No. 6 (June 1990)
activation antigens (e.g., transferrin and interleukin-2
[IL-2] receptors or la) on their surface; 2) the byproducts of activated T cells. like ?interferon (y-IFN)
or 1L-2, should be produced in the joint; 3) analysis of
locally accumulated T cells should demonstrate clonal
restriction that reflects the specificity of the inciting
antigen; and 4) therapy directed against T cells should
ameliorate the disease.
With regard to the first prediction, most articular T cells are surprisingly small and quiescent. CD4positive helper cells (the putative responders in the T
cell models) are usually located in perivascular regions, at a distance from antibody-secreting cells,
while CD8-positive cells are in closer proximity to B
cells (1). Mitotic figures are extremely rare throughout
the synovium. and < I % of DNA synthesis occurs in
the synovial lymphoid population (2.3). Occasional
cells within the lymphoid aggregates express Ki67, a
nuclear antigen found in cells that are not in the Go
phase (4). However, the majority of T cells that are in
the S phase are CD8-positive cells and not CD4positive helper cells. as might have been predicted
with a T cell-driven immune response (3). The expression of some cell surface activation markers, such as
transferrin and IL-2 receptors, is low on articular
lymphocytes (3,
and the level of IL-2 receptor messenger R N A (mRNA) is similar to that of resting
peripheral blood mononuclear cells (6). This phenotype is more typical of resting cells, although it does
not exclude a state of “post-activation’’ or arrested
activation. Although many synovial tissue and synovial fluid T cells express Ia molecules on their surface,
the amount is relatively low compared with that of
synovial macrophage-like cells (1). Moreover, the significance of la-bearing T cells in the rheumatoid
EDITORIAL
joint is clouded by the fact that comparable numbers of
T cells in effusions from patients with a variety of
other diseases (including gout) are Ia positive (7).
The second prediction of the "T cell-centnc"
paradigm is that products of T cell activation (i.e.,
lymphokines) should be synthesized and secreted in
the synovium. These T cell-derived molecules could
then spread in a centrifugal manner, altering the endothelium of adjacent blood vessels, causing the proliferation and differentiation of nearby B cells. and
directly influencing the macrophages and synoviocytes
in the lining above them. Ultimately, these soluble
mediators would diffuse into the synovial fluid. This
scenario is not consistent with most available data.
For instance, assays of IL-2 (6), 1L-3 (6), IL-4 (8),
y-IFN (9),and tumor necrosis factor p (TNF-P) (lo),
each of which is an important lymphokine produced by
activated T cells, have been performed on RA synovial
effusions and/or synovial tissues. In each case, the
concentrations of cytokines found are negligible in
comparison with either the amounts produced by
activated T cells in vitro or the amounts required to
induce a physiologic response in target cells ( I I ) . This
latter point is particularly pertinent, because articular
T lymphocytes are primarily of the memory type
(12.13) and are more resistant to stimulation by cytokines (14).
According to the third prediction, a restricted
population of T cells should migrate into the joint and
selectively proliferate in response to the putative antigen. The most sophisticated approach to this question is through the use of the tools of molecular biology
that examine the heterogeneity of T cell receptor
rearrangements. This method is capable of identifying
oligoclonal V, rearrangements involving as few as 1%
of the cells in a population. Using this technique,
restricted populations of T cells have been noted in the
cerebrospinal fluid from patients with multiple sclerosis (15) and in the bronchoalveolar lavage fluid from
patients with pulmonary sarcoidosis (16). Specific Vp
genes are also used preferentially in animal models of
autoimmunity in which the inciting antigen is well
characterized. as in experimental allergic encephalitis
(17). In contrast, although clonal dominance has been
reported in RA (18), data from investigators who have
studied T cells in RA do not support the notion of a
homogeneous T cell population in the rheumatoid joint
or in peripheral blood (19-23).
There are 2 caveats to this argument. First, it is
possible that the pertinent rearrangements in RA might
involve T cells that would not necessarily be detected
769
using p chain probes. This is particularly relevant
considering the current interest in heat shock proteins
(HSP) and mycobacterial antigens that might use the
y/S T cell receptor. It appears that $6 receptorbearing T cells are sequestered in the joint in RA (24).
and synovial fluid T cells proliferate in response to
HSP (25). Second. it is not known how prevalent
antigen-specific T cells must be in an immune response, that is, whether only a very low percentage of
cells within a lesion needs to be activated. For instance, in positive tuberculin skin test reactions (a T
cell-mediated delayed hypersensitivity response), less
than 1% of the cells contain immunoreactive IL-2
protein (26). Hence. it is possible that the methods
used might not be sensitive enough to detect such a
limited number of cells.
The fourth prediction is that therapies targeted
toward lymphocytes should be effective in treating
RA. Several modalities purported to be T cell specific
have been tried. including total lymphoid irradiation
(TLI), thoracic duct drainage, and cyclosporine. With
each, there appears to be some benefit, although
improvement is generally limited and temporary. In
fact, the suppression of T helper cell function persists
despite relapse of the joint disease following TLI. The
continued presence of serum rheumatoid factors has
been cited as evidence for polyclonal B cell activation
that does not require T cells (27). Furthermore, TLI
does not involve irradiation of the synovium. If RA is
caused by local accumulation of T cells and their
subsequent activation and proliferation in response to
an intra-articular antigen, then why does irradiation of
distant lymphoid sites provide relief! Certainly, the
efficacy of these therapies cannot be ignored, and T
cells likely do play a role, but other mechanisms of
perpetuating synovitis need to be considered as alternatives, or as complementary, to traditional paradigms
of rheumatoid synovitis.
In contrast to the evidence for T cell activation,
there is no question that macrophage-like cells and
fibroblast-like cells in the synovium are highly activated based on their morphology, surface la expression, and elaboration of cytokines (for a comparison of
cytokine production by various synovial cells, see
Table I ) . Products of these cells, such as 1L-I (28-31),
TNF-a (10). IL-6 (32,33), granulocyte-macrophage
colony-stimulating factor (GM-CSF) (34), macrophage
CSF (61, prostaglandins. and collagenase, are abundant in synovial fluids and synovial tissues.
Results of recent studies using in situ hybridization to quantify cytokine production at the level of
FIRESTEIN AND ZVAIFLER
770
Table 1.
Cellular sources of synovial cytokines in RA'
Produced by RA synovium
Products of T cells
11.-2
IL-3
I L-4
IL-6
yIFN
1°F-a
TNF-B
GM-CSF
Products of macrophagest
IL-l
IL-6
TNF-a
M-CSF (CSF-I)
a-IFN
GM-CSF
Products of fibroblasts$
IL-6
GM-CSF
+++
+
+
++
2
+
+++
+
* Production by rheumatoid arthritis ( K A ) synoviurn based on a
scale of - to + + + , where - = absent or negligible and + + =
present in large quantity. IL = inferleukin; IFN = interferon; TNP
= tumor necrosis factor; GM-CSF = granulocyte-macrophage
colony-stimulating factor; M-CSF = macrophage colony-stimulating
factor.
t Products are tissue macrophages and/or type A synoviocytes.
$ Products are tissue fibroblasts and/or type B synoviocytes.
-
gene expression confirm the findings of experiments
that detected high levels of secreted cytokines in
culture supernatants of synovial tissue cells and in
synovial effusions (35). For instance. IL-Ij3 and TNFa genes were expressed by large numbers of synovial
cells (- 10% and -5% of cells, respectively). Using a
fluorescence-activated cell sorter to separate enzymatically dispersed synovial cells into macrophages and
non-macrophages. only the macrophages were found
to express the IL-Ip and TNF-a genes, with more than
40% of the macrophages expressing the IL-10 gene
and 15% expressing the TNF-a gene. 1L-6 probes
hybridized to nearly 20% of R A synovial cells.
Although T cells can produce IL-6 under some
circumstances, in situ hybridization experiments
clearly showed that the vast majority of 1L-6 gene
expression occurs in thc non-macrophage. non-T cell
population, and that these cells are located mainly in
the intimal lining of the joint. GM-CSF and TGF-j3
gene expression were observed in a smaller percentage
of cells (1-2%). As predicted from our previous studies
on synovial y I F N production (9). the yIFN probe did
not bind to synovial tissue cells. Interestingly, very
little cytokine m R N A , including IL-Ij3. TNF-a, and
IL-6, was detected in mononuclear cells isolated from
synovial effusions. indicating that the synovium is the
source of most articular cytokines.
The cytokine profile of the rheumatoid synovium suggests an alternative to the traditional paradigms of T cell-driven perpetuation of synovitis; that
is, inflammation is sustained by factors produced by
neighboring macrophages and synovial fibroblasts in
the joint lining in a paracrine or autocrine model. Some
animal models support a non-T cell pathogenesis of
synovitis. For instance, synoviocytes from rats injected with Freund's complete adjuvant show evidence of activation (surface class I1 major histocompatibility complex antigen) before the onset of arthritis
or the influx of mononuclear cells in the synovial
membrane (36). Also, T cell-dependent autoantibody
production directed against type I1 collagen in the
MRL/I mouse arthritis model is probably triggered by
cartilage destruction and is. therefore, a secondary
phenomenon (37).
Many factors already identified in the joint
could participate in a paracrine/autocrine system and
explain lining cell hyperplasia, la induction, and synovial angiogenesis. A simplified schematic diagram of
the complex cytokine circuits that exist between synovial cells is shown in Figure 1. For example, 1L-1 and
TNF-a (synovial macrophage products) stimulate fibroblast proliferation and increase secretion of IL-6,
GM-CSF, and collagenase (32,3840). GM-CSF,
which is produced by synovial macrophages and ILIpstimulated or TNF-a-stimulated fibroblast-like
synoviocytes (unpublished observations). is a potent
inducer of IL-I secretion, and increases la expression
on macrophages (41,491. The latter activity is particularly interesting. since supernatants of cultured synovial tissue cells contain an Ia-inducing factor that is
neutralized by antibodies to GM-CSF but not to antiy I F N (42). GM-CSF is probably the elusive noninterferon macrophage-activating factor responsible
for the high levels of la antigens on the intimal lining
cells of the joint. TNF-a can synergize with GM-CSF
and probably contributes to macrophage HLA-DR
expression (42). The local production of cytokines by
macrophages and fibroblasts could also have an impact
on T cells and contribute to the modest degree of T cell
activation observed. B cell activation and rheumatoid
factor production might result from T cell-independent mechanisms or as-yet-undefined cell products.
An important prediction of the paracrinel
autocrine model of RA is that T cells are not necessarily sequestered in the joint in response to a specific
antigen: rather, they accumulate under the influence of
77 1
EDITORIAL
Angiogencsis
7
GM-CSF
1
Post Capillary Vcaule
lmmunoglobulin
Figure 1. Cytokine interactions in rheumatoid arthritis synovium. GM-CSF = granulocytemacrophage colony-stimulating factor; SC = synoviocyte: IL = interleukin: TNF = tumor
necrosis factor; MB = monocyte.
factors made in the lining. If this is true, however, then
the joint should contain T lymphocyte subsets in a
distribution like that in the blood, and this is not the
case. The synovium has an overrepresentation of
mature memory helper cells (the CDCpositive, 4B4/
UCH1,- I-positive subset), while naive 2H4-bearing
cells (the suppressor-inducer subset) are conspicuously absent (12). This can be explained by the fact
that the movement of lymphocytes from the circulation into the joint is not a random process. Their site of
egress is the postcapillary venules, notably through
those with "high" endothelium. Cytokines, IL-1 and
TNF-a in particular, increase the ability of T cells to
bind to and migrate through vascular endothelium via
the induction of adhesion molecules, such as the
intercellular adhesion molecule 1 (ICAM-I ) and/or the
lymphocyte function-associated antigen 3 (LFA-31,on
the surface of high endothelial venules (43,44). A
recent immunofluorescence study of RA synovium
demonstrated large amounts of these molecules on the
surface of synovial fibroblasts and endothelial cells
(45). The ligands for ICAM-I and LFA-3 (LFA-1 and
CD2, respectively) are expressed on all T cells, but are
found in' significantly greater amounts on mature 4B4-
positive cells (46). A consequence might be the preferential accumulation of cells with this phenotype in
inflamed synovium.
The observation of very late activation (VLA)
markers on lymphocytes has been cited as evidence of
in situ stimulation of T cells (47). In fact, 4B4 is an
antibody that recognizes the common p chain of VLA
(48). The VI,A heterodimers comprise a family of
important matrix proteins including collagen, fibronectin, and laminin. This suggests an alternative explanation for the accumulation of mature 4BCpositive
helper cells in connective tissues, namely, their retention as a result of adherence to matrix molecules.
Indeed, it makes sense teleologically to have a mechanism for stockpiling lymphocytes that have a memory
of prior exposure to antigens in inflammatory lesions.
The critical issue is not whether T cells are in the
synovium, but whether they are restimulated. If not,
they become little more than innocent bystanders
attracted by the inflammatory process-much
like
spectators at a fire.
The paracrine/autocrine model of RA described
herein does not identify the etiology of arthritis. It
does, however, attempt to explain the perpetuation of
FIRESTEIN AND ZVAIFLER
772
the local inflammatory response, based on t h e knowledge of the products of inflammation that are actually
measurable in the inflamed joint. T h e s e data suggest
that much of t h e tissue destruction in R A results from
activation of non-T cells. The corollary is that therapeutic endeavors aimed at interrupting the flow of mononuclear cells into the joint or controlling the activation of
synovial fibroblasts and/or macrophages will be more
successful than current methods of treatment.
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