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Clinical and Diagnostic Laboratory Immunology, July 1998, p. 427-429, Vol. 5, No. 4
Cellular Immunity in Osteoarthritis: Novel Concepts
for an Old Disease
Department of Medicine, Uniformed Services
University of the Health Sciences, Bethesda, Maryland
20814,1 and
Department of Clinical
Physiology, Walter Reed Army Institute of Research, Washington, D.C.
20307-51002
Osteoarthritis (OA) is the most
common chronic joint disease. A vast majority of the elderly have
radiographic signs of OA, and the majority of those experience clinical
manifestations such as pain, joint destruction, and long-term
disability. There is little disagreement that OA is a heterogeneous
disease. In some cases, joint trauma can lead to accelerated or
premature secondary OA, which may represent a common degenerative
pathway. Nevertheless, in other cases, an initiating factor cannot be
pinpointed. OA is believed to be a disease of the articular cartilage
but the agent(s) or event(s) that triggers and perpetuates the
relentless cartilage destruction remains unknown. It is clear now that
this constellation of events is not associated with aging, and
traumatic, hormonal, environmental, and genetic factors are the obvious
culprits in the pathogenesis of OA.
The participation of the immune system and of inflammatory mediators in
the pathogenesis of OA has been a subject of debate, which has led
even to different names for the disease, like "osteoarthrosis" or
"degenerative joint disease." It is known that periods of profound inflammation appear during the course of the disease in many patients and that inflammatory infiltrates can be found in the synovial membrane
in OA joints. It is of importance to find out the exact contribution of
immune system-mediated damage since this not only would improve our
understanding of the disease but might also alter our therapeutic
approaches. Current treatment of OA is symptomatic, empiric,
unsatisfactory, and totally unable to either halt, delay, or modify the
progressively relentless articular destruction that characterizes the
course of OA (reviewed in reference 4).
T cells in Ag (or autoAg)-mediated inflammatory disease.
T
cells recognize antigen (Ag) using variable domains of the clonotypic
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/
(or 
/
) chains, which are part of the specific cell
surface Ag receptor (T-cell receptor [TCR]). This recognition leads
to activation, proliferation, and secretion of soluble products (e.g.,
cytokines); expression of novel cell surface markers; acquisition of
effector functions; or anergy, tolerance, and apoptosis
(32). The presence of specific Ag(s) leads to preferential
(clonal) expansion of T cells bearing the relevant clonotypic TCRs.
Polyclonal T-cell expansion should indicate either nonspecific or
superantigen-mediated processes. On the other hand, while monoclonality
is a marker of neoplasia, oligoclonal T-cell expansion is considered to
be an indirect indicator of the presence and persistence of specific Ag(s).
) (TH1 pattern). In contrast to these cellular immune
responses, the TH2 cytokine pattern is associated with the release of
IL-4 and IL-5 encountered in allergic diseases and parasitic infections
(22).
/
or the nonconventional / clonotypic TCR chains. Different dominant epitopes of the suspected autoAg (myelin basic protein) in MS
are identified by T-cell clones in different patients. These antigenic
epitopes give rise to a few dominant clones, which persist for a long
time in the same patient (1, 33, 34). Human MS and
experimental allergic encephalomyelitis, the animal model counterpart
of human MS, are characterized by cellular immune abnormalities and TH1
type cytokine production (12).
Restricted repertoires in the use of genes encoding the TCR variable
regions have also been reported for patients with SLE. Clonal expansion
of the T cells has been found in the peripheral blood of lupus
patients, and the TCR -chain repertoire is biased (20). T
cells bearing either / or / TCRs have been clonally expanded in vitro and have been shown to react preferentially with
histone epitopes (24). The properties of these
histone-reactive lupus T-cell clones have been well characterized. They
represent clones with helper activity despite their phenotype, which
commonly does not belong to the classic CD4+ subtype.
Moreover, recent studies revealed other interesting properties of these
autoAg-specific clones from patients with SLE. First, the clones
recognize their respective histone epitopes in a major
histocompatibility complex-unrestricted fashion, and second, they
become readily activated without the need for CD4 co-cross-linking
(26).
Recent studies on the nature and properties of the infiltrating cells
in GCA also yielded valuable information. T cells found in the
inflammatory granulomatous lesions of GCA have undergone clonal
expansion and secrete a restricted pattern of cytokines consistent with
a TH1 profile. Only a few T-cell clones were identified in the lesions,
and the T cells that are responsible for the production of cytokines
like IFN- were even fewer. These studies indicate that a small
number of specifically activated T cells represent the pathogenetically
relevant cells (16, 17, 31).
In systemic sclerosis the skin-infiltrating /-bearing T cells
display oligoclonal expansion. It is interesting that the same clones
have been identified in the peripheral blood and in other organ
lesions. The same clones persist in the same patient over long periods
of time, but different patients display different T-cell clones,
suggesting that even if the suspected autoAg is a single macromolecule,
different epitopes are involved in different patients (36).
For patients with RA several studies have shown the presence of
oligoclonal T cells in the peripheral blood, rheumatoid nodules, and
the synovial membrane in affected joints. These T-cell clones bear
either / or / TCRs, and interestingly, the same clones have
been identified in the synovial membranes of different affected joints
and the peripheral blood of the same patient (9, 11, 14, 19,
21).
Oligoclonal T cells have been found in psoriatic skin lesions
(2), in the pancreas in insulin-dependent diabetes patients (35), in the jejunum in celiac disease patients
(23), in the peripheral blood of patients with Behcet's
disease (3), in labial lacrimal lesions of patients with
Sjögren's syndrome (29), and in cells obtained by
bronchoalveolar lavage from patients with sarcoidosis (8).
Different T-cell clones have been identified in patients with different
subtypes of juvenile rheumatoid arthritis (7).
Oligoclonality is not a feature of autoimmune diseases only, since it
has also been reported for T cells of the peripheral lymphoid organs of
patients with human immunodeficiency virus infection (18) as
well as in the tumor-infiltrating lymphocytes of patients with bladder,
renal-cell, and other malignancies (5, 15, 30).
In the final stages of the so-called collagen diseases nonspecific
inflammation is the prevalent feature. Thus, the presence of T cells in
such inflammatory infiltrates is no surprise. It is of interest to
determine whether these infiltrating T cells are activated and
furthermore if they are activated in a specific manner by an
identifiable Ag. Specific activation of T cells means TCR-mediated
activation and the production of IL-2.
Specifically activated T cells in the synovium in OA. In this issue Sakkas et al. report the presence of specifically activated T cells in the inflammatory infiltrates of synovial membranes obtained from patients with OA (25). The presence of inflammation in some patients with OA is well known, even though it is not generally considered a characteristic feature of the disease. Since this is a chronic form of inflammation, the presence of T cells in such infiltrates is not surprising. Indeed, T-cell aggregates were found in 65% of patients with OA. Other groups have previously reported accumulation of inflammatory cells in synovial tissue derived from patients with OA (6, 10).
Do the OA synovial-tissue-infiltrating cells represent oligoclonally expanded T lymphocytes? It has been reported that a limited number of activated T-cell clones, as detected by Southern blotting, predominate at the site of tissue injury in rheumatoid synovial membranes as well as in synovial tissue form patients with OA (28), suggesting that these disorders may represent two clinical syndromes that share a pathogenic process. It may also be stated that additional genetic or environmental factors may modify this process and direct it towards the OA or RA clinical picture. Do T cells become activated following their homing at the OA synovial membranes, or do they represent activated cells recruited from the peripheral blood? Sakkas et al. report that the T cells that belong to the aggregates encountered in the synovial membrane in OA patients bear early (CD69), intermediate (CD25 and CD38), and late (CD45RO and HLA class II molecules) cell surface activation markers. The detection of early and late activation molecules on the surface of synovial-membrane T cells indicates that these cells homed inappropriately in the synovial membrane, where they were exposed to locally available and underwent activation. It should be noted that these Ags may represent autoAgs or environmental Ags that are deposited in the synovial tissue. Are the activated T cells Ag specific or nonspecific? The authors show that in approximately 50% of OA patients synovial-membrane T cells produce IL-2 and IFN- but not IL-4, i.e., they show a TH1 pattern. T
cells that infiltrate the synovial membranes of patients with RA also
produce IL-2 and IFN- but not IL-4. It should be noted that other
groups have found a mixed, TH1/TH2 pattern (13). While the
presence of IL-2 transcripts denotes specific (TCR-mediated) T-cell
activation, the presence of IFN- may have different implications
that are of importance in the pathogenesis of OA. Recently, it was
claimed that macrophage activation products (IL-1, tumor necrosis
factor alpha), expression of HLA class II molecules on the surface of
chondrocytes, and decreased collagen synthesis are factors that
contribute to the pathogenesis of OA (4). All these may be
attributed to the action of IFN-.
This study utilized synovial specimens from patients undergoing joint
replacement surgery. Therefore, the specimens did not originate from
patients with early joint disease, and the study did not examine
synovial T-cell biology at the onset of the disease. At this final
stage it is thought that the inflammation encountered in RA patients is
not characteristic as in earlier phases of the disease and that at this
point the classic inflammatory nature of the disease reverts to a more
degenerative pattern. This may be responsible for the surprising
similarity of finding for RA and OA infiltrates described in this
study. The advanced stage of the disease at the point of study
precludes the drawing of conclusions on early pathogenetic events. The
nature of the initial insult in OA remains elusive. Nevertheless, the
present study offers a new insight into the nature of more advanced
disease, which is the problem every rheumatologist faces in everyday
clinical practice.
Based on the evidence presented in the above study, in a good
proportion of patients with OA a new player is revealed. The presence
of T-cell aggregates undergoing in situ activation in a rather specific
manner and the preferential production of TH1 cytokines which mediate
macrophage activation among other functions support the hypothesis that
a cell-mediated specific immune response is occurring in the OA
synovium. The potentially antigenic or autoantigenic driving force(s)
for this response is totally unknown.
Whatever the responsible Ag may be, therapeutic approaches such as TCR
targeting with specific vaccines or anergy-inducing peptides may be at
reach for patients with inflammatory OA. The observed TH1/TH2 imbalance
should ignite considerations regarding therapeutic cytokine
manipulation. Finally, the interesting data of this study put into
question the rather dogmatic view that OA is a noninflammatory disease.
As many as 50%, at least, of advanced-OA patients clearly do not
conform to this rule.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Clinical Physiology, Walter Reed Army Institute of Research, 14th & Dahlia St. NW, Bldg. 40, Rm. 3078, Washington, DC 20307-5100. Phone: (202) 782-9146. Fax: (202) 782-3160. E-mail: gtsokos{at}usa.net.
The views expressed in this Commentary do not necessarily reflect the views of the journal or of ASM.
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Clinical and Diagnostic Laboratory Immunology, July 1998, p. 427-429, Vol. 5, No. 4
1071-412X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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