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Synovial lymphocytes can indicate specific microbiologic causes of rheumatoid arthritis.

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ARTHRITIS & RHEUMATISM Volume 36
Number 10, October 1993, pp 135G1352
0 1593, American College of Rheumatology
1350
VIEWPOINT
SYNOVIAL LYMPHOCYTES CAN INDICATE
SPECIFIC MICROBIOLOGIC CAUSES OF
RHEUMATOID ARTHRITIS
DENYS K . FORD
In 1979, a study of patients with reactive arthritis (ReA) was initiated, in which synovial fluid lymphocytes were cultured in the presence of crude antigens
derived from organisms related clinically to the precipitation of ReA. The antigenic preparations were
crude because purification might have resulted in the
loss of relevant antigens. It was immediately found
that the 3H-thymidine uptake response was maximal
from lymphocytes exposed to the specific antigen that
was etiologically implicated in the individual case of
ReA. The findings applied to both enteric and sexually
acquired ReA (1-3); usually, simultaneously measured
peripheral blood lymphocyte responses were significantly lower or even absent. These observations have
been confirmed in studies from England, Finland, and
Germany (4-6).
The discriminatory capability of these lymphocytes derived from the site of disease enables them to
distinguish between the different enteric pathogens
causing ReA (7). It can be concluded from these
results that synovial lymphocytes from patients with
ReA can indicate the cause of the ReA by their
responses to appropriate microbiologic antigen stimulation in vitro.
Since 1986, intrasynovial chlamydial antigen
(8,9), DNA (lo), and RNA (11) have been found in
patients with sexually acquired ReA; similarly, in
patients with enteric ReA, salmonella (12), yersinia
From the Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, British Columbia,
Canada.
Denys K. Ford, MD: Emeritus Professor of Medicine.
Address reprint requests to Denys K. Ford, MD, The
Arthritis Center, 895 West 10 Avenue, Vancouver, British Columbia
V5Z 1L7, Canada.
Submitted for publication January 27, 1993; accepted in
revised form April 7 , 1993.
(13), and shigella (14) antigens have been observed in
the synovium. It therefore seems likely that the inflammatory lesion in the joint in ReA is the result of
antigen-specific synovial lymphocytes reacting to intrasynovial homologous microbiologic antigen (7).
In 1984, it was reported that synovial lymphocytes from some patients with persistent or recurrent
knee synovitis would respond to stimulation with the
same enteric or chlamydiahreaplasma antigens that
cause specific responses in ReA, even though these
patients did not have ReA (15). Subsequently, intrasynovial chlamydial antigen was found in 5 of 15
women with seronegative sligoarthritis (16), a disease
that is in many ways analogous to ReA. More recently,
synovial lymphocytes from patients with adult oligoarthritis have shown specific responses to stimulation
by chlamydial antigen, and this finding was associated
with the presence of chlamydial antigen in the synovium (17). Additionally, a study of boys with pauciarticular juvenile chronic iirthritis (18) has revealed
specific synovial lymphocyte proliferation in response
to chlamydial antigen in 6 cases and in response to
yersinial antigen in 11 cases.
None of the patients in the above investigations
had reactive arthritis by the usual criteria. These
observations therefore see.m to indicate that both
chlamydia and yersinia are etiologically related to
oligoarthritis in adults and to pauciarticular arthritis in
boys, and consequently, that these agents can cause
forms of arthritis other than ReA. Thus, the data
suggest that not only can the same clinical syndrome
be caused by multiple microbiologic agents (19), but
that the same agent can cause different clinical types of
arthritis (20). Moreover, it would also seem that investigation of the response of synovial lymphocytes to
VIEWPOINT: SYNOVIAL LYMPHOCYTE RESPONSES IN RA
microbiologic antigen stimulation is helpful in studying
types of arthritis other than ReA.
In distinction to ReA, rheumatoid arthritis (RA)
has had no known clinical associations or circumstantial evidence to suggest microbiologic causation. However, the recognition that arthritis is often a complication of rubella, parvovirus, Ross River fever, and
borrelia infections suggests that a number of microbiologic agents might conceivably be involved. During
the last 10 years, therefore, the response of synovial
lymphocytes to stimulation with a variety of microbiologic antigens has been examined in patients with “rheumatoid arthritis.” In the majority of cases, lymphocytes
were tested against chlamydia, ureaplasma, salmonella,
and candida, as well as the viral antigens of rubella,
mumps, adenovirus, cytomegalovirus (CMV), influenza,
parainfluenza, herpes type 1, and respiratory syncytial
viruses; other enteric and viral antigens were used in
certain cases.
Particular attention was given to cases in which
significant stimulation in response to one particular
antigen was shown to be consistent on repeated testing. Whenever possible, attempts were made to obtain
corroborative evidence from virus isolation, or the
demonstration of intrasynovial antigen, or intrasynovial agent-specific nucleotide sequences. However,
due to the sophistication and expense of the techniques required, this was possible only occasionally,
through collaborative arrangements. The following
summarizes the most suggestive findings, which represent -15% of the total cases studied.
In 5 cases, rubella antigen elicited significant
responses and in 3 of these patients, rubella virus was
isolated despite the absence of any history of recent
rubella infection (21,22). In 1 of these consistent
rubella responders, 16 repeated observations, employing a total of 22 microbiologic antigens, were made
over 7 years, and not only was intrasynovial rubella
virus isolated, but the patient was found to have a
defective immune response to rubella virus (23). Another patient from whom rubella virus was isolated
had RA with rheumatoid nodules.
In 6 cases, the maximal synovial fluid lymphocyte reaction was consistently found in response to
adenovirus, and in 1 of the 6, adenoviral nucleotide
sequences were demonstrable in a synovial biopsy
specimen (24).
In 3 cases, chlamydial antigen caused repeated
maximal stimulation. One of these patients had rheumatoid factor and radiographic bone erosions, and
synovectomy showed intrasynovial chlamydia1 anti-
1351
gen (25); another of the 3 also had rheumatoid factor in
high titer.
In 8 cases, the synovial lymphocytes responded
maximally to CMV antigen on 2 or more occasions
(26). One patient had RA with rheumatoid factor and
bone erosions, and each of 6 tests over 13 months gave
maximal responses to CMV. His synovial, but not
blood, lymphocytes responded to CMV stimulation in
vitro, with a significant increase in T4 DR+ cells. It
was not possible to correlate the synovial lymphocyte
responses with the demonstration of CMV virus, antigen, or DNA, since the expertise for performance of
such tests was not available in the given setting.
However, a recent report from Germany describes the
demonstration of CMV DNA in synovial tissue of
patients with RA; only in patients with both RA and
intrasynovial CMV DNA was the titer of CMVspecific antibodies in synovial fluid higher than that in
serum (27). Additionally, this same group reported in
1992 that intrasynovial B 19 parvovirus DNA was
found in some patients with RA (28).
Two other cases presented suggestive findings.
One RA patient had 9 tests over 6 years, each resulting
in maximal responses to mumps antigen, although his
blood lymphocytes never responded to mumps (29).
Another patient had 3 tests, with a maximal response
to salmonella antigen shown on each occasion.
In summary, the above-described investigative
approach, employing the relatively simple and microbiologically restricted techniques that were available,
seemed to show that, in -15% of “rheumatoid arthritis” patients, synovial fluid lymphocyte responses
suggested that the pathogenesis of their disease was
related to a particular microbiologic agent. It might
thus be that the use of this methodology, extended to
include a greater number of microbiologic antigens,
could prove as informative in RA as it is in ReA. The
recent developments of molecular biology now enable
us to manufacture individual antigens of specific infective agents. If diseases such as RA are due to aberrant
immune responses to particular antigens of specific
infective agents, then it is possible that we will soon be
able to correct specific defects. The development of
therapies with this objective may be a more attractive
approach than the use of treatments based on essentially “blind” attacks on the patient’s overall immune
system.
REFERENCES
1 . Ford DK, da Roza DM, Shah P, Wenman WM: Cell-mediated
immune responses of synovial mononuclear cells in Reiter’s
1352
syndrome against ureaplasmal and chlamydial antigens. J Rheumatol7:751-755, 1980
2. Ford DK, da Roza DM, Schulzer M: The specificity of synovial
mononuclear cell responses to microbiological antigens in Reiter’s syndrome. J Rheumatol 9561-567, 1982
3. Ford DK, da Roza DM, Schulzer M: Lymphocytes from the site
of disease but not blood lymphocytes indicate the cause of
arthritis. Ann Rheum Dis 44:701-710, 1985
4. Hermann E, Fleischer B, Mayet WJ, Poralla T, Meyer zum
Buschenfelde KH: Response of synovial fluid T cell clones to
Yersinia enterocolitica antigens in patients with reactive yersinia arthritis. Clin Exp Immunol 75:365-370, 1989
5. Gaston JSH, Life PF, Granfors K, Merilahti-Palo R, Bailey L,
Consalvey S, Toivanen A, Bacon PA: Synovial T lymphocyte
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Hughes R , Keat A, Panayi GS: Synovial T lymphocyte-specific
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7. Ford DK: Lymphocytes from the site of disease in reactive
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triggered reactive arthritis (letter). J Rheumatol 19500, 1992
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FORD
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correlate with distribution of HLA. Arthritis Rheum 27:11571164, 1984
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Rheumatol9:420-423, 1982
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Sequential studies on synovial lymphocyte stimulation by rubella antigen, and rubella virus isolation in an adult with
persistent arthritis. Ann Rheum Dis 44:564568, 1985
23. Ford DK, Reid GD, Tingle AJ, Mitchell L , Schulzer M:
Sequential follow up observations of a patient with rubella
associated persistent arthritis. Ann Rheum Dis 51 :407-410, 1992
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adenovirus is one cause of persistent or recurrent inflammatory
arthritis. J Rheumatol 20:31CL313, 1993
25. Ford DK, Reid GD, Magge S, Schumacher HR: Synovial
lymphocyte response to chlamydial stimulation associated with
intrasynovial chlamydial antigen in a patient with “rheumatoid
arthritis.” Arthritis Rheum 31:914-917, 1988
26. Ford DK, da Roza DM, Schulzer M, Reid GD, Denegri JF:
Persistent synovial lymphocyte responses to cytomegalovirus
antigen in some patients with rheumatoid arthritis. Arthritis
Rheum 30:700-704, 1987
27. Einsele H, Steidle M, Muller CA, Fritz P, Zacher J, Schmidt H,
Saal JG: Demonstration of cytomegalovirus (CMV) DNA and
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29. Ford DK, Stein HB, Schulzer M: Persistent synovial lymphocyte responses to mumps and adenovirus antigens. J Rheumatol
15:1717-1719, 1988
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