вход по аккаунту


Pathogenesis of spondylarthropathies.

код для вставкиСкачать
Val. 38, No. 11, November 1995, pp 1547-1554
0 1995, American College of Rheumatology
Persistent Bacterial Antigen, Autoimmunity, or Both?
The term spondylarthropathy applies to a group
of different, although closely related, diseases: ankylosing spondylitis (AS), reactive arthritis (ReA), a
subset of psoriatic arthritis (PsA), arthritis/sacroiliitis
in inflammatory bowel disease (IBD), and undifferentiated spondylarthropathy . All these diseases have
HLA-B27 association, sacroiliitis, peripheral joint involvement, and some extraarticular manifestations in
common (1). Their pathogeneses are not clear (2).
Several characteristics make the spondylarthropathies uniquely interesting among the immunemediated diseases: the detection of bacterial antigens
in synovial fluid and synovial membranes in ReA (3,4),
the finding of a specific synovial fluid T cell response
to the triggering bacterium in ReA (5-7), improved
understanding of the role of the major histocompatibility complex (MHC) class I molecule in the immune
response (8), and results indicating that HLA-B27
might behave not simply as a restriction element
(9,lO). They offer a special opportunity for evaluating
the interaction between bacterial antigen, MHC molecules, and T cells, which leads either to hypersensitivity (damage from the immune response rather than
direct damage to cells by microbes) or to autoimmunity.
Evidence for and against the following hypotheses will be discussed herein (Table 1): 1) Bacterial
antigen persisting in the joint is presented, through
HLA-B27, to CD8+ T cells, which then mediate an
Supported by a grant from the “Bundesministerium fur
Forschung und Technologie’’ and by a grant from the “Eberhard
Bode Stiftung.”
Joachim Sieper, MD: Klinikum Benjamin Franklin, Free
University of Berlin, Germany, and the Deutsches Rheumaforschungszentrum Berlin, Germany; Jurgen Braun, MD: Klinikum
Benjamin Franklin, Free University of Berlin.
Address reprint requests to Joachim Sieper, MD, Department of Medicine, Rheumatology, Klinikum Benjamin Franklin,
Hindenburgdamm 30, 12000 Berlin, Germany.
Submitted for publication February 7, 1995; accepted in
revised form June 1, 1995.
irnmunopathologic response. 2) HLA-B27-positive individuals fail to mount the effective CD8+ response
needed for eliminating bacteria resident in the joint,
with an ensuing immunopathologic response caused
by CD4+ T cells. 3) Autoimmunity is evoked by
bacteria in the joint cross-reacting with self antigens
that are presented by HLA-B27 to CD8+ T cells. 4)
Finally, HLA-B27-derived peptides are presented by
class I1 MHC to CD4+ T cells, and tolerance (or
“ignorance” [ 113) of these peptides is terminated by
cross-reactivity with bacterial peptides.
Bacterial antigen persisting in the joint as the cause of
Thus so far, the hypothesis that spondylarthropathy is caused by the persistent presence of bacterial
antigen in the joint has been confined to ReA. Causative bacteria have not been definitely identified in the
other spondylarthropathies, although some have been
suggested, such as Klebsiella pneumoniae in AS, gut
bacteria in IBD (because of mucosal lesions), and skin
bacteria such as streptococci in PsA (because of skin
lesions). A pathogenetic mechanism related to that in
IBD could apply to AS and other spondylarthropathies, because gut lesions are also found in some
patients with these diseases (12). Chlamydia trachomatis, Yersinia enterocolitica, Salmonella typhimurium, and Shigella jlexneri are the most likely causes
of urogenital or gastroenteral infection preceding ReA
(13). All of these bacteria are either obligate (Chlamydia) or facultative intracellular bacteria.
CDS response in spondylarthropathies. Surprisingly little is known about the immune response to
infection by these pathogens in humans. In general,
the immune system recognizes foreign antigen in a
way that is dependent on their cellular location. The
class I1 MHC antigen processing pathway presents to
Table 1. Hypotheses of T cell-mediated pathogenesis in the spondylarthropathies*
1 . HLA-B27 presents persistent bacterial antigen
to CD8 cells.
2. HLA-B27 inhibits the protective antibacterial
CD8+ immune response: dominant CD4
3. HLA-B27 presents self-antigens to CD8 T cells.
4. HLA-B274erived peptides presented by class
I1 MHC molecules become target of autoimmune attack by CD4 T cells.
One (or a few) conserved arthritogenic epitope
shared by many triggering bacteria.
HLA-B27 molecule is not involved. Rather, a
molecule encoded by an HLA-B27-linked gene
interferes with normal processing of bacterial
HLA-B27 captures the protective epitope(s) from
other potentially more effective class I MHC
HLA-B27-restricted CD8 repertoire is biased
toward inhibitory (?Th2) cytokines.
Cross-reactivity with a conserved bacterial epitope.
A cross-reacting bacterial peptide awakens a
response to an HLA-B27 peptide not normally
noticed by CD4 T cells.
= major histocompatibility complex.
CD4+ T cells peptides from proteins that are either
extracellular or have access to the endosomal pathway. The class I MHC processing pathway presents to
CD8+ T cells peptides from proteins that are either
cytosolic or nuclear (but able to enter the cytosol) (8).
Proteins of extracellular pathogens or intracellular pathogens residing in vacuoles (e.g., Chlamydia,
Yersinia, and Salmonella) are normally presented by
pathway 11, and pathogens with access to the cytoplasm (e.g., Shigella) by pathway I. However, the
ReA-triggering bacteria, Salmonella (14,15), Yersinia
(16), and C trachomatis (17,18), can also induce a
CD8+ T cell response. The mechanism by which they
do so is unknown, as is its relevance to an effective
immune response against these bacteria. For Shigella,
one might speculate that the CD8 response will be
found to be as important (19) as it is for Listeria (20),
because of the similarity in the intracellular behavior
of these organisms. In the context of the HLA-B27
association, therefore, the question arises as to
whether an arthritogenic bacterial peptide presented
by HLA-B27 to CD8+ T cells drives the pathogenesis.
Information acquired to date indicates that the
synovial response of T cells to bacterial antigens has,
with few exceptions (16), been confined to CD4+ cells
in ReA (6). There could be various reasons for this.
First, CD8+ T cells may play no role at all in the
immune response to ReA-associated bacteria, in
which case another explanation for the HLA-B27
association has to be found, as will be discussed below
with regard to autoimmunity. Second, technical difficulties may impede presentation via pathway I in in
vitro experiments. In that case, the CD8+ response
may still play an important role in the immunopathol-
ogy (hypothesis 1 in Table l), as has been shown for
viruses (21) and bacteria such as Mycobacterium tuberculosis, Listeria monocytogenes (22), or Plasmodiumfalciparum (23). CD8+ T cells have been found
recently in -30% of synovial fluid mononuclear cells
from ReA patients (24) and in -20% of cellular infiltrates in the synovial membrane of the joint that is
most pathognomic in the spondylarthropathies, the
sacroiliac, suggesting that CD8+ T cells may indeed
play a role in the disease pathogenesis (25).
A third possibility is that the CD8+ response is
crucial for elimination of bacterial antigen, and is
somehow inhibited in B27-positive individuals. This
failure might permit ongoing stimulation of CD4+ T
cells, which in turn could mediate an immunopathologic response in the joint (hypothesis 2 in Table I). It
has been shown in one family that B27-positive members could not present certain peptides that are normally presented by B27 to T cells (26,27). Because this
was not due to a defect in the B27 molecule itself, an
alteration in antigen processing or transportation that
is genetically linked to the B27 gene has been suggested. Differences between patients and healthy controls in the proteasome genes, responsible for protein
degradation in the cytoplasm, or the transporterassociated proteins (“TAP”) genes, responsible for
the transport of peptides through the endoplasmatic
reticulum, have not been found to date. However, the
possibility of such a difference has not been excluded,
and furthermore, other ill-defined mechanisms might
lead to qualitatively or quantitatively different epitope
presentation (28).
Another version of this hypothesis is that B27
itself does not present an arthritogenic antigen effec-
tively to CDS+ T cells. This could result either from
competition for an epitope with the other class I MHC
molecules present, or from competition of different
epitopes for HLA-B27 (29). Regarding the first possibility, a hierarchy of peptide affinities for different class
I1 MHC molecules has been suggested to explain the
complex class 11 MHC genetics of insulin-dependent
diabetes mellitus (30). We suggest that this hypothesis
could also apply to class I MHC molecules. Protection
against a microbe would fail if a dominant peptide has
a higher affinity for B27 but can induce an effective
immune response only if presented by another class I
MHC molecule. In that case, the immune response
would depend on what other class I MHC molecules
besides B27 were present. It has been reported recently that competition among class I MHC molecules
for the same peptide can alter the immune response
(31). Coexpression of HLA-B8 and HLA-B*2702 prevented the presentation of influenza-derived immunodominant peptides by HLA-B8 to CD8+ T cells,
through competition for the peptide occurring between
the 2 HLA class I molecules. A higher susceptibility to
AS in B27-positive individuals if HLA-Bw60 is also
present has indeed been found (32).
Yet another version of this hypothesis is that
the B27-restricted CD8 response is somehow biased
toward inhibitory (in this context presumably Th2)
cytokines (33).
Immunodominant antigens. If the immune response is driven by a persistent bacterial antigen and if
this antigen is presented by B27, then this would need
to be a common antigen shared by all the pathogens
that are implicated in the pathogenesis. In most cases
of ReA, the triggering bacterium can be identified by
means of an antigen-specific proliferative response of
synovial fluid T cells (5-7,34-37). Each bacterium has
several intracellular antigens recognized by CD4+ T
cells. The membrane proteins that are important for
the humoral response are hardly recognized by synovial T cells of Chlamydia- or Yersinia- induced ReA
patients (38-40). This correlates nicely with the downregulation of bacterial membrane proteins and upregulation of the 60-kd heat-shock protein observed
during persistent infection of cells with C trachomatis
in vitro (41), a situation similar to that in arthritis. It
has been shown recently that intracellular protein
concentration is correlated directly with antigenicity
in Listeria infection, thus emphasizing the importance
of the amount of protein expressed, for immunodominance (28).
Among the immunodominant proteins of Yer-
sinia and Chlamydia are the highly conserved ribosomal proteins L2 and L23 and the 19-Kd subunit
of the urease of Yersinia (40); the conserved 18-kd
histone-like protein and the 60-kd heat-shock protein
of C trachomatis are also immunodominant in ReA
(39). Thus, the specificity of the CD4 response for each
bacterium and the presence of different immunodominant antigens for Chlamydia and Yersinia are evidence against CD4+ T cells recognizing a common
bacterial antigen.
The situation might be different for the class
I-restricted CD8+ response. This is, as with other
bacteria such as Listeria, narrowly confined to a few
proteins and often to only 1 epitope on each (28). This
makes it more likely that CD8+ T cells would recognize a common epitope shared by different bacteria.
The identification of an immunodominant antigen for
CD8+ T cells might help answer the question of
whether such an antigen is shared by several ReAassociated bacteria. It is less clear how frequently
such an epitope is located on a protein that is also
immunodominant for CD4+ T cells.
Persistent bacterial antigen: only proteins, or live
bacteria? Chlamydia, Yersinia, and Salmonella infect
mainly epithelial cells and macrophages, and it is
known that they can persist for a long time in macrophages. There is growing evidence that Chlamydia can
be detected in synovial fluid and synovial membrane
not only in acute, but also in chronic, forms of ReA
(42). The detection of chlamydia1 DNA (43) and RNA
(42,44) confirms that whole viable organisms are likely
to be present. However, all attempts thus far to find
Yersinia DNA in the joint have failed, in spite of the
presence of Yersinia antigen detectable by immunologic techniques (45,46). This may merely represent a
technical difficulty, or there may be a genuine difference between Yersinia and Chlamydia. The latter
possibility is supported by the fact that antibiotic
treatment seems to decrease the duration of illness in
patients with Chlamydia-induced ReA, but not in
patients who have been infected with Yersinia or
Campylobacter (47). Persistent elevation of Yersiniaspecific IgA levels in ReA is evidence for persistence
of Yersinia in the gut mucosa (48), from which bacterial protein might reach the joint. Identification of
Salmonella DNA or RNA has not yet been attempted.
In contrast, Shigetla infects mainly epithelial
cells (although a special role for macrophages has
also been demonstrated recently) (49), where it produces only an acute infection, similar to that of Listeria; long-term intracellular persistence seems unlikely
and has not been demonstrated. Shigella is a crucial
pathogen in terms of this entire discussion, because
Shigella-induced ReA has the highest B27 association
and the highest association with complete Reiter’s
syndrome and with a chronic course of ReA (36,50).
Therefore, a study in which the (PCR) technique is
used to investigate for the presence of Shigella in the
joint in Shigella-induced ReA is eagerly awaited.
Why is the presence or absence of live organisms in the joint so informative? Only proteins (and
not, for example, lipopolysaccharide) can induce the
specific T cell responses present in ReA, and it is
highly improbable that proteins could remain undegraded inside cells over months or years. Although
there is some debate about how long the immune
system can maintain memory without being restimulated by antigen (5 l), the higher bacteria-specific T cell
frequency in synovial fluid compared with peripheral
blood provides evidence that a local antigen in the
joint is responsible for T cell stimulation (52,53).
Debris transported to the joint from bacteria residing
elsewhere should be presented only as exogenous
antigen, via antigen presentation pathway 11.
Taken together, the presence of bacterial antigen in the joint and an antigen-specific CD4+ T cell
response provide evidence that locally persistent bacterial antigen drives the immune response in ReA.
However, this does not explain the role of CD8+ T
cells and of HLA-B27. Furthermore, the failure to
detect live Yersinia in the joint and the improbability
of chronic persistence of Shigella cast doubt on the
hypothesis of a bacterium-derived arthritogenic peptide presented by HLA-B27. We must take into account the different biologic features of the ReAassociated bacteria, and also the pathogeneses of the
other spondylarthropathies. Although it is possible
that the ReA-associated bacteria play a causative role
in the other Spondylarthropathies, the bacteria, that
are also usually discussed in this context (although
direct evidence is missing) such as Klebsiella and
Streptococci, are extracellular, and should therefore
be presented by class I1 MHC molecules only.
Autoimmunity as a cause of spondylarthropathy
Are there perhaps other explanations for the
association of bacteria, HLA-B27, and disease manifestation? Although cross-reactivity between bacterial
peptides and self peptides on the humoral level is
unlikely (54), such cross-reactivity could occur at the
T cell level and could result in breakage of tolerance
(or “termination of ignorance”), leading to autoimmunity (hypothesis 3 in Table 1). Under certain circumstances, peptides from different proteins can crossreact even if they share only 2 or 3 critical positions in
the peptide nonamer (55). How tolerance can be
broken has been clearly shown with mice transgenic
for the lymphocytic choriomeningitis virus (LCMV)
glycoprotein gene linked to an insulin promoter, which
is expressed exclusively in the insulin-producing cells
of the pancreatic islets (56). Autoimmune diabetes
occurred only when these animals were infected with
live LCMV, in which case the T cells invading the
islets were mainly anti-LCMV CD8+. Additional proteins of the virus were evidently needed to break
tolerance, presumably by generating inflammation,
and possibly via intermolecular help (1 1).
As has been discussed above, the immunodominant proteins of Chlamydia and Yersinia seem to be
highly conserved, not only between different bacterial
species but also between prokaryotes and eukaryotes.
The L23 ribosomal protein has 32% identity and an
overall homology of 56% between YerJinia and humans (40). The B27-binding peptides derived from
such proteins might be highly cross-reactive or even
identical between humans and bacteria. Presentation
of such peptides by B27 could thus lead to autoimmunity. All of the known immunodominant proteins of
Chlamydia and Yersinia are nuclear and/or cystosolic.
The hypothesized self peptides might therefore be
derived from self proteins with a similar distribution,
in which case they would be presented preferentially
via the class I pathway to CD8+ T cells.
Two recent findings suggest another possible
form of autoimmunity (hypothesis 4 in Table 1). First,
naturally processed self peptides extracted from class
I1 MHC molecules comprise predominantly peptides
derived from MHC molecules expressed on the same
cell (10). Furthermore, MHC-derived promiscuous
self peptides, capable of binding to multiple HLA-DR
alleles, have been identified. Which self peptide from
which MHC molecule is presented by class I1 MHC
depended on the HLA type. In another study, self
peptides eluted from HLA-DR4 molecules were derived mainly from HLA class I heavy chain molecules,
preferentially from HLA-B molecules (57). Second,
the HLA-B27 transgenic rat model of spondylarthropathy depends on a high copy number of B27 genes
(9), and the disease can be transferred to low-copy B27
transgenic rats only by bone marrow cells expressing a
high density of B27 molecules on their surface (58).
T cell transfer is not effective, although T cells are
needed for the rats to get the disease. Furthermore,
germ-free animals do not become ill, indicating that
bacteria are needed either to be presented by HLAB27 or to break tolerance to self antigens (59).
Given these findings, a hypothesis based on
presentation of B27-derived peptides by class I1 MHC
molecules is worth considering. This could depend on
the class I1 MHC allele (a DR1 association in AS
patients has recently been found [Wordsworth P:
personal communication]) and/or on the level of HLAB27 expression, as in the B27 transgenic rat model.
Differential expression of class I MHC genes in human
tissues has been reported (60,61), and a role in the
pathogenesis of diabetes mellitus postulated (62).
However, the importance of this in terms of disease
pathogenesis is less clear. We have reported that
HLA-B27 is expressed in inflamed tissue of the sacroiliac joint (25), but the level of expression in different
tissues of B27-positive patients or in B27-positive
spondylarthropathy patients versus B27-positive
healthy controls has not been compared. One study
performed with peripheral blood mononuclear cells
did not demonstrate a significant difference (63). Differential B27 expression on cell surfaces could conceivably be due to polymorphism in the promotor
region, as has been proposed for the X and Y boxes in
the promoter-proximal region of class I1 MHC genes
Tolerance to B27 could be broken by crossreactivity between B27 peptides and bacterial peptides. In this context, 2 recent reports are of interest:
1 study demonstrated that B27 peptides show the
highest homology of all class I MHC molecules to
gram-negative enteric bacteria (66), and the other
showed that the 2-Md plasmid of Shigella, which
shows some homology with HLA-B27, was present
only in arthritogenic, and not in nonarthritogenic,
shigellae (67). Support for a crucial role of B27-derived
peptides in the pathogenesis of spondylarthropathy
comes also from a study showing reactivity of peripheral blood mononuclear cells to a B27 peptide in
patients with HLA-B27-associated uveitis (a disease
related to spondylarthropathy) but not in controls (68).
Furthermore, in an animal model of experimental
uveitis, oral tolerance could be induced by feeding the
animals the same B27 peptide (68).
An alternative possibility, not related to crossreactivity, is that cryptic or latent self epitopes in the
B27 molecule or other self molecules become able to
provoke a response as a result of nonspecific inflam-
mation (29). This could occur, for example, after
bacterial infection or trauma.
Persistent bacterial antigen and autoimmunity
How does this discussion about autoimmunity
fit with the evident presence of live Chlamydia in the
joints of some patients? The presence of bacteria
either in the joint or elsewhere in the body could lead
to a continuous breakage of tolerance to B27 peptides
and therefore to a more chronic course of disease.
Thus Chlamydia-induced ReA, with its greater likelihood of live bacteria in the joint, shows a higher
frequency of chronicity (-40%, compared with 1 s
20% in enteric ReA) (69). However, bacterial persistence might not be a universal prerequisite for chronicity in B27-positive patients (see discussion above
regarding autoimmunity). B27-negative ReA might
represent a different disease, in which persistent bacterial antigen is necessary to drive the inflammation, as
in Lyme disease (although the possibility of autoimmunity has also been discussed in that disease) (70).
The typical pattern of joint involvement is not unique
to the spondylarthropathies: a similar pattern with
asymmetric involvement of the lower limb joints is
also found in other infection-mediated rheumatic diseases such as Lyme arthritis. This view is also supported by the fact that B27-negative ReA patients
frequently lack the extraarticular and/or spinal symptoms typical of the spondylarthropathies (7 1).
Cytokines in the pathogenesis of spondylarthropathy
Undoubtedly, cytokines are of crucial importance for mounting an effective immune response
against intracellular bacteria. Thl cells, mainly secreting interferon- y (IFNy), help to eliminate these bacteria while Th2 cells, mainly secreting interleukin-4
(IL-4) and IL-10, prevent effective elimination (72).
We have shown recently that IL-4 was more often
present in ReA patients compared with rheumatoid
arthritis patients, possibly mediating bacterial persistence in the joint by inhibition of IFNy effects (73).
The importance of an optimal IFNy concentration for
effective elimination of Chlamydia and Yersinia has
recently been demonstrated in vitro (41) and in an
animal model (74,75). Therefore, in those cases of ReA
and spondylarthropathy in which bacterial antigen is
present in the joint, the presence of IL-4 may indicate
an ineffective immune response. The situation regarding Thl and Th2 in autoimmunity is less clear, al-
though in this case IL-4 might act beneficially by
suppressing the immune response (76).
Summary and conclusion
We have discussed partially mutually exclusive, partially overlapping models for the pathogenesis
of the spondylarthropathies. Not all possibilities have
been presented here; others are discussed elsewhere
(77,78). Furthermore, we have not addressed the issue
of B27-negative spondylarthropathy . However, in our
opinion, the key to understanding the pathogenesis of
the spondylarthropathies lies in the interaction between the class I MHC molecule HLA-B27 and the T
cell response. Although a T cell response driven by
persisting bacterial antigen is still an attractive hypothesis, it does not explain all the known aspects of
spondylarthropathy pathogenesis. The possibility of
autoimmunity triggered by bacterial infection needs
also to be considered, especially the new idea of
HLA-B27-derived peptides presented by class I1
MHC molecules. The predominant involvement of
joints is not easily explained in the case of autoimmunity. Cross-reactivity to joint-specific structures such
as type I1 collagen (79) and/or bacteria inside the joint
at the beginning of the immune response, with induction of local autoimmunity, might be involved.
Most of the issues raised here could be tested
by experiment, and we can expect to learn soon whether
any of these models will explain the pathogenesis, or if
we have to look further. The PCR technique will
facilitate the search for bacteria not only in peripheral
joints, but also now in sacroiliac biopsy samples from
patients with AS and other spondylarthropathies. A
prospective study on ReA in an endemic area should
teach us more about predisposing factors (for example
for Shigella-induced enteritis, which occurs in many
parts of the world outside Europe and the US) (80). It
is fascinating to see how research on the cause of this
interesting group of diseases is benefiting from the
rapid progresses made in immunology, molecular biology, and genetics; hopefully these advances will lead
to cure and prevention.
The authors thank A. N. Mitchison for fruitful discussions, advice, and critical review of the manuscript.
1. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B,
Calin A, Cats A, Dijkmans B, Olivieri I, Pasero G, Veys E,
Zeidler H: The European Spondylarthropathy Study Group
preliminary criteria for the classification of spondylarthropathy.
Arthritis Rheum 34: 1218-1227, 1991
2. Kingsley G, Sieper J: Current perspectives in reactive arthritis.
Immunol Today 14:l-5, 1993
3. Schumacher HR Jr, Magge S, Cherian PV, Sleckman J, Rothfuss SE, Clayburn G, Sieck M: Light and electron microscopic
studies of the synovial membrane in Reiter’s syndrome: immunocytochemical identification of chlamydia1 antigen in patients
with early disease. Arthritis Rheum 31:937-946, 1988
4. Granfors K, Jalkanen S , von Essen R, Lahesmaa-Rantola R,
Isomaki 0, Pekkola-Heino K, Merilahti-Palo R, Saario R,
Isomaki H, Toivanen A: Yersinia antigens in synovial fluid cells
from patients with reactive arthritis. N Engl J Med 320:216-221,
5 . Ford DK, daRoza DM, Shah P: Cell-mediated immune responses to synovial mononuclear cells to sexually transmitted,
enteric and mumps antigens in patients with Reiter’s syndrome,
rheumatoid arthritis and ankylosing spondylitis. J Rheumatol
8:22&232, 1981
6. Gaston JSH, Life PF, Granfors K, Merilahti-Palo R, Bailey L,
Consalvey S, Toivanen A, Bacon PA: Synovial T lymphocyte
recognition of organisms that trigger reactive arthritis. Clin Exp
Immunol 76:348-353, 1989
7. Sieper J, Kingsley G, Palacios-Boix A, Pitzalis C, Treharne J,
Hughes R, Keat A, Panayi GS: Synovial T lymphocyte-specific
immune response to Chlamydia trachomatis in Reiter’s disease.
Arthritis Rheum 34:588-598, 1991
8. Germain RN: MHC-dependent antigen processing and peptide
presentation: providing ligands for T lymphocyte activation.
Cell 76:287-299, 1994
9. Taurog JD, Maika SD, Simmons WA, Braban M, Hammer RE:
Susceptibility to inflammatory disease in HLA-B27 transgenic
rat lines correlates with the level of B 27 expression. J Immunol
150:4168-4178, 1993
10. Chicz RM, Urban RG, Gorga JC, Vignali DAA, Lane WS,
Strominger JL: Specificity and promiscuity among naturally
processed peptides bound to HLA-DR alleles. J Exp Med
178:2747, 1993
I . Zinkernagel RM, Cooper S, Chambers J, Lazzarini RA, Hengartner H, Arnheiter H: Virus-induced autoantibody responses
to a transgenic viral antigen. Nature 345:68-71, 1990
2. Mielants H, Veys EM: The gut in the spondyloarthropathies. J
Rheumatol 17:7-10, 1990
3. Kingsley G, Panayi GS: Antigenic responses in reactive arthritis. Rheum Dis Clin North Am 18:4946, 1992
4. Heifer JD, Wick MJ, Roberts RL, Findlay K , Normark SJ,
Harding CV: Phagocytic processing of bacterial antigens for
class I MHC presentation to T cells. Nature 361:359-362, 1993
15. Pope M, Kotlarski I, Doherty K: Induction of Lyt-2+ cytotoxic
T lymphocytes following primary and secondary Salmonella
infection. Immunology 81:177-182, 1994
16. Hermann E, Yu DTY, Meyer zum Buschenfelde K-H, Fleischer
B: HLA-B27-restricted CD8 T cells derived from synovial fluids
of patients with reactive arthritis and ankylosing spondylitis.
Lancet 342:646-650, 1993
17. Beatty PR, Stephens RS: CD8+ T lymphocyte-mediated lysis of
Chlamydia-infected L cells using an endogenous antigen pathway. J Immunol 153:4588-4595, 1994
18. Starnbach MN, Bevan MJ, Lampe MF: Protective cytotoxic T
lymphocytes are induced during murine infection with Chlamydia trachomatis. J Immunol 153:5183-5189, 1994
19. Sansonetti PJ: Molecular and cellular biology of Shigella flexneri invasiveness: from cell assay system to Shigellosis. Curr
Top Microbiol Immunol 180:1-19, 1992
20. Brunt LM, Portnoy DA, Unanue ER: Presentation of Listeria
monocytogenes to CD8+ T cells requires secretion of hemoly-
sin and intracellular bacterial growth. J Immunol 145:3540-3546,
Doherty PC, Allan JE, Lynch F, Ceredig R: Dissection of an
inflammatory process induced by CD8+ T cells. Immunol
Today 1155-59, 1990
Kaufmann SHE: Immunity to intracellular bacteria. Annu Rev
Immunol 11:129-163, 1993
Hill AVS, Elvin J, Willis ,AC, Aidoo M, Allsopp CEM, Gotch
FM, Gao XM, Takiguchi M, Greenwood BM, Townsend ARS,
McMichael AJ, Whittle HC: Molecular analysis of the association of HLA-BS3 and resistance to severe malaria. Nature
360:434439, 1992
Braun J, Grolms M, Sieper J: Three colour flow cytometric
examination of CD4/CD45 subsets reveals no difference in
peripheral blood and synovial fluid between patients with reactive arthritis and rheumatoid arthritis. Clin Exp Rheumatol
12:17-22, 1994
Braun J, Bollow M, Neure L, Seipelt E, Seyrekbason F, Herbst
H, Eggens U , Distler A, Sieper J: Use of immunohistologic and
in situ hybridization techniques in the examination of sacroliac
joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 38:499-505, 1995
Pazmany L, Rowland-Jones S, Huet S, Hill A, Sutton J, Murray
R, Brooks J , McMichael A: Genetic modulation of antigen
presentation by HLA-B27 molecules. J Exp Med 175:361-369,
Rowland-Jones SL, Powis SH, Sutton J, Mockridge I, Gotch
FM, Murray N, Hill AB, Rosenberg WM, Trowsdale J, McMichael AJ: An antigen processing polymorphism revealed by
HLA-B8-restricted cytotoxic T lymphocytes which does not
correlate with TAP gene polymorphism. Eur J Immunol 23:
1999-2004, 1993
Villanueva MS, Fischer P, Feen K, Pamer EG: Efficiency of
MHC class I antigen processing: a quantitative analysis. Immunity 1:479-489, 1994
Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A,
Moudgil K: Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 11:729-766, 1993
Nepom GT: A unified hypothesis for the complex genetics of
HLA associations with IDDM. Diabetes 39: 1153-1 157, 1990
Tussey LG, Rowland-Jones S, Zheng TS, Androlewicz MJ,
Cresswell P, Frelinger JA, McMichael AJ: Different MHC class
I alleles compete for presentation of overlapping viral epitopes.
Immunity 3:65-77, 1995
Robinson WP, van der Linden SM, Khan MA, Rentsch H-U,
Cats A, Russell A, Thomson G: HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum 32: 1 135-1 141, 1989
Erard F, LeGros G: Th2-like CD8 T cells: their role in protection against infectious diseases. Parasitol Today 10:313-315,
Sieper J, Braun J, Brandt J, Miktsis K, Heesemann J, Laitko S,
Sorensen H , Distler A, Kingsley G: Pathogenetic role of Chlamydia, Yersinia and Borrelia in undifferentiated oligoarthritis. J
Rheumatol 19:1236-1242, 1992
Sieper J, Braun J, Doring E, Wu P, Heesemann J, Treharne J,
Kingsley G: The etiological role of reactive arthritis-associated
bacteria in pauciarticularjuvenile chronic arthritis. Ann Rheum
Dis 51:1208-1214, 1992
Sieper J, Braun J, Wu P, Hauer R, Laitko S: The possible role
of Shigella in sporadic enteric reactive arthritis. Br J Rheumatol
3232-585, 1993
Braun J, Laitko S, Treharne J, Eggens U, Wu P, Distler A,
Sieper J: Chlamydia pneumomiae: a new causative agent of
reactive arthritis and undifferentiated oligoarthritis. Ann Rheum
Dis 53:100-105, 1994
Hassell AB, Reynolds DJ, Deacon M, Gaston JS, Pearce JH:
Identification of T-cell stimulatory antigens of Chlamydia trachomatis using synovial fluid derived T-cell clones. Immunology 79~513-519, 1993
Deane K, Jeacock R, Hassell A, Pearce J, Gaston JSH: Identification of two target antigens recognized by synovial fluid T
cells in Chlamydia-induced reactive arthritis (abstract). Arthritis
Rheum 37(suppl9):S367, 1994
Mertz A, Daser A, Skurnik M, Wiesmiiller K-H, Braun J, Appel
H, Bratford S, Wu P, Distler A, Sieper J: The evolutionary conserved ribosomal protein L23 and the cationic urease Psubunit
of Yersinia enterocolitica 0 3 belong to the immunodominant
antigens in Yersinia-triggered reactive arthritis: implications for
autoimmunity. Mol Med 1:44-55, 1994
Beatty WL, Byrne GI, Morrison RP: Morphological and antigenic characterization of interferon-? mediated persistent Chlamydia trachomatis infection in vitro. Proc Natl Acad Sci U S A
85:4000-4004, 1993
Nanagara R, Li F, Beutler A, Hudson A, Schumacher HR Jr:
Alteration of Chlamydia trachomatis biologic behavior in synovial membranes: the mechanism of inapparent infection in
reactive arthritis and Reiter’s syndrome (abstract). Arthritis
Rheum 37(suppl 9):S366, 1994
Taylor-Robinson D, Gilroy CB, Thomas BJ, Keat ACS: Detection of Chlamydia trachomatis DNA in joints of reactive arthritis patients by polymerase chain reaction. Lancet 340:81-82,
Rahman MU, Cheema MA, Schumacher HR, Hudson AP:
Molecular evidence for the presence of Chlamydia in the
synovium of patients with Reiter’s syndrome. Arthritis Rheum
355 2 1-529, 1992
Viitanen A-M, Arstila TP, Lahesmaa R, Granfors K, Skurnik
M, Toivanen P: Application of the polymerase chain reaction
and imrnunofluorescence techniques to the detection of bacteria
in Yersinia-triggered reactive arthritis. Arthritis Rheum 3433996, 1991
Nikkari S, Merilahti-Palo R, Saario R, Soderstrom K-0, Granfors K, Skurnik M, Toivanen P: Yersinia-triggered reactive
arthritis: use of polymerase chain reaction and immunocytochemical staining in the detection of bacterial components from
synovial specimens. Arthritis Rheum 3k682-687, 1992
Lauhio A, Leirisalo-Rep0 M, Lahdevirta J, Saikku P, Rep0 H:
Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis with special reference to Chlamydia arthritis. Arthritis Rheum 34:6-14, 1991
De Koning J, Heesemann J, Hoogkamp-Korstanje JAA, Festen
JM, Houtman PM, Oijen PLM: Yersinia in intestinal biopsy
specimens from patients with seronegative spondylarthropathy:
correlation with specific serum IgA antibodies. J Infect Dis
159:1W112, 1989
Perdomo OJJ, Cavaillon JM, Huerre M, Ohayon H, Gounon P,
Sansonetti PJ: Acute inflammation causes epithelial invasion
and mucosal destruction in experimental Shigellosis. J Exp Med
180:1307-1319, 1994
Keat A: Reiter’s syndrome and reactive arthritis in perspective.
N Engl J Med 309:16&1615, 1983
Matzinger P: Memories are made of this? Nature 369:605-406,
Sieper J, Braun J, Wu P, Kingsley G: T cells are responsible for
the enhanced synovial cellular immune response to triggering
antigen in reactive arthritis. Clin Exp Immunol91:96103, 1993
Braun J, Grolms M, Distler A, Sieper J: The specific
anti-bacterial proliferation of reactive arthritis synovial T cells is
not due to their higher proportion of CD45RO+ cells compared
to peripheral blood. J Rheumatol 21:1702-1707, 1994
Lahesmaa R, Skurnik M, Granfors K, Mottonen T, Saario R,
Toivanen A, Toivanen P: Molecular mimicry in the pathogenesis of spondylarthropathies: a critical appraisal of cross-
reactivity between microbial antigens and HLA-B27. Br J
Rheumatol 31:221-228, 1992
55. Selin LK, Nahill SR, Welsh RM: Cross-reactivities in memory
cytotoxic T lymphocyte recognition of heterologous viruses. J
Exp Med 179:1933-1943, 1994
56. Oldstone MBA, Nerenberg M, Southern P, Price J, Lewecki H:
Virus infection triggers insulin-dependent diabetes mellitus in a
transgenic model: role of anti-self (virus) immune response. Cell
65:319-331, 1991
57. Hayden JB, Davey MP: An RA associated MHC molecule
(DRB1*0404) naturally selects different peptides than a non-RA
associated molecule (abstract). Arthritis Rheum 37(suppl 9):
S282, 1994
58. Breban M , Hammer RE, Richardson JA, Taurog JD: Transfer of
the inflammatory disease of HLA-B27 transgenic rats by bone
marrow engraftment. J Exp Med 178:1607-1616, 1993
59. Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M,
Fernandez-Sueiro JL, Balish E, Hammer RE: The germfree
state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 180:235512364,
60. Daar AS, Fuggle SV, Fabre JW, Ting A, Moms PJ: The detailed
distribution of HLA-A, B, C antigens in normal human organs.
Transplantation 38:287-292, 1984
61. Garrido F, Cabrera T, Concha A, Clew S, Ruiz-Cabello F, Stern
PL: Natural history of HLA expression during tumour development. Immunol Today 14:491499, 1993
62. Faustman D, Li X, Lin HY, Fu Y, Eisenbarth G, Avruch J, Guo
J: Linkage of faulty major histocompatibility complex class I to
autoimmune diabetes. Science 254: 17561761, 1991
63. Creamer P, Edmonds J, Sullivan J, Matthews S: Measurement
of HLA class I expression in ankylosing spondylitis. Ann
Rheum Dis 51:1138-1142, 1992
64. Benoist C, Mathis D: Regulation of major histocompatibility
complex class41 genes: X, Y and other letters of the alphabet.
Annu Rev Immunol8:681-715, 1990
65. Yao Z, Kimura A, Hartung K, Haas PJ, Volgger A, Briinnler G,
Bonisch J, Albert ED: Polymorphism to the DQAl promoter
region (QAP) and DRBl, QAP, DQAl, DQBl haplotypes in
systemic lupus erythematosus. Immunogenetics 38:421429,
66. Scofield RH, Warren WL, Koelsch G, Harley JB: A hypothesis
for the HLA-B27 immune dysregulation in spondyloarthropathy: contributions from enteric organism, B27 structure peptides bound by B27, and convergent evolution. Proc Natl Acad
Sci U S A 90:9330-9334, 1993
67. Stieglitz H, Lipsky P: Association between reactive arthritis
and antecedent infection with Shigella flexneri carrying a 2-Md
plasmid and encoding an HLA-B27 epitope. Arthritis Rheum
36:1387-1391, 1993
Wildner G , Thurau SR: Cross-reactivity between an HLA-B27derived peptide and a retinal autoantigen peptide: a clue to
major histocompatibility complex association with autoimmune
disease. Eur J Immunol 24:2579-2585, 1993
Leirisalo-Rep0 M, Helenius P, Laasila M: Prognostic factors in
reactive arthritis (abstract). Scand J Rheumatol Suppl 98: 159,
Lengl-Janssen B, Straws AF, Steere AC, Kamradt T: The T
helper cell response in Lyme arthritis: differential recognition of
Borrelia burgdorferi outer surface protein A in patients with
treatment-resistant or treatment-responsive Lyme arthritis. J
Exp Med 180:2069-2078, 1994
Linssen A, Feltkamp TEW: B27 positive diseases versus B27
negative diseases. Ann Rheum Dis 44:431439, 1988
Paul WE, Seder RA: Lymphocyte responses and cytokines.
Cell 76:241-251, 1994
Simon AK, Seipelt E, Sieper J: Divergent T-cell cytokine
patterns in inflammatory arthritis. Proc Natl Acad Sci U S A
91:8562-8566, 1994
Autenrieth IB, Beer M, Bohn E, Kaufmann SHE, Heesemann
J: Immune responses to Yersinia enterocolitica in susceptible
BALB/c and resistant C57BL/6 mice: an essential role for
gamma interferon. Infect Immun 62:2590-2599, 1994
Bohn E, Heesemann J, Ehlers S, Autenrieth IB: Early gamma
interferon mRNA expression is associated with resistance of
mice against Yersinia enterocolitica. Infect Immun 62:30273032, 1994
Liblau RS, Singer SM, McDevitt HO: Thl and Th2 CD4+ T
cells in the pathogenesis of organ-specific autoimmune diseases.
Immunol Today 16:34-38, 1995
Inman RD, Scoefield RH: Etiopathogenesis of ankylosing spondylitis and reactive arthritis. Curr Opin Rheurnatol 6:360-370,
Kellner H, Yu D: The pathogenetic aspects of spondyloarthropathies from the point of view of HLA B27. Rheumatol Int
12:121-127, 1992
Gao XM, Wordsworth P, McMichael A: Collagen-specific cytotoxic T lymphocyte responses in patients with ankylosing
spondylitis and reactive arthritis. Eur J Immunol24: 1665-1670,
Burmester GR, Daser A, Kamradt T, Krause A, Mitchison NA,
Sieper J, Wolf N: Immunology of reactive arthritis. Annu Rev
Immunol 13:229-249, 1995
Без категории
Размер файла
863 Кб
spondylarthropathies, pathogenesis
Пожаловаться на содержимое документа