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Juvenile rheumatoid arthritis and the trimolecular complex hla t cell receptor and antigen.

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ARTHRITIS & RHEUMATISM Volume 37
Number 5, May 1994, pp 601-607
Q 1994, American College of Rheumatology
Arthritis & Rheumatism
Official Journal of the American College of Rheumatology
CURRENT COMMENT
JUVENILE RHEUMATOID ARTHRITIS
AND THE TRIMOLECULAR COMPLEX
(HLA, T CELL RECEPTOR, AND ANTIGEN)
Differences from Rheumatoid Arthritis
ALEXEI A. GROM, EDWARD H. GIANNINI, and DAVID N. GLASS
is likely to determine differences in future therapeutic
approaches to the two diseases.
JRA is a chronic, idiopathic, inflammatory disorder with diverse clinical symptoms, both at onset
and during the course of illness. Classification of this
heterogeneous disease has been based primarily on the
type of onset, i.e., clinical manifestations during the
first 6 months (5-7). There are at least three major
onset types: pauciarticular (4 or fewer joints involved
at onset), polyarticular (5 or more joints), and systemic. Pauciarticular JRA is subdivided into early- and
late-onset types, sometimes called type I and type 11,
which have somewhat different clinical features and
outcome. Early onset is defined as occurring at or
before 6 (sometimes, 8) years of age. The polyarticular
type is also divided into two subtypes, on the basis of
age and the presence or absence of IgM rheumatoid
factor (IgM-RF).
Current hypotheses on the cause of the chronic
inflammatory arthropathies and other autoimmune diseases hold that pathogenic immune responses ensue
when TCRs of disease-promoting T lymphocytes recognize a particular peptide antigen that is presented in
the context of specific class I1 major histocompatibility
complex (MHC) molecules. Antigen recognition leads
to the proliferation of lymphocytes with receptor specificity for this antigen-MHC complex. The resulting
release of inflammatory cytokines and proteolytic enzymes eventually leads to recruitment of other cells,
The therapy of juvenile rheumatoid arthritis
(JRA) is still influenced by many of the paradigms that
guide the therapeutic approach to adult rheumatoid
arthritis (RA) (1). Recent molecular and immunologic
advances offer the promise of more selective immunotherapeutic interventions that have not been available
hitherto. It is thought that trimolecular complexes
comprising an HLA product, a T cell receptor (TCR),
and an antigen play a critical role in JRA as well as in
other forms of autoimmune disease (2,3). Animal
models of these diseases clearly show that each component is a potential target for immunotherapy (4).
This report reviews the available data regarding each
component of the trimolecular complex in JRA, emphasizing the ways in which they differ from those in
adult RA. The nature of these trimolecular complexes
Supported in part by The Schmidlapp Foundation, Children’s Hospital Research Foundation, and NIH grants R01-39979
and P20-AR-42632. Dr. Grom is recipient of an Arthritis Foundation
Fellowship.
Alexei A. Grom, MD: The University of Cincinnati School
of Medicine, Children’s Hospital Medical Center, Cincinnati, Ohio;
Edward H. Giannini, MSc, DrPH: The University of Cincinnati
School of Medicine, Children’s Hospital Medical Center; David N.
Glass, MD: The University of Cincinnati School of Medicine,
Children’s Hospital Medical Center.
Address reprint requests to Alexei A. Grom, MD, William
S. Rowe Division of Rheumatology, Children’s Hospital Medical
Center, Elland and Bethesda Avenues, Pav 1-129, Cincinnati, OH
45229-2899.
Submitted for publication July 1, 1993; accepted in revised
form October 26, 1993.
60 1
602
including macrophages and B cells, and to tissue
damage.
The characteristic histopathologic findings in
diseased joints support this concept, as do the strong
associations between different forms of JRA and certain MHC genes. The histopathology of the inflammatory response of JRA resembles that of classic
delayed-type hypersensitivity reactions (8). The inflamed synovium is characterized by marked mononuclear cell infiltration in which CD4+ T lymphocytes in
various stages of activation are the predominant cell
population. Numbers of dendritic cells within the
synovial membrane and fluid are also increased (9);
they are typically in close juxtaposition with T lymphocytes. A distinctive feature of these dendritic cells
is their high levels of HLA-DQ and HLA-DR gene
expression (10); evidence suggests that such cells are
particularly potent as antigen presenters (11). It is
reasonable to believe, therefore, that antigen presentation occurs in inflamed synovium. This hypothesis is
also supported by the demonstration that dendritic
cells from the joints of some JRA patients stimulate
syngeneic peripheral blood lymphocytes, suggesting
that an antigen may be present on the dendritic cell's
surface (12).
HLA studies
Early studies of HLA disease associations,
conducted using serologic typing methods, reinforced
the idea that most JRA patients did not resemble adult
RA patients with regard to inherited predisposition.
Well before the development of DNA-based technologies for genotyping, it had become clear that JRA was
as heterogeneous genetically as it was clinically.
Early-onset (type I) pauciarticular JRA, also
called EOPA-JRA, has no adult counterpart; it is both
the most common form of JRA and the most comprehensively studied immunogenetically. Associations
with class I1 HLA-DR8 (13), HLA-DRS (14), and,
more recently, HLA-DR6 (15,16) and HLA-DPw2
(17,18) specificities have been reported. An HLA-A2
class I association has been found quite consistently
(19). Two HLA class I1 specificities, HLA-DR4 and
HLA-DR7, are significantly reduced in frequency,
i.e., protective, in EOPA-JRA. DNA sequencedependent methodologies have defined more precisely
the HLA alleles associated with JRA. It appears that
disease susceptibility is associated with particular alleles of each serologically or cellularly defined speci-
GROM ET AL
ficity, for example HLA-DRB1*0801 of DR8 and
HLA-DPB1*0201 of DPw2 (for review, see ref. 20).
HLA associations and outcome. Determination
of HLA specificities using oligonucleotide dot-blots
has also better defined the genetic markers of disease
outcome in EOPA-JRA. Two examples include the
identification of alleles that 1) predispose to the development of chronic iridocyclitis and 2) are predictive of
progression of pauciarticular disease to a polyarticular
erosive course. Among our patients, haplotypes carrying HLA-DRB 1*0801, HLA-DRB 1* 1301, and
HLA-DPB1*0201 alleles appear to predispose to
pauciarticular JRA in general. In contrast, HLADRBl* 1104 haplotypes predispose to eye disease (21);
HLA-DQAl*O101 haplotypes predispose to a polyarticular, erosive disease outcome, but are protective
against the development of eye disease (22). The
HLA-DRBl*OlOl split of HLA-DRl is another allele
present on HLA-DQAl*OlOl haplotypes that has
been shown to be associated with a polyarticular
course. Whether the HLA-DQAl"0101 allele or, as
suggested by Ploski and colleagues (23), the HLADRBl"0101 allele is a better marker for the haplotype
is uncertain, but there are data that are compatible
with either possibility.
Polygenic inheritance. HLA genes from 4 loci
(HLA-A, HLA-DR, HLA-DQ, and HLA-DP) are
involved in inherited predisposition to pauciarticular
JRA, raising the possibility that these genes make up a
potential susceptibility haplotype. However, the absence of linkage disequilibrium between the specific
HLA genes involved suggests otherwise, and provides
evidence indicating an independent genetic effect at
3 loci, i.e., that EOPA-JRA is truly a polygenic disease. This is illustrated in Table 1, which demonstrates
the odds ratio obtained by the cumulative addition of
risk factors. Such interactions have been demonstrated in other series (24).
In a significant proportion of EOPA-JRA patients, especially those with uveitis, there is evidence
that the development of the disease is associated with
the presence of 2 susceptibility alleles of either
HLA-DR or HLA-DQ. For example, patients who are
heterozygous for HLA-DRYDR8 have a particularly
increased risk of developing eye disease (25). An
HLA-DP gene and a class I gene, HLA-A2, contribute as well, appearing as independent risk factors.
Class I1 gene homozygosity is not increased in the
pauciarticular JRA patient population, suggesting that
a dosage effect of any individual gene does not increase risk in patients (25).
603
TRIMOLECULAR COMPLEX IN JRA
Table 1. Polygenic risk in early-onset pauciarticular juvenile rheumatoid arthritis*
Risk factors
DRB1*0801 study (n = 98)
Female sex
Female sex + HLA-A2
Female sex + HLA-A2, DRB1*0801
Female sex + HLA-A2, DRB1*0801, DPB1*0201
DRBI*1301 study (n = 102)
Female sex
Female sex + HLA-A2
Female sex + HLA-A2, DRBl*1301
Female sex + HLA-A2, DRBI*1301, DPB1*0201
No.
%
,$
P
Cumulative
odds ratiot
89
67
21
10
90.8 14.12 <0.001
68.4 29.71 <0.001
21.4 17.21 <0.001
10.2 8.96 <0.01
4.51
8.74
63.00
119.00
93
74
21
13
91.2 14.44 <0.001
72.5 7.28 <0.01
20.6 9.78 CO.01
12.7 13.21 <0.001
4.55
5.55
10.50
52.00
* Based on homogeneous populations of 98 patients studied for DRB 1*0801 and of 102 patients studied
for DRB I * 1031, from the Cincinnati/Indianapolisarea.
t Calculated based on a risk of 1.00 for individuals negative for all risk factors.
HLA DNA sequences and critical diseaseassociated epitopes. Disease-associated HLA genes
having been found, the problem of identifying the
critical disease-associated nucleotide sequences
arises. Analysis of the DNA-defined splits of the
serologically associated DR specificities has not
helped to establish a putative epitope (as was the case
in RA and insulin-dependent diabetes mellitus
[IDDM]). Haas and colleagues have postulated that
DR associations are in fact markers for DQ alleles,
which are more likely to be primarily involved in
pathogenesis (26). In other words, it is an HLA-DQA
DNA sequence common to the HLA-DR3, HLADR5, and HLA-DRS haplotypes that is the important
motif directly involved in the pathogenetic process.
The suggested epitope is located at the site that is
likely to be involved in an interaction with antigenic
peptide and/or with TCR. However, this hypothesis
does not allow for disease associations with the
DRB 1* 1301 haplotype (20,27). The HLA-DRB 1* 1301
haplotype carries an HLA-DQA allele that lacks the
molecular motif common to the HLA-DR3, HLADR5, and HLA-DRS haplotypes. Furthermore, the
HLA-DQA hypothesis explains neither the especially
increased risk of disease associated with DR8 haplotypes and with double heterozygosity of the HLA-DR/
HLA-DQ loci, nor the relatively low level of risk
associated with homozygosity.
Other possible explanations for the complexity
of HLA associations in pauciarticular JRA are mixed
dimer formation (as has been suggested in IDDM [28]),
MHC restriction with another MHC molecule as the
target antigen, or involvement of multiple antigens in
the disease (MHC or otherwise). Finally, it remains a
possibility that linked genes are involved, that is, that
the identified genes are markers for neighboring genes
directly involved in the disease process.
JRA and the HLA-DRl/DR4 shared epitope
hypothesis. RA is associated with the presence of the
DNA sequence common to HLA-DR1 and some
HLA-DR4 specificities (29,30). However, the shared
epitope hypothesis applied to RA is not useful for
pauciarticular JRA, in which HLA-DR4 is protective
but HLA-DR1 haplotypes predispose to a polyarticular outcome. Pauciarticular JRA patients thus show a
disassociation in the effects of the haplotypes involved
in this hypothesis: one predisposes and others are
protective. Patients with the seronegative polyarticular JRA, recently associated with HLA-DPw3 and
possibly the MHC-linked peptide transporter genes,
do not carry the appropriate epitopes (27,31). Older
JRA patients with polyarticular disease who are
IgM-RF positive and who have the childhood equivalent of adult RA are the only JRA group in whom this
shared epitope hypothesis may hold, probably accounting for fewer than 10 percent of all children
with JRA.
TCR studies
Given the substantial HLA associations with
different types of JRA, disease-specific TCR-HLA
interactions may be anticipated. TCRs can be analyzed for relevance to disease pathogenesis by two
approaches: indirectly, through genomic analysis, and
directly, by determining the TCRs carried on lymphocytes from inflamed joints. Both approaches have been
used in the study of JRA.
Genomic polymorphisms and TCR Vp deficiency
in JRA. The discovery of allelic polymorphisms of
GROM ET AL
604
some TCR genes has prompted studies of TCR genetic
associations with JRA. Thus, a recently identified
allele of the TCR Vp6.1 gene (Vp6.1B) was shown to
be associated with a subset of type I pauciarticularonset JRA, i.e., patients whose disease will evolve to
become polyarticular and who have a reduced frequency of iridocyclitis. This association was found to
be even stronger when patients were stratified by HLA
haplotype, especially HLA-DQAl*OlOl (32). The
Vp6.1A and Vp6.1B polymorphisms differ by 4 amino
acids, including a cys-tyr mutation at position 92 in
Vp6.1B. The loss of cys in Vp6.1B would prevent the
formation of conserved disulfide bonds. Hence, this
product could not participate in the normal Ig domainlike structure of a TCR, making Vp6.1B a null allele
(33). Of two other studies of JRA patient series, Vp6.1
null allele association has been found in one (34), but
not in the other (35); the former study also documented an association with a Vp20 null allele.
This finding of increased frequencies of TCR Vp
null genes in JRA raises several possibilities in the
context of a disease association. The Vp6.1A allele
may be protective against polyarticular disease. Alternatively, a hole left in the TCR repertoire by Vp6.1B
may permit progression to polyarticular disease. Studies using the murine type I1 collagen arthritis model
have suggested that defective TCR expression protects against joint disease (36); however, there is not
yet a consensus on this.
TCR expression in JRA. Analysis of TCRs expressed in the main site of the disease, inflamed joints,
may help to identify critical TCRs that are directly
involved in the pathogenetic process. A few attempts
have been made to assess the randomness of the TCR
repertoire expressed in JRA synovium compared with
peripheral blood. The assumption that antigens primarily stimulate T cells whose receptors contain certain Vp segments has led to comparison of TCR Vp
gene expression in peripheral blood and synovial fluid
in JRA patients (37). Using freshly isolated synovial
fluid T lymphocytes from individual patients, specific
Vp gene families were found to be overexpressed.
Those authors also noted further restriction of Vp
usage by synovial fluid interleukin-2 receptor-positive
T cells. The Vp2, Vp 18, and Vp20 families appeared to
be utilized most frequently. Limited sequencing data
revealed signs of clonality among T lymphocytes possessing the TCR Vp20 fragment.
In studies using a similar approach, we have
demonstrated that a proportion of JRA patients overexpressed a limited number of TCR Vp families (Vp2,
7, 8, 14, 20) in the synovial compartment compared
with the peripheral blood. Sequencing studies showed
that this overexpression was often accompanied by the
presence of oligoclonal T cell populations bearing
these particular Vp fragments. Evidence for the clonal
expansion of T lymphocytes possessing the TCR Vp14
gene (implicated in RA pathogenesis) was limited to
patients who had a polyarticular course and, in most
cases, the presence of DR4 haplotypes and IgM-RF
(38). One of these, RF+, DR4+ patients with polyarticular JRA had a very aggressive arthritis requiring
replacement of both hip joints early in the disease
course. Therefore, synovial tissue was available on
two separate occasions during the course of the study,
providing a unique opportunity to analyze directly the
T cell repertoire in the synovium from different joints
during early stages of the disease. The use of semiquantitative polymerase chain reaction techniques
demonstrated that the Vp14 gene family was the only
family significantly overexpressed in synovium. Specifically, sequence analysis revealed the presence of
the dominant clone, which was found both in synovial
fluid and in synovial tissue. These findings were consistent in all joints examined and persisted over a
2-year period, suggesting a role for this dominant clone
in this patient.
Clonal expansion of Vp14+ T lymphocytes is
likely to be a feature in seropositive polyarticular JRA
patients who possess DR4 haplotypes and thus have a
disease resembling adult RA. No signs of Vp14+ T cell
clonality were observed in other JRA groups, indicating that further studies are necessary to identify TCRHLA interactions specific for EOPA-JRA. Furthermore, the trimolecular complex in pauciarticular JRA
is different from that in RA, with respect to both HLA
and TCRs (38).
Possible antigens
The instances of oligoclonal expansion of T
cells bearing specific Vp gene products as described
above are likely to be the result of antigenic stimulation in inflamed joints. In fact, several antigens (both
self and non-self) have been shown to be able to trigger
a proliferative response of T lymphocytes from JRA
patients in vitro (39). Although numerous attempts
have been made to identify infectious agents that
might trigger JRA, there is at present no consensus on
this. Among the possible viral agents, rubella has
received particular attention. First, evidence of prolonged rubella infection and continued immune re-
TRIMOLECULAR COMPLEX IN JRA
sponse to the virus in JRA came from a study by Ogra
et a1 (40). A persistently increased IgM rubella antibody response was demonstrated in that study. In
addition, the rubella virus antigen was detected in
synovial tissues of some JRA patients. Later (in 198%
Chantler et a1 isolated rubella virus from peripheral
blood and synovial fluid mononuclear cells of 7 of 19
children with the pauciarticular, polyarticular, or systemic form of JRA (41). Joint disease was not associated with recent infection or immunization with rubella virus in any of these patients.
Bacterial antigens have also been implicated.
An increased antibody response to peptidoglycan, a
bacterial cell wall constituent, was demonstrated in
patients with type I (early-onset) pauciarticular JRA
(42). Sieper et a1 (43) studied the cellular immune
response to reactive arthritis-associated bacteria in
blood and synovial fluid from children with pauciarticular JRA and observed an increased synovial T cell
response after stimulation with Chlamydia trachomatis and Yersinia enterocolitica in patients with type 11,
but not type I, pauciarticular JRA. In another study,
C trachomatis was detected in synovial fluids from
6 patients with an EOPA-like syndrome accompanied by
iridocyclitis. Interestingly, antibacterial treatment effected marked clinical improvement in these patients (44).
De Graeff-Meeder and colleagues (45) have
shown that synovial T cells from patients with JRA
proliferate in response to mycobacterial 65-kd heat
shock protein (hsp65) and to the homologous human
hsp60. This cross-reactivity between human and bacterial heat shock proteins suggests that an immune
response could be initiated by infection and perpetuated by abnormal expression of human hsp60, acting
as an autoantigen, in the joint. ML30 monoclonal
antibodies, which recognize human hsp60, were used
to demonstrate high levels of heat shock protein expression in synovial lining cells from JRA patients (46).
Although conclusive evidence is still lacking, it
is very likely that several antigens, both self and
non-self, are potentially involved in the pathogenesis
of JRA.
Mechanisms of chronicity
It appears that expansion of a limited number of
antigen-specific T cell clones against arthritogenic
antigens may initiate JRA, but that as the disease
progresses, additional mechanisms for amplification of
the immune response become important. First, nonspecific recruitment of other proinflammatory cells
605
into the synovium occurs. The increased binding of T
cells to the endothelium of the postcapillary venules
induces the migration of activated T cells into synovium (47); this is likely to be controlled by cytokines
(mostly two macrophage-derived cytokines, i.e., interleukin-1B and tumor necrosis factor a).For example,
CD4+, HLA-DR+ lymphocytes from the peripheral
blood of children with arthritis adhere to human umbilical vein endothelial cells activated by tumor necrosis factor a (48). Very late activation antigen type 1, a
surface protein from the integrin family that mediates
leukocyte adhesion to matrix proteins, is significantly
overexpressed on lymphocytes from JRA patients,
further suggesting that the nonspecific recruitment of
proinflammatory cells into the synovium may be important in JRA at later stages (49).
Another possibility is that joint destruction
caused by the disease may create new epitopes and
stimulate the appearance of other T cell clones. This
appears to have been an important mechanism demonstrated in a study of a patient with Graves’ disease
(50); T cell clones derived from the patient’s thyroid
tissue revealed marked heterogeneity because of the
involvement of multiple proteins, epitopes, and HLA
restriction elements. Nonetheless, the relevance of
different clones to pathogenesis may vary, depending
on the immunogenecity of the epitopes recognized.
We have noted the long-lasting persistence of a dominant clone expanded in multiple joints in some of our
patients. This observation implies that an ongoing
specific immune response may be a substantial component of the pathogenetic process for prolonged
periods, and thus could be a target for specific immunotherapeutic intervention.
Conclusions
Strong HLA associations and the presence of
clonally expanded synovial T lymphocyte populations
are characteristic features of both RA and JRA, suggesting an antigen-driven process. Sufficient data are
available, however, to predict that the trimolecular
complex involved in lymphocyte activation in JRA
differs substantially from that found in RA and that
these differences involve all 3 elements of the complex: HLA, TCR, and antigen. It will be important to
identify disease-specific TCR-HLA interactions as
well as antigens in order to formulate specific interventions for the treatment of JRA.
606
GROM ET AL
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