MARK J. SOLOSKI1* AND ELEANOR S. METCALF2
ReA is an autoimmune disease that largely consists of painful joint inflammation but also can include inflammation of the eye, gastrointestinal tract, and skin. ReA is a member of a broad spectrum of chronic inflammatory disorders termed the seronegative spondyloarthropathies (SNSpAs) that includes ankylosing spondylitis (AS), psoriatic arthritis, and enteropathic arthritis (24). The clinical manifestations of ReA, which is generally described as an episode of aseptic peripheral arthritis, occur within 2 to 4 weeks after the onset of intestinal or genitourinary bacterial infection. The results of infection can range from severe acute disease to colonization. Therefore, a clear etiological link between infection and the development of ReA exists. The idea that SNSpAs occur as a consequence of a recent urogenital or gastrointestinal infection is not new. However, no definitive infectious trigger as yet has been found for AS, despite early studies suggesting that Klebsiella can induce AS (21). In contrast, an infectious origin for other SNSpAs, such as ReA, has been widely documented (98). The most common infectious agents associated with ReA are the gram-negative enteric pathogens Salmonella, Shigella, Yersinia, and Campylobacter, as well as Chlamydia. In addition, ReA has been associated with enteropathogenic Escherichia coli as well as E. coli urinary tract infections (58, 66). A variety of new infectious agents have also been implicated in ReA, but the incidence and prevalence of ReA caused by these organisms (98) have yet to be documented. This chapter will focus on Salmonella-induced ReA.
While the studies mentioned above reached different conclusions, these studies as well as the wide range in the incidence of ReA following infection point out that genetic variations in bacterial pathogenicity and/or persistence need to be considered in discussions of ReA immunopathogenesis. Indeed, these variations must play a role since Salmonella serovars Enteritidis and Typhimurium have been implicated in the induction of postinfection ReA whereas the closely related enteric pathogen serovar Typhi has not (20, 25, 40, 98).
As with all diseases, the incidence of disease is determined by many factors, both genetic and environmental. In the case of SNSpAs that appear to have an infectious origin, such as ReA, the dynamics that define host-parasite interactions are critical to our understanding of disease pathogenesis. Thus, it is imperative that both sides of this equation be analyzed and understood if one is to truly understand the pathogenic mechanisms operative in this group of diseases. Both the virulence levels and the natures of the bacterial pathogens, as well as immunogenetic factors of the host, must be understood to make progress in the development of therapeutic approaches. The following sections will consider specific variables that may result in Salmonella persistence and ReA.
As mentioned earlier, serovar Typhi can disseminate systemically whereas serovar Typhimurium and serovar Enteritidis do not normally pass in significant numbers beyond the MLN. Recent studies have shown that the oral infection of genetically Salmonella-resistant mice with serovar Typhimurium results in the establishment of a persistent infection that lasts up to a year (77, 78). Importantly, the authors of these studies demonstrated that viable serovar Typhimurium resides in macrophages in the MLN, where it is protected from host immune mechanisms (77). The bacterial load in these macrophages was determined to be low, which may be related to the organisms’ ability to survive. This study suggests that the MLN can act as an extra-articular source of Salmonella antigens for extended periods of time. In humans, serovar Typhi can also establish a persistent infection but the host organ of the "carrier" state for serovar Typhi appears to be the gall bladder (3, 76). It should be reiterated here that serovar Typhi has not yet been shown to be an etiologic agent of ReA, but this conclusion may be revisited should a significant cohort of typhoid fever patients be evaluated in the future. It is also possible that Salmonella-infected mucosal DC could migrate to the MLN and become a source of persistent Salmonella antigens; to date, we are unaware that a study of this possibility has been undertaken, although it has recently been shown that gut commensal organisms are phagocytized by mucosal DC and migrate to the MLN (69).
Cano et al. have recently described an intriguing aspect of the ability of serovar Typhimurium to survive in synovial fibroblasts (14). These investigators and others reported that the growth of wild-type serovar Typhimurium in fibroblast cell lines is restricted and results in the establishment of a latent, nongrowing state (14, 70). Further analysis demonstrated that the prolonged intracellular residence of serovar Typhimurium in fibroblasts allows the emergence of small-colony variants (SCV) (15). A genotypic analysis of SCV revealed mutations conferring auxotrophy for aromatic amino acids (mutations in aroD and aroA), consistent with results of earlier studies demonstrating the ability of aroA and purA mutants to persist in vivo (120). Although these studies were conducted with fibroblast cell lines, the results are consistent with the notion that serovar Typhimurium may establish a persistent infection in synovial fibroblasts through the development of SCV. These results also suggest that the failure to recover viable Salmonella by culturing specimens from joints of ReA patients in earlier studies may have been due to alterations in the bacterial phenotype that impaired detection.
As described by others, ReA is a consequence of the interaction of arthritogenic bacteria (e.g., Salmonella species) and a predisposed host. By "predisposed host," we mean someone who is genetically predisposed to generate a host response that is cross-reactive with a self-response. Many studies have analyzed the association of the HLA class I molecule, HLA-B27, with SNSpAs. Whereas B27 has been shown to be present in 90 to 95% of cases of AS (11, 12, 82), the association of the B27 haplotype with other SNSpAs is more tenuous. Although Salmonella-induced ReA has been extensively studied with regard to the host expression of B27, the data are divergent. Previous studies suggested that hospital-based cases showed the highest correlation between ReA and the presence of the HLA-B27 haplotype. In a retrospective hospital study of post-Salmonella-infection ReA, Leirisalo-Repo et al. found that 88% of the patients were B27 positive (62). Hakansson et al. showed that 69% of patients hospitalized with symptoms of ReA were HLA-B27 positive (31). However, in these studies, the high correlation may be due to the fact that these patients were hospitalized and therefore were the most severely afflicted. Clinical studies generally suggest that most people with post-Salmonella-infection ReA do not require hospitalization. In a series of nonhospital cohort studies of Salmonella-induced ReA, the frequency of B27 positivity ranged from 0 to 60% (reviewed in reference 61). Note that in the two studies in which the percentages of B27 positivity were the highest, the total numbers of individuals that had ReA were only four (34) and five (97). These cohort studies also suggested that the risk of developing ReA and HLA-B27 expression may be related to the strain of Salmonella and the age of the individual (40). Insufficient data are currently available to substantiate these observations. Some long-term studies of individuals with Salmonella-induced ReA have established that a correlation exists between B27 positivity and the development of a more severe and prolonged course of ReA (22, 62). However, chronic arthritis has also been observed in B27-negative patients with post-Salmonella-infection ReA (60) and in other studies a correlation between B27 and the severity of disease was not observed (34, 61). Collectively, these data show that the association between B27 and ReA remains controversial. B27 does not appear to predispose to the initiation of Salmonella infections but may be related to the severity and length of the ReA episode. Additional genetic complexities in the relationship between B27 expression and ReA may need to be considered. Tuokko et al. analyzed the HLA class II association with ReA. They found a positive correlation between the expression of B27 and DRB1*0408 and between B27 and DQG1*0301 in ReA patients but not controls (113). These findings indicate that susceptibility to ReA is a complex genetic trait and that additional genetic markers remain to be identified.
In contrast to humans, murine models have yielded information on the adaptive immune response to serovar Typhimurium. Studies using these models have demonstrated that both CD4+- and CD8+-T-cell responses are needed for full protection against lethal infection with serovar Typhimurium (39, 63, 64, 73). In the murine model system, the CD4+ T cells appear to play a large role since CD4-deficient mice are several orders of magnitude more susceptible than CD8-deficient hosts (39, 64). Interestingly, characterization of the T-cell response to serovar Typhimurium infection reveals the presence of a CD8+-T-cell population that recognizes a nonamer peptide derived from the Salmonella GroEL (Hsp60) protein (63). These CD8+ T cells also recognize an analogous peptide, identical at seven of nine positions, derived from the mammalian Hsp60 counterpart of GroEL. Furthermore, these serovar Typhimurium-induced Hsp60-reactive CD8+ cytotoxic T lymphocytes (CTLs) recognize uninfected targets that have been placed under stress conditions. Collectively, these results imply that following serovar Typhimurium infection a subset of bacterial antigen-reactive T cells develops with the potential to recognize and damage uninfected cells undergoing physiological stress. Such cells may contribute to an autoimmune disease process (102). Interestingly, the antigen-presenting structure identified in the presentation of GroEL (Hsp60) peptides to CD8+ CTLs is the murine class Ib molecule Qa-1. Human HLA-E is the functional counterpart of Qa-1, raising the intriguing possibility that analogous bacterial antigen-induced T cells that cross-recognize self-epitopes develop in the human setting.
ReA is an immunopathologic disease, and phagocytes and lymphocytes from ReA patients have been reported to exhibit an activated phenotype compared with controls. For example, the increased expression of the monocyte markers CD11b, CD11c, and CD14 in ReA patients has been reported (53). However, in another study no change over controls was seen (57). When lymphocytes were examined, Konttinen et al. showed that lymphocytes in ReA patients display an activated phenotype as indicated by the increased expression of IL-2R, the transferrin receptor, and the gp40/80 glycoprotein 4F2 on synovial mononuclear cells (56).
If there is in fact an etiological link between infection and ReA, bacterial antigen-reactive T cells would be predicted to be present at the sites of disease. Indeed, this is the case, as CD4+ and CD8+ T cells directed against bacterial antigens have been identified in the synovial fluid and synovium of patients with ReA. Although serovar Typhimurium is associated with a significant number of ReA cases, there have been few studies investigating the involvement of bacterial antigen-reactive T cells in Salmonella-induced disease. In one study, CD4+ T cells recognizing an unknown antigen derived from Salmonella or Campylobacter were cloned from the synovial fluid of a single patient with Salmonella-induced ReA (37). In contrast, there have been several reports of bacterial antigen-reactive CD4+ and CD8+ T cells being recovered from patients with Yersinia-induced ReA (5, 36, 74, 84, 118). Strong CD4+-T-cell responses against peptides derived from Hsp60 and the β-subunit of the urease protein have been identified (74). Interestingly, cross-reactivity with self-antigens was demonstrated in at least one report, raising the question of whether such bacterial antigen-induced CD4+ T cells are relevant to ReA (74).
A role for HLA-B27 in the pathogenesis of bacterium-induced arthritis such as ReA is therefore supported not only by genetic linkage data but also by the identification of HLA-B27-restricted CTLs that recognize bacterial and/or self-antigens obtained from patients with ReA associated with bacterial infections. Collectively, these observations support a model in which bacterium-induced effector T cells recognize a cross-reactive arthritogenic self-peptide presented by HLA-B27 on uninfected targets (99). In this manner, HLA-B27 may function as an antigen presentation structure and target for autoimmune effector cells.
In an effort to identify peptides bound to HLA-B27 that are relevant to ReA, the peptide repertoire presented by the B27 molecule has been analyzed. Ramos and colleagues eluted peptides from B27 of Salmonella-infected and uninfected cells and found the chromatographic profiles to be minimally different (85). In separate studies, Ringrose et al. concluded that the total numbers of peptide species eluted from B27 molecules of infected and uninfected cells were not significantly different (89, 90, 91). However, the latter investigators noted an increase in the frequency of specific self-peptides in Salmonella-infected B27-positive cells (90). In these studies, the investigators used a B-cell line (C1R-B27) transfected with HLA-B*2705. It was concluded that a dominant arthritogenic peptide could not be identified by this approach. However, it is possible that the B27-bound peptides in Salmonella-infected and uninfected cells would have been different if classic antigen-presenting cells had been utilized for these studies.
A central role for HLA-B27 in ReA was solidified through the generation of HLA-B27 transgenic rats and mice. In 1990, Hammer et al. reported that rats expressing the HLA-B27 molecule through a transgene develop a spontaneous inflammatory disease that shares many features with the spondyloarthropathies, including ReA (32). Although spontaneous, the disease was dependent on the gut flora, especially species of Bacteroides (86). Interestingly, the severity of disease correlated with the HLA-B27 transgene copy number (109). A similar disease could be induced in HLA-B27-positive mice deficient in endogenous β2 microglobulin (β2m), a subunit of class I molecules required for normal major histocompatibility class I (and HLA-B27) surface expression (50, 52). The involvement of a bacterial trigger in this model was also suggested, since mice raised under pathogen-free conditions did not develop disease. Collectively, the results from these animal models support a central role for HLA-27 in the pathogenesis of the spondyloarthropathies.
Recently, the role of HLA-B27 has been reconsidered and alternative models have been offered. The first indication that HLA-B27 may have functions in addition to a role as a "conventional" antigen presentation structure of CD8+ T cells was the dependency on high gene copy numbers in the B27 transgenic rat model (109). This finding suggested that the abnormal expression of HLA-B27 is related to disease. This notion was further supported by the finding that mice coexpressing HLA-B27 and human β2m instead of murine β2m also develop disease while expressing significant levels of a cell surface HLA-B27 heavy chain lacking β2m (50). Therefore, novel cell surface forms of HLA-B27 may themselves represent targets, an idea further supported by the discoveries that the induction of murine disease does not require the Tap-dependent loading of peptides and that CD8+ T cells are not required in the rat model of ReA (51, 71).
Studies on the biosynthesis and expression of HLA-B27 have revealed that HLA-B27 can be expressed as a free heavy chain devoid of β2m, which can exist as homodimers and oligomers. Multimeric forms of HLA-B27 are also expressed in the rat and murine HLA-B27 transgenic models, suggesting that these multimeric forms may be immune targets responsible for the induction and/or progression of disease (2, 4, 18). Employing dimeric HLA-B27 tetramers devoid of β2m, Kollnberger et al. demonstrated that dimeric HLA-B27 is a ligand for several KIR and leukocyte Ig-like receptors (55). Another hypothesis suggests the involvement of HLA-B27-recognizing CD4+ T cells (9, 10). This idea is supported by the CD8+-T-cell independence of the rodent models, the observation that novel forms of HLA-B27 can bind peptides considerably longer than nonamers (16 to 33 amino acids) (26, 115), and the recovery of HLA-B27-restricted CD4+ T cells from patients with AS (9) and HLA-B27 transgenic mice (92). Collectively, these results suggest various ways in which HLA-B27 may serve as a target for pathological immune responses. The relevance of these mechanisms to ReA remains to be determined.
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