Under most circumstances, the host is able to mount a protective inflammatory response that contains the invading pathogen and resolves the infection. However, when the infection is not quickly cleared by the host, the potent activation of the immune response with the associated high levels of cytokines and reactive oxygen species leads to joint destruction. High cytokine concentrations increase the release of host matrix metalloproteinases (including stromelysin and gelatinase A/B) and other collagen-degrading enzymes. When monoclonal antibodies or steroids attenuate these cytokines, cartilage degradation is minimized. The joint is further damaged by the release of lysosomal enzymes and bacterial toxins. Host proteoglycans are initially degraded, and this is followed by collagen degradation. In fact, the polymorphonuclear response with subsequent release of these proteolytic enzymes can lead to permanent destruction of intra-articular cartilage and subchondral bone loss in as little as 3 days. Metalloproteinases and the antigen-induced inflammatory response may persist and continue to damage the joint architecture even after the infection has been cleared. The infectious process induces a joint effusion that increases intra-articular pressure, mechanically impeding blood and nutrient supply to the joint. Thus, increased pressure destroys the synovium and cartilage. Because of the proximity of the epiphyseal growth plate to the joint, direct extension of a joint infection to any of the articulating bones may lead to decreased bone growth in infants and children. While bone mineralization is preserved, cartilage destruction causes joint space narrowing and erosive damage to the cartilage and bone if left untreated. In addition, the infection can spread to surrounding soft tissue, form sinus tracts, and disrupt ligaments and tendons in the untreated state.
S. aureus infects and elicits a strong native immune response, cytokine release, and high T-cell activation. This pathogen is able to use a number of immunoavoidance strategies during this time while the host immune system simultaneously causes damage to “self” tissues and blood vessels in the area of infection. This damage may cause local circulatory and immune system compromise. The high T-cell activation eventually results in apoptosis and a weakened immune system, enabling the pathogen to effectively produce a sustained and destructive infection. While the bacterial products have been shown to increase joint damage in acute septic arthritis, many more S. aureus virulence factors have not yet been tested. The interaction of the bacteria and host is of utmost importance in the initiation and prolongation of infection and cartilage damage. There is a subtle balance between an effective immune response to eliminate the infecting organism from the host and the over-activation of this response that causes the majority of infection-related joint destruction.
LYME ARTHRITIS
The Lyme disease agent, Borrelia burgdorferi, causes infection by migration through tissues, adhesion to host cells, and evasion of immune clearance. Both innate and adaptive immune responses, especially macrophage- and antibody-mediated killing, are required for optimal control of the infection and spirochetal eradication.
Evidence suggest autoimmunity as a potential sequel of infection - at the same time, one should not gloss over the paucity of evidence directly implicating infection as the cause of any of the important candidate autoimmune diseases. The ongoing synovial inflammation in patients with treatment-resistant Lyme arthritis may be caused by factors other than persistent B. burgdorferi infection. Ideas about the path from infection to autoimmunity divide into two groups: antigen specific, and antigen nonspecific. For the first set of ideas, what is important is T cell epitopes. The hypothesis of molecular mimicry predicts that microbial peptide sequences occasionally mimic sequences in the host. Once T cells respond to the microbial peptide, the hitherto peaceful self-antigen is also recognized and disease ensues. The antigen nonspecific set of ideas assumes inflammatory cytokines to be the major culprits. One example would be hypersensitivity that develops to traces of persistent antigen.
Both HLA-DR4 and a T cell response against B. burgdorferi OspA are associated with the treatment-resistant form of Lyme arthritis. Therefore, the HLA-DR4-restricted response to B. burgdorferi OspA has been suspected to trigger chronic synovitis via molecular mimicry. Compatible with this hypothesis, it was shown that T cells from the synovial fluid of patients with treatment-resistant Lyme arthritis recognized both an immunodominant OspA epitope and a highly homologous peptide derived from LFA-1. This is similar to the original report of cross-reactive T cells that recognize both a microbial peptide and a highly homologous self-peptide. In several instances, autoimmunity was elicited by immunization of experimental animals with such cross-reactive peptides, albeit at much reduced incidence and severity or only at significantly higher antigen doses than the homologous self-antigen.
Novel techniques such as combinatorial peptide libraries have more recently been used for the study of T cell cross-reactivity. Studies have shown that T cell recognition of multiple different peptides occurs much more frequently than previously assumed and that sequence similarity is not a prerequisite for such cross-recognition. Several regulatory mechanisms normally prevent cross-reactive T cells from causing injury. First, both the microbial peptide and the self-peptide must be processed and presented by antigen presenting cells. Also, the self-antigen must be present at high enough concentrations and the T cells at high enough numbers. Third, the T cells must receive the appropriate co-stimulatory signals from antigen presenting cells to produce the proinflammatory cytokines required for tissue damage rather than protective cytokines. Fourth, the T cells must be capable of migrating to the tissue where the cross-reactive self-antigen is expressed and must escape immunoregulation. Finally, some degree of autoreactivity seems to be necessary for the survival of naive T cells and possibly also for memory T cells.
The idea that cross-reactivity between one particular microbial peptide and one particular self-peptide is indicative of pathogenicity is thus probably too simple. Nevertheless, molecular mimicry remains one attractive hypothesis for the pathogenesis of autoimmune disease. For example, microbial peptides might help to maintain the pool of memory T cells specific for an autoantigen. Furthermore, persistent or recurrent infections could bring the number of autoreactive T cells over a critical threshold, thereby supporting the development of autoimmune disease.
Mononuclear cells or T cell clones derived from the synovial fluid of patients with Lyme arthritis produce a Th1 cytokine pattern. B. burgdorferi can induce Th1 phenotype development in naive Th cells and early data seemed to indicate an association of Th1 responses with susceptibility to arthritis in murine models. More recently, however, it has become clear that there is no clear correlation between Th1 or Th2 responses and susceptibility to Lyme arthritis in murine models of the disease.
In addition, cytokines such as IL-1β, IL-6, IL-10, IL-11, or IL-12 that are produced by cells of the innate immune system have been implicated in the regulation of arthritis severity in patients or animal models. B. burgdorferi lipoproteins such as OspA are mitogenic for B cells and potently activate cells of the innate immune system via their binding of Toll like receptor-2. B. burgdorferi thus induces, in host cells, the production of IL-1β, IL-6, IL-10, IL-12, and tumour necrosis factor-α. B. burgdorferi OspA, via its activation of the innate immune system, also induces the differentiation of Th cells that co-express IL-17 and tumour necrosis factor-α both in mice and in humans. IL-17 is a proinflammatory cytokine in candidate autoimmune diseases (such as rheumatoid arthritis) that induces the production of other proinflammatory mediators such as IL-6. The reciprocal enhancement of IL-17 and IL-6 could therefore contribute to infection-induced immunopathology of chronic inflammatory diseases such as treatment-resistant Lyme arthritis.
Altogether, it is likely that antigen-nonspecific mechanisms mediate, perhaps in synergy with antigen-specific mechanisms, the immunopathology that finally leads to treatment-resistant Lyme arthritis in susceptible patients.
REACTIVE ARTHRITIS
Current understanding postulates the existence of two forms of reactive arthritis:
- Reactive arthritis of the type chronic infectious arthritis
Certain forms of reactive arthritis may represent authentic chronic infectious arthritis caused by slow growing organisms which are very difficult to cultivate and hence impossible to identify. In the light of current knowledge, this hypothesis would appear to hold for Chlamydia, Mycoplasma, and Borrelia, although not for enterobacteria. Such microbes enter the articular cavity during bacteraemia or within monocytes and can survive in small numbers in a "vegetative" state, probably with intermittent periods of replication triggered by still unknown phenomena.
These microbes have an attenuated virulence, unlike those responsible for septic arthritis. Such forms of reactive arthritis are thus related to a "slow" intrasynovial infection, a condition also called "slow infectious arthritis" or "infection reactive arthritis". Similarly, it is by invoking the same mechanisms that one explains today the arthritis of Whipple's disease, whereas for many years it was not possible to identify or cultivate this slow growing organism.
- Reactive arthritis of the type infection triggered aseptic arthritis
Some forms of reactive arthritis are probably aseptic and if so it is the persistence of bacterial antigens (lipopolysaccharides, heat shock proteins) which may explain the appearance of an inflammatory reaction in the synovium. This hypothesis applies above all to enterobacteria (Yersinia, Salmonella…), microbes not found in the joint except possibly in authentic (but rare) cases of acute septic arthritis. In chronic forms, it is unlikely that viable and active bacteria persist in the synovium, although it has occasionally been possible to detect bacterial DNA and even recently intrasynovial RNA in a case of reactive arthritis caused by Yersinia pseudotuberculosis. Conversely, it is likely that these bacteria survive at an extra-articular site, in particular in the mucosal membranes of the digestive system and/or the lymphatic ganglions, and are carried to the joint by monocytes, probably in recurrent fashion. In support of this theory, there is some evidence indicating that a preferential connection exists between gut and joints. It has been observed that mucosal leucocytes collected from patients with an inflammatory bowel disease can bind well to synovial vessels. This homing implies many receptors and their ligands, which differ according to the leucocyte subset, and mononuclear cells from peripheral blood do not share the binding characteristics of gut derived cells. Although these results only concern inflammatory bowel diseases, the concept can probably be applied to enteric reactive arthritis. After the homing, the bacterial antigens can subsequently persist sometimes for a long time in the synovium, in certain cases in the form of bacterial "ghosts" without nucleic acid. This type of arthritis, triggered by bacterial antigens originating from an extra-articular site in the absence of any viable intra-articular microbe, may be called "infection triggered reactive arthritis".
The appearance of arthritis is a consequence of the encounter between an arthritogenic bacterium and a predisposed host. Thus the key to the mystery of reactive arthritis will undoubtedly lie in a detailed study of these host-bacterium interactions, of which we already know some of the subtleties;
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All bacteria do not have the same arthritogenic potential. As an example, certain strains of Shigella flexneri contain a plasmid with a gene coding for a peptide sequence homologous to the HLA-B27 molecule, which could confer particular arthritogenic properties. The arthritogenic strains of Yersinia also possess plasmid and chromosome virulence factors which can modulate the processes of cellular adhesion and invasion.
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The immunogenetic characteristics of the host likewise have an important role, especially HLA-B27, but not necessarily as an antigen presenting molecule because studies based on this mechanism remain inconclusive. Indeed, it has been shown that the adhesion molecules of certain bacteria (Yersinia, Salmonella) use HLA-B27 as a ligand to attach to cells of the synovial environment. Moreover, in some genetically predisposed subjects, HLA-B27 appears to lack the ability to eliminate infected macrophages normally, thus facilitating the intra-articular persistence of the microbe (Salmonella). Recently, a new attractive hypothesis was proposed about the role of HLA-B27 in reactive arthritis, in that during the antigen processing and assembly pathway into the endoplasmic reticulum, HLA-B27 has a tendency to misfold even without any ß2m or peptide deficiency. This misfolding implicates the B pocket of the molecule and may, at least partially, explain the link between HLA-B27 and arthrogenicity. Misfolding can lead to a stress response which could increase the production of proinflammatory cytokines by an activation of NF-κB. Moreover, accumulation of HLA-B27 heavy chains might induce the formation of abnormal homodimers at the cell surface and in this way activate the immune system. However, some types of reactive arthritis are not linked to HLA-B27 but probably to other immunogenetic factors and one can distinguish at present the forms dependent on and independent of HLA-B27.
RHEUMATOID ARTHRITIS
Like Sisyphus, researchers attempting to develop models of rheumatoid arthritis have endured a wearisome existence. Much is still unknown concerning the pathogenesis of RA, but it is thought that to be triggered by exposure of an immunogentically susceptible host to an arthritogenic microbial antigen. Joint damage is mediated by the autoimmune reaction which activates CD4+ helper T cells, and causes the local release of inflammatory mediators & cytokines. Current thinking breaks down the pathogenesis into four major catergories; genetic susceptibility (which won’t be discussed here), joint damage mediators, autoimmunity and microbial agents.
Epstein-Barr virus is the current suspect as the microbial initiator of disease, with an interesting proposed mechanism. It has been demonstrated that most patients with RA have autoimmunity to Type 2 collagen. EBV and Type 2 collagen have some homologous HLA-DRB chain epitopes – so it’s possibly that an immunologic reaction against the EPV might cross-react to a joint cartilage rich in Type 2 collagen.
Following the initiation of inflammatory synovitis, whatever the exogenous agent might be – the chronic destructive nature of RA is mediated by the T-cells activated as part of the autoimmune reaction. Furthermore to the previous suggestion of Type 2 collagen as an autoantigen – it’s also postulated that glycoprotein-39 make have a role as it has been shown that it binds to DR4 peptides allowing the possibility of targeting by T-cell regulated immune reaction. Initially CD4+ cells dominate in the affected joints, but following the expression of ICAM-1 they are soon joined by other inflammatory cells, namely CD4 and T cells. The cytokines released by these inflammatory cells, especially IL-15, result in chronic immunological injury. In addition to this, CD4+ cells also activate B cells resulting in antibody production, including rheumatoid factor (an autoantibody to the Fc portion of autologous IgG). The IgM antibodies seem to predominate, and once in the circulation self-associate (RA-IgG) to form immune complexes which is a possible mechanistic explanation for the extra-articular manifestations of RA. However, one must note that there are a significant proportion of RA patients who are seronegative for rheumatoid factor & it is also present in the population without disease.
The destructive-proliferative synovitis is mediated mainly by cytokines, TNF, IL-1, IL-6, IL-15, interferon and growth factors (as well as proteases & elastases). The upregulation on synoviocytes of VCAM-1 facilitates the accumulation of white blood cells in the inflamed synovium. Furthermore, the VCAM-1 expressing synoviocytes adhere to the cartilage matrix that promotes the destruction of the articular surface by the synoviocytes.
In conclusion, it is clear to see that there is much interplay between the immune system & infectious agents in the pathogenicity of arthritis. It is clear that there is a balance that needs to be achieved by the immune system in dealing with infectious agents – and it seems that subtle imbalances can lead to the most heinous of diseases. Although there is still much for the scientific community to learn about the mechanistic pathology involved, our current knowledge is allowing relatively effective treatment of different manifestations of arthritis and offering a continually improving prognosis for sufferers.
