Arthritogenic peptide hypothesis

Because the main function of HLA Class I molecules is to present peptide antigens to cytotoxic CD8+ T-cells it has been proposed that the antigen presenting properties of HLA-B27 could be crucial in the pathogenesis of spondy-loarthropathies, the so called 'arthritogenic peptide hypothesis' [24]. It suggests that some B27 subtypes, due to their unique amino acid residues, bind specific arthritogenic peptides, which are recognised by CD8+ T-cells. Furthermore, in response to these bacterial peptides, autoreactive T-cells recognising antigens with sufficient structural similarity between bacteria and self might become activated by self-peptides.

One major support for this hypothesis comes from the differential association of some of the HLA-B27 subtypes with AS (see above), because the relevance of the single AA-substitutions in the antigen-binding groove of the HLA-B27 molecule can best be explained by presentation of peptide(s) by the susceptible HLA-B27 subtype, but not by the resistant one, to CD8+ T-cells.

To prove this hypothesis researchers have tried in the past to identify antigens presented by HLA-B27 to CD8+ T-cells. Most studies were performed first in patients with ReA because in this disease the triggering bacteria are known. After an early report about an HLA-B27-restricted CD8+ T-cell response against whole bacteria in ReA patients [25] we could demonstrate more recently a synovial CD8+ T-cell response to a peptide from Yersinia heat shock protein 60 in patients with Yersinia-induced ReA [26] and also an HLA-B27-restricted CD8+ T-cell response to peptides derived from several Chlamydial proteins in patients with Chlamydia-induced ReA [27]. In the latter study a novel approach for the search of the whole Chlamydial proteom for arthritogenic peptides was applied to identify peptides which stimulate patients' derived CD8+ T-cells in an HLA-B27 restricted manner. For this we combined two computer prediction algorithms, first, for the binding of peptides to the HLA-B27 molecule and, second, for the cleavage of proteins/peptides by proteasomes in the cytosol [27].

Although a bacterial trigger seems to be necessary to set the disease off there is currently no evidence that microbial antigens do persist in such diverse structures as the sacroliliac joint, the enthesis, or the eye. Thus, CD8+ T-cell responses directed against autoantigens, which are presented by HLA-B27, have also been investigated in the past. Along this line, a CD8+ T-cell response to an EBV-epitope derived from the LMP2 protein and to a sequence-related self peptide from the autoantigen 'vasoactive intestinal peptide receptor (VIP) 1' was reported [28], suggesting that molecular mimicry might play a role.

However, such a ubiquitous autoantigen could not explain the location of inflammation (sacroiliac joint and spine) found in AS. More recently, the question about the primary target of the immune response in AS has been discussed intensively [29]. Based mostly on magnetic resonance imaging (MRI) and immunohis-

tology studies several recent articles have proposed that the cartilage is the primary target of the immune response in AS/SpA [29-32]. Therefore, extracellular matrix proteins from human cartilage and fibrocartilage are attractive candidate targets of an immune response in this disorder. The G1-domain of the proteogly-can aggrecan has been of special interest in the past because inflammation could be induced in an animal model resembling AS by immunisation with this protein [33]. We could also show an antigen-specific HLA-B27 restricted CD 8+ T-cell response and the occurrence of arthritis in HLA-B27-transgenic mice immunised with aggrecan-derived peptides [34, 35]. Furthermore, we showed recently that PB CD4+ T-cells and CD8+ T-cells derived from AS patients are reactive to aggrecan-specific antigens [36]. However, we could also show that in humans such a CD8+ T-cell response to peptides derived from the G1-domain of aggrecan is not HLA-B27 restricted [37], making it unlikely that the aggrecan protein is the source of an arthritogenic peptide. Collagens, especially collagen type II, are also important proteins of cartilage. In an earlier study the HLA-B27 restricted CD8+ T-cell response to four peptides (two from collagen II, two from collagen XI), which showed a good binding to HLA-B27 in vitro, were studied in patients with AS and reactive arthritis, but only one ReA patient and none of the AS-patients showed an HLA-B27-restricted CD8+ T-cell response specific for one of these peptides [38].

Recently we used a more comprehensive approach to look for potentially arthri-togenic peptides in AS patients. We investigated all cartilage-derived proteins for the presence of peptides which would be presented by HLA-B27 and would be immun-odominant for CD8+ T-cells derived from the synovial fluid from AS patients. For this we used again the two computer prediction programs (for HLA-B27-binding of peptides and for cleavage of peptides by proteasomes), as described above. Interestingly, we could determine one nonameric peptide from collagen type VI which was recognised by CD8+ T-cells in four out of seven AS-patients [39]. Further studies are in progress to test whether CD8+ T-cells specific for cartilage-derived peptide can be found at the site of inflammation.

An oligoclonal expansion of T-cells has also been demonstrated for CD8+ T-cells in ReA. The synovial fluid derived from different HLA-B27 positive patients suffering from ReA and triggered by different bacteria revealed an astonishing high homology of T-cell receptors [40]. These results lead to the suggestion that similar antigens are recognised by these oligoclonally expanded CD8+ T-cells which implies the possibility that under certain conditions specific arthritogenic peptides might indeed be produced and presented to the hosts immune system.

Because none of these HLA-B27-restricted CD8+ T-cell responses were directed against bacterial and/or self antigens, a pathogenetic role could not be proven -other hypotheses have been put forward and tested to explain the association between HLA-B27 and AS and other SpA.

The HLA-B27 misfolding hypothesis and the formation of beta-2-m-free HLA-B27 homodimers

The 'HLA-B27 misfolding hypothesis' states that HLA-B27 itself is directly involved in the pathological process of SpA, a hypothesis that does not include the physiological role of HLA-B27 to present specific antigens. It has been shown that HLA-B27 has a tendency to misfold in the endoplasmatic reticulum which could then induce a proinflammatory stress response [41]. The misfolding is suggested to be due to a particular feature of HLA-B27: newly synthesised HLA-B*2705 seems to fold by and associate with beta 2-microglobuline more slowly in comparison to other MHC Class I molecules.

Allen and co-workers [42] reported that, possibly as a consequence of HLA-B27 misfolding, free HLA-B27 heavy chains (HC) can form abnormal HC homodimers. These researchers could indeed show subsequently that beta(2)m-free HLA-B27 homodimers and multimers are expressed both intracellularly and at the cell surface of leukocytes, dendritic and other cells. They could further demonstrate that such HLA-B27 homodimers expressed by antigen presenting cells can interact with paired immunoglobulin-like receptors on monocytes or B-cells, a process which could then induce or perpetuate immunopathology, independently from specific antigens [43].

HLA-B27-restricted CD4+ T-cell responses

Recently HLA-B27 restricted CD4+ T-cells have been described [44]. It was speculated that the B27-homodimers might mimic MHC Class II molecules and might therefore be capable to present a yet unidentified (auto-)antigen to CD4+ T-cells, which could then be responsible for the local immunopathology found in AS and other SpA [45].

HLA-B27 and intracellular survival of bacteria

A completely different hypothesis is based on the finding that bacteria survive longer after invasion of HLA-B27+ cells compared to HLA-B27-negative cells. Again, the significantly slower folding rate (misfolding) of HLA-B27 intracellularly had been discussed as a possible explanation for this finding [46]. A more recent study could also show in in vitro experiments that wild-type HLA-B27-positive cells were more permissive of intracellular replication of Salmonella enteritides compared with HLA-A2-transfected control cells [47]. By substituting single amino acids these authors provided evidence that the bacteria permissive phenotype was dependent on glutamic acid substitution at position 45 in the B pocket of the HLA-B27 molecule.

However, the exact mechanism of how this could contribute to a different behaviour of intracellular bacteria was not clarified.

Unfortunately, until now none of the hypotheses presented here to explain the strong association between HLA-B27 and ankylosing spondylitis could be proven. Therefore, more than 30 years after the first description of this association there remains an interesting field for future research.

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