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Peptides derived from amino acid sequence 60-80 of HLA-B27 (B27PA, aa 60-72 and B2702PA, aa 60-80) mimic cytokeratin and are able to induce in vitro proliferation of human peripheral blood lymphocytes as well as arthritis in Lewis rats. Here we show that the pathogenic epitope recognized by autoaggressive rat T cells is located at the N-terminus of the sequence, between aa 60 and 72. A C-terminally elongated 25mer peptide (B2702.60-84) showed increased pathogenicity, indicating either a second arthritogenic epitope or an immunomodulatory region within this peptide. B2702.60-84 has been described to inhibit murine and human CD8 + cytotoxic T cells (CTL) and was even successfully used for the treatment of allograft rejection. In addition to pathogenicity we have investigated the immunomodulatory effect of peptide B2702.60-84 in our rat model of experimental autoimmune uveitis (EAU), induced with retinal S-Antigen peptide PDSAg. We found that disease exacerbated following coimmunization of PDSAg with B2702.60-84. In vitro, the B27-peptide enhanced the proliferation of CD4+ T cell lines specific for retinal autoantigen peptides during coincubation of B2702.60-84 with the respective antigen. Oral tolerance induction, an effective mechanism to prevent uveitis in Lewis rats, is abrogated by cofeeding peptide B2702.60-84 with the tolerogen PDSAg. In rat EAU, naturally occurring regulatory T cells and orally induced gamma deltaTCR+ suppressor cells are CD8+ which might be impeded by peptide B2702.60-84. As a consequence of their abrogated suppressive capacity disease was exacerbated. We propose a similar role of HLA-B27 in man: disturbing the mechanisms down-regulating self-responses might lead to autoimmune diseases. This could explain the high association of HLA-B27 with a variety of autoimmune diseases targeting different organs or tissues.

Oral tolerance induction with peptide B27PD had an ameliorating effect in uveitis patients, which was also observed in the five-year follow-up period. Repeated treatments with peptide B27PD were also effective. Side effects did not occur in this patient group, not even in patients receiving peptide for up to 42 weeks.

Gamma-delta T cells from orally tolerized rats adoptively transfer suppression of experimental autoimmune uveitis. In vivo and in vitro these regulatory cells specifically recognize retinal autoantigen peptide PDSAg and its mimotope B27PD, but not other mimicry peptides. Proliferation of gamma/delta T cells was MHC class II and CD8 dependent.

Ankylosing spondylitis (AS) is highly associated with HLA-B27. We have previously shown that peripheral blood lymphocytes from AS patients respond to stimulation with a peptide from the sequence of HLA-B27. Here we report on molecular mimicry of peptides from HLA-B27 and cytokeratin, the latter being specifically expressed in synovial membranes and eyes, the main targets of the autoaggressive immune response in AS patients. Immunization of rats with these peptides induced an inflammatory response in joints, spine and eyes, resembling the symptoms in AS. Furthermore, both HLA-B27- and cytokeratin-derived peptides, are effective oral tolerogens: feeding these peptides ameliorated arthritis and uveitis induced with the cytokeratin peptide. Our model might elucidate the role of peptides from the sequence of HLA-B27 as an antigen of the immune response in AS, introducing a new aspect of antigenic mimicry between HLA-B27 and tissue-specific antigens. We propose this as a mechanism directing a systemic autoimmune response to specific target organs by antigenic mimicry of T cell epitopes.

Immune response to retinal autoantigens plays a central role in the pathogenesis of uveitis. A synthetic peptide (B27PD) from a common sequence of various HLA-B molecules associated with uveitis, such as HLA-B27 and 51, which shares amino acid homologies with a retinal-S antigen (S-Ag)-derived peptide (PDSAg), was shown to be immunogenic in human and experimental uveitis in the rat. In this study we investigated T cell responses to B27PD and PDSAg in patients with Behçet's disease and posterior uveitis (BD-posterior uveitis; n = 33) in comparison with non-Behçet anterior uveitis (AU, n = 14), Behçet's patients without uveitis (BD, n = 15) and healthy controls (HC, n = 32) in a 6-day proliferation assay. Patients with BD and posterior uveitis had significantly higher responses (stimulation index (SI) 2.8 +/- 1.3) than those with AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.1 +/- 0.4) and HC (SI 1.1 +/- 0.6) for B27PD (P < 0.0001). Responses to PDSAg were also higher in BD with posterior uveitis patients (SI 3.3 +/- 1.6) than AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.2 +/- 0.3) and HC (SI 1.1 +/- 0.6) (P < 0. 0001). A significant correlation between the responses to PDSAg and B27PD (r = 0.56, P < 0.001) was observed. Elevated levels of IL-2 and tumour necrosis factor-alpha were also observed in culture supernatants obtained from peripheral blood mononuclear cells after stimulation with the peptides, but no correlation was found between the proliferative responses and cytokine levels. These results suggest that cellular immunity to cross-reactive HLA-B and S-Ag-derived peptides might play a role in the pathogenesis of posterior uveitis in BD.

Endogenous uveitis is a T cell mediated autoimmune disease leading to impairment of visual acuity. The association of different uveitis entities with HLA-class I antigens and the discovery of antigenic mimicry between a peptide of uveitis-associated HLA-class I antigens and a peptide of retinal autoantigen led to a new hypothesis for the pathogenesis of uveitis. On the basis of this mechanism an open trial of oral tolerance induction with the HLA-peptide B27PD was initiated for nine patients with long lasting, therapy-refractive uveitis. Within 6 weeks of oral peptide treatment all patients responded with a marked decrease of intraocular inflammation, which allowed a reduction of systemic corticosteroids in seven patients. One patient, who suffered from an acute relapse, responded within 2 weeks, followed by an increase of visual acuity. In addition, two patients discontinued azathioprine immediately prior to oral tolerance induction without the occurrence of relapses. Visual acuity remained unchanged or increased in 14 of 16 eyes. One patient did not finish oral peptide treatment. None of these patients experienced any adverse events. It was concluded that the oral application of highly tolerogenic peptides might be a potent approach for the treatment of autoimmune diseases.