Retinal S-antigen Th1 cell epitope mapping in patients with Behcet’s disease

Abstract

Background Retinal S-antigen (S-Ag) is a most characterized autoantigen of autoimmune uveitis. The recognized immunodominant epitope of human S-Ag in patients with uveitis has not been identified. In this study, we selected certain patients with active uveitis to map the Th1 cell epitope spectrum of human S-Ag in Behcet's disease(BD). Methods Blood samples were taken from eight active BD patients who showed an immune response to 40 mixed overlapping peptides spanning the entire sequence of human S-Ag. Peripheral blood mononuclear cells were isolated and stimulated with single S-Ag peptide at 5 μg/ml or 20 μg/ml. Single-cell immune responses were measured by IFN-γ ELIspot assay. Results BD patients heterogeneously responded to the SAg peptides at two concentrations. In general, the responses to 5 μg/ml peptides were slightly stronger than those to 20 μg/ml peptides, while the maximum SFC frequency to single peptide at the two concentrations was similar. Several peptides including P31, P35 and P40 induced a prominent response, with the frequency of S-Ag specific cells being about 0.007%. Significant reactivity pattern shift was noted in patients with different disease courses. Conclusions Certain active BD patients have S-Ag specific Th1 cells with a low frequency. The S-Ag epitope specificity between patients is highly heterogeneous, and varies with the uveitis course.

Advances in Pathogenesis of Behcet’s Disease and Vogt- Koyanagi-Harada Syndrome

“…The increased levels of IFN-γ and T-bet, which is considered as the critical transcriptional factor for Th1 cells, have been observed in the peripheral blood of the patients with active uveitis of BD and VKH syndrome [11][12][13][14]. Our study found that S-Ag specific T cells may be involved in the pathogenesis of BD via the production of Th1-dominant cytokines, but not Th17 cytokines [15]. The increased levels of Th1 cell specific cytokines and chemokines in the cerebrospinal fluid (CSF) of VKH patients and in the lesions of active BD patients were also reported [16][17].…”

Effective Arrestin–Specific Immunotherapy of Experimental Autoimmune Uveitis with RTL: A Prospect for Treatment of Human Uveitis

“…In fact, a number of patients have shown in vitro lymphocyte proliferation against multiple arrestin peptides. 21,23,24,40,41 Our results show that RTL351 effectively inhibited T cell proliferation against pathogenic epitope Arr 291-310 and also induced other tolerogenic responses to protect the mice from disease. EAU in DR3 þ Tg mice is driven by a combination of the T cell-and antibody-effector mechanisms.…”

“…The effectiveness of the treatment with a monospecific RTL351 designed to target the Arr 291-305 -specific CD4 T cells also induced tolerogenic effects, leading to the suppression of EAU induced by the whole arrestin molecule that contains multiple epitopes in these mice 31 and also in humans. 23,35,40 Next, we attempted to determine the minimal effective dose of RTL351 in suppression of EAU in treatment experiments using from 10 to 100 lg RTL351. The dose of 100 lg RTL351 was extremely effective and completely suppressed anterior and posterior intraocular inflammation in majority of humanized mice with arrestin-induced EAU.…”

“…19 Patients showed significant blood lymphocyte proliferative responses against various arrestin peptides. 21,22,35,40,41 The maximum T cell proliferation was found in response to peptides from the 231-270 amino acid region of the human arrestin sequence, and also in response to arrestin uveitogenic ''N'' peptide 281-302 and ''M'' peptide 303-320, suggesting that these epitopes play a major role in pathogenesis of a subset of human uveitis. 35 Pathogenic epitopes corresponding to the previously identified peptide ''N'' were also defined in the humanized HLA-DR3 transgenic mouse model of arrestin-induced EAU.…”

Decreased Expression of the Aryl Hydrocarbon Receptor in Ocular Behcet’s Disease

“…Although the pathogenesis of BD is still not completely understood, it is currently thought that environmental factors may trigger the development and recurrence of this disease in a genetically susceptible host [ 3 ]. It is classified as an example of an autoinflammatory disorder with marked involvement of both Th1 and Th17 lymphocyte subsets [ 4 – 7 ]. Consistently, strategies aimed at suppressing the abnormal Th1 and Th17 cell response have been reported as a therapeutic approach in BD patients, which is supported by findings in experimental autoimmune uveitis (EAU) models in mice [ 8 , 9 ].…”