Ponse cross-reactive with a self-derived B27 ligand displaying antigenic mimicry, hence
Ponse cross-reactive using a self-derived B27 ligand showing antigenic mimicry, as a result breaking the self-tolerance and triggering an autoimmune attack (25). Despite the fact that this mechanism does not satisfactorily explain AS pathogenesis, because the HLAB27-associated spondyloarthopathy in transgenic rats will not need CD8 T-cells (26), it may effectively play a role in exacerbating the proinflammatory nature of HLA-B27, particularly in ReA. Certainly, splenocytes from rats immunized with HLA-B27 and stimulated in vitro with Chlamydia-treated cells from HLA-B27 transgenic rats resulted within the generation of Chlamydia-specific CD8 T-cells (27). Moreover, splenocytes from HLA-B27 transgenic rats immunized with HLA-B27 developed HLA-B27-directed autoreactivity upon exposure to C. trachomatis in vitro (28). The immunological relationship among Chlamydia and HLA-B27 revealed by these studies was suggestive of molecular mimicry between bacterial and self-derived HLA-B27-restricted epitopes. In spite of issues in substantiating molecular mimicry as a mechanism of autoimmunity (29), it played a key ATM custom synthesis function inside the pathogenesis of Chlamydia-induced autoimmune myocarditis in mice (30). Thus, there’s a sound basis to search for HLA-B27-restricted chlamydial T-cell epitopes and their doable connection to self-derived HLAB27 ligands (31). Predictive binding and proteasomal cleavage algorithms had been utilized to localize putative chlamydial epitopes. The candidates were tested for recognition by specific CTL from transgenic mice or HLA-B27 ReA individuals (32) or utilized for creating B27 tetramers to detect peptide-specific T-cells (33). These studies ACAT1 Compound identified some HLA-B27-restricted epitopes for which distinct CTL may be identified in Chlamydia-infected ReA sufferers. Having said that, because of the intrinsic cross-reactivity of T-cells (34), recognition of a synthetic peptide in vitro does notSEPTEMBER six, 2013 VOLUME 288 NUMBERguarantee that this peptide could be the actual immunogenic epitope in vivo. The direct biochemical identification of endogenous chlamydial T-cell epitopes from infected cells has been achieved only in the mouse technique (35, 36). It truly is hardly feasible in humans, resulting from the extremely low amounts of bacterial epitopes on infected cells, the issues linked with functioning with massive amounts of Chlamydia-infected human cells, and, particularly, the down-regulation of MHC-I expression and induction of apoptosis by C. trachomatis (19, 37). Therefore, we developed an alternative method involving the stable expression of chlamydial fusion proteins on HLA-B27 human cells. Endogenously processed chlamydial peptides, including a predicted T-cell epitope, were identified by comparing the HLA-B27-bound peptidomes from transfected and untransfected cells. These research (38, 39) were based on comparative MALDI-TOF MS and concerned three chlamydial proteins containing sequences extremely homologous to recognized human-derived HLA-B27 ligands or from which synthetic peptides were recognized by CTL from ReA sufferers: DNA primase (DNAP) (CT794), Na -translocating NADH-quinone reductase subunit A (NQRA) (CT634), and pyrroloquinoline-quinone synthase-like protein (PqqC) (CT610). In two different research, depending on a predictive search for HLA-B27-restricted chlamydial ligands in ReA patients (32, 33), a sequence from ClpC protein, spanning residues 75, was recognized as a synthetic peptide by CD8 T-cells from many people, suggesting that this epitope might be immunodominant. Right here we applied MS t.
