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Epidemiology, Pathogenesis, and Genetics of Ankylosing Spondylitis
Published in Barend J. van Royen, Ben A. C. Dijkmans, Ankylosing Spondylitis Diagnosis and Management, 2006
Andrew E. Timms, B. Paul Wordsworth, Matthew A. Brown
Whether these unusual properties of B27 have any relevance to human disease remains unproven. A further level of complexity is that there are different hypotheses as to how homodimers may cause disease. One hypothesis suggests that B27-homodimers induce disease as a consequence of intracellular accumulation. However, it has also been proposed that they may act by some extracellular mechanism such as aberrant presentation of peptides or recognition by immune cells [either natural killer (NK) cells or cytotoxic T-lymphocytes] (66). B27 can be expressed on the surface of cells in the absence of the TAP complex, tapasin, and peptide (67–70). This may explain the finding that mice B27+ mβ2m-/-hβ2m+ TAP1- mice develop arthritis as do mice with intact TAP (B27+ mβ2m-/- hβ2m+ TAP1+), although with a lower frequency (54% vs. 69%) (71). B27 homodimers are expressed on the cell surface, but do not appear to be derived from intracellular sources; rather they are produced from B27 heterodimers either at the cell surface or in endocytic compartments (66). High affinity peptide-binding by B27 heterodimers appears to reduce the homodimer formation (66). Further, high affinity binding of a B27-specific peptide in B27-transgenic rats reduces the incidence of spondyloarthritis, perhaps by effects on homodimer formation (72). It has therefore been postulated that bacterial triggering infections may promote homodimer formation by interference with the peptide-loading complex, or by changing the intracellular oxidative conditions promoting disulfide bond formation (66). It has been demonstrated that a variety of B and T lymphocytes and synovial and peripheral blood monocytes express receptors for B27 homodimers (73). Whether these have any pathogenic significance remains unknown.
The role of immunoinformatics in the development of T-cell peptide-based vaccines against Mycobacterium tuberculosis
Published in Expert Review of Vaccines, 2020
David Ortega-Tirado, Aldo A. Arvizu-Flores, Carlos Velazquez, Adriana Garibay-Escobar
MHC-I molecules display peptides that come from the degradation of cytosolic proteins both pathogenic and self-proteins. These proteins are ubiquitin ligated with the subsequent degradation of the proteasome into 8–16 aminoacids peptides which are translocated by the TAP complex (transporter associated with antigen processing complex) into the lumen of endoplasmic reticulum (ER) [22,23]. TAP selects peptides on the basis of the size and C-terminal position, giving preference to the peptides with hydrophobic residues in this position [22,23]. The MHC-I molecules are assembled in the ER and coupled to tapasin and the chaperones calreticulin and Erp57 to form the peptide loading complex (PLC). Before peptides can be loaded into MHC-I molecules, they undergo trimming by the aminopeptidase ERAAP to generate 8–10 aminoacids peptides which are preferred by MHC-I molecules [20]. After this process, PLC catalyzes the binding of high affinity peptides to MHC-I molecules. Finally the peptide-MHC-I complex is transported to the surface of the APC (antigen presenting cell) to be presented to a CD8+ T-cell Figure 1.
ERAP1: a potential therapeutic target for a myriad of diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Emma Reeves, Yasmin Islam, Edward James
The initial steps in antigen presentation begin in the cytosol, where the first processing event is undertaken by the proteasome, or under inflammatory conditions, the immunoproteasome. Proteins are targeted for degradation by the ubiquitin-proteasome system, and results in the generation of smaller peptide fragments [5]. The proteasome/immunoproteasome cleavage pattern often results in a hydrophobic C-terminal residue, which is optimal for loading into the F-pocket of the peptide binding groove of most MHC I [5]. A subset of proteasomal products are translocated into the ER by the transporter associated with antigen processing (TAP) heterodimer. Interestingly, the preferences of TAP for longer peptides (10–16 amino acids) means that many peptides enter the ER as extended precursors that will require further processing by ER aminopeptidase 1 (ERAP1), and to a lesser extent ERAP2, before they are of optimal length for MHC I binding [6]. pMHC I assemble in the ER from a polypeptide heavy chain, β2microglobulin and peptide, usually of 8–10 amino acids in length. These peptides are edited and loaded on to MHC I in association with the peptide loading complex (PLC); TAP, tapasin, ERp57 and calreticulin (Figure 1). Interestingly, the peptide binding groove of most MHC I is highly polymorphic, giving rise to multiple MHC I alleles that can each display a variety of different peptides. Binding of peptides into the peptide binding groove stabilizes the pMHC I complex, which subsequently dissociates from the PLC and transits to the cell surface for immunosurveillance [4].
Proteogenomics: advances in cancer antigen research
Published in Immunological Medicine, 2019
Takayuki Kanaseki, Toshihiko Torigoe
The antigen processing begins in the cytoplasm where endogenous proteins are digested by the proteasomes. The fragmented polypeptides are transported into the endoplasmic reticulum (ER) through the transporter associated with antigen processing (TAP). In the ER, the peptide precursors are trimmed by the ER-resident aminopeptidase associated with antigen processing (ERAP1 or ERAAP) and optimized for HLA class I binding. Peptide loading complex (PLC) that comprises tapasin, ERp53, calreticulin, and TAP helps form stable pHLA I most likely by peptide exchange. Lack of any of the machinery influences the presentation mechanism, thereby alters pHLA I surface repertoire. Thus, pHLA I on display samples a wide range of ‘gene-chips’ of the cell according to the elaborated, but complicated, antigen-processing pathway [4,5].