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Modulating Cytolytic Responses to Infectious Pathogens
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Rebecca Pogue Caley, Jeffrey A. Frelinger
Once the peptides are generated in the cytosol, they are transported into the lumen of the endoplasmic reticulum (ER), where they are bound by the class I heavy chains (Figure 1). The major mechanism in the antigen presentation pathway for peptides to be transported is through the transporter complex. The transporter associated with antigen processing (TAP) consists of two subunits, TAP-1 and TAP-2. Cells lines which lack functional TAP molecules show a marked decrease in their cell surface levels of class I [12,15]. Some human leukocyte antigen A2 (HLA-A2) class I complexes which reach the cell surface in the mutant cell line T2 have bound signal sequence derived peptides [16,17]. While the signal sequence pathway provides some of the peptides bound to class I, the majority of peptides entering the antigen presentation pathway enter via the TAP pathway. Transfection of the TAP genes into the TAP-deficient cell lines restores antigen presentation and cell surface MHC levels [18–20]. The subunits of TAP-1 and TAP-2 are 76 and 70 kDa, respectively, and are noncovalently associated. They are thought to function as a dimer, although it is unclear whether high-order multimers occur. The TAP molecules belong to a family of transport proteins which contain an adenosine triphosphate-(ATP)-binding cassette [21]. The TAP-dependent peptide transport is ATP-dependent [22].
Major Histocompatibility Complex and Autoimmune Disease
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Ursula Holzer, Gerald T. Nepom
When considering an association of autoimmune diseases and HLA class II polymorphism, it is often considered whether other genes in the class II region may be involved in the pathogenesis of some of these diseases. TAP1 and TAP2 genes are localized in the class II region between HLA-DP and HLA-DQ,2 and TAP gene polymorphism may influence the specificity of peptides preferentially presented by the MHC molecules and the outcome of the immune response.11 Whereas some groups find an association of particular TAP alleles with autoimmunity e.g., with systemic lupus erythematosus (SLE) or rheumatoid arthritis,14,13 others do not.14,15
Biochemical Aspects of Nickel Hypersensitivity: Factors Determining Allergenic Action
Published in Jurij J. Hostýnek, Howard I. Maibach, Nickel and the Skin, 2019
Baldassarré Santucci, Emanuela Camera, Mauro Picardo
Isolated studies concerning HLA class III polymorphisms in nickel-sensitive subjects put in evidence a statistically significant high frequency of the subtype BF FB (Orecchia et al., 1992). The authors suggested that this polymorphic serum protein might be involved in the pathogenesis of the disease. Recently, a study was undertaken to see whether the genes TAP1 and TAP2, whose alleles control the immune response to peptides, were involved in the susceptibility to nickel allergy (Silvernnoinen-Kassinen et al., 1997). Two populations of 55 nickel-sensitive subjects and 54 nonsensitive subjects were TAP1 and TAP2 typed by amplification refractory mutation system-polymerase chain reaction. While the allele and phenotypic frequencies of TAP2B were significantly increased, the allele frequency of TAP2C was decreased in nickel-sensitive subjects. The conclusion drawn by the authors was that TAP2B increases the risk for nickel allergy with a considerably high etiological factor.
Hypoxia increases mutational load of breast cancer cells through frameshift mutations
Published in OncoImmunology, 2020
Goutham Hassan Venkatesh, Pamela Bravo, Walid Shaaban Moustafa Elsayed, Francis Amirtharaj, Bartosz Wojtas, Raefa Abou Khouzam, Husam Hussein Nawafleh, Sandeep Mallya, Kapaettu Satyamoorthy, Philippe Dessen, Filippo Rosselli, Jerome Thiery, Salem Chouaib
Since our data point out an alteration of DNA repair and an increase of somatic mutations in hypoxic breast carcinoma cells, we finally investigated whether hypoxic conditions lead to the generation of neoantigens. Neo-antigen predictions were performed using the exome sequence data using NeoPredPipe. We observed a global increase in the number of neoantigen in both hypoxic MCF-7 and MDA-MB-231 cells (Figure 4a), regardless of the binding. The number of neoantigen generated from the frameshift mutations was higher in MDA-MB-231 in comparison to MCF-7, irrespectively of the hypoxic exposure. Further, the number of weakly binding neoantigens were much higher in comparison to strong-binding across chronic and intermittent hypoxic conditions in both cell types (Figure 4a). Among the total neoantigens (includes weak- and strong-binding), all of them were of the clonal type. Furthermore, our microarray analysis demonstrated the upregulation of antigen processing and presentation pathway, in MDA-MB-231 cells with respect to chronic and intermittent hypoxia (Figure 4b). Validation through quantitative PCR also showed an increase in expression of TAP1 and TAP2 genes in MDA-MB-231 cells (Figure 4c).
Identification of miR-200a-5p targeting the peptide transporter TAP1 and its association with the clinical outcome of melanoma patients
Published in OncoImmunology, 2020
Maria-Filothei Lazaridou, Evamaria Gonschorek, Chiara Massa, Michael Friedrich, Diana Handke, Anja Mueller, Simon Jasinski-Bergner, Reinhard Dummer, Peter Koelblinger, Barbara Seliger
To further determine the effect of miR-200a-5p on TAP1 expression in melanoma cell lines, miR-200a-5p mimics and a miR mimic NC were transiently transfected into BUF1379, FM3 and FM81 cells. Overexpression of miR-200a-5p was obtained in all three melanoma cell lines, while cells transfected with the NC showed a relative expression pattern when compared to parental cells (Figure 6A). For Western blot analysis, melanoma cells only transfected with the transfection reagent named “Control” served as an additional control to the NC. Overexpression of miR-200a-5p in BUF1379 and FM3 cells caused a 40% downregulation of TAP1 mRNA and protein levels compared to that of the NC or control samples (Figure 6B,G,H). Furthermore, miR-200a-5p overexpression only caused a downregulation of TAP1, but not of other APM components, such as TAP2, TPN, LMP2 and HLA-I HC (Figure 6C–G). This was accompanied by a decreased HLA-I surface expression particularly of HLA-BC in the miR-200a-5p transfectants (Figure 6I–kK). As expected, the mRNA and protein expression levels of control transfectants were comparable to that of parental samples.
Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas
Published in OncoImmunology, 2019
Daniëlle Verver, Vichnou Poirier-Colame, Gorana Tomasic, Khadija Cherif-Rebai, Dirk J. Grunhagen, Cornelis Verhoef, Stefan Suciu, Caroline Robert, Laurence Zitvogel, Alexander M.M. Eggermont
Notewithstanding, ulceration is the overriding determinant of activity of adjuvant IFN therapy. Kirkwood’s group evaluated STAT1 and STAT3 jointly as mediators of type 1 IFN effects in the setting of a prospective neoadjuvant trial of high dose IFNa2b (HDI), in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1 and pSTAT3 was performed on paired fixed or frozen biopsies in about 20 patients. HDI tilted the balance between pSTAT1 and pSTAT3, upregulating the former and down regulating the latter. Higher pSTAT1/pSTAT3 ratios in tumor cells or lymphocytes pretreatment were associated with longer overall survival. Moreover, TAP2 was augmented by HDI (but not TAP1 and MHC class I/II).60 pSTAT1 results from IFNAR1/IFNAR2 receptor signaling cascade, culminating in type 1 IFN or ISG transcription. Our data showing that MHC class I molecules and surrounding Mx1 expression characterized ulcerated lesions imply that the IFNAR signaling cascade may be intact and trained in tumor cells of ulcerated lesions, accounting for the ability of IFNa2b to promptly phosphorylate STAT1 downstream of this cascade.