Disease relevance of SILV

• Tyrosinase and gp100 are expressed in a higher percentage of melanomas than TRP-1(gp75), and the expression of these three antigens was discordant [1].
• All three patients positive for Pmel17 antibodies (aged 50-63 years) had had vitiligo of the symmetrical type for > 1 year and all of them also had an associated autoimmune disorder: GD in one and autoimmune hypothyroidism in two [2].
• In contrast, sera from 20 healthy controls, 10 patients with Hashimoto's thyroiditis and 10 patients with Graves' disease (GD) were all negative for Pmel17 antibodies [2].
• Angiomyolipomas (AMLs) show a characteristic immunoreactivity with melanocyte differentiation markers such as monoclonal antibody (mAb) HMB45, which detects melanocyte differentiation antigen gp100 and mAb A103 reacting with Melan-A/MART-1 [3].
• METHODS: Three pigment cell specific (PCS) markers-tyrosinase, Pmel-17, and MART-1-and one cancer testis antigen (CTA)-MAGE-3-were selected for use in a multimarker RT-PCR assay [4].

High impact information on SILV

• In this study, immunodominant peptides from the gp100 melanoma-associated antigen were identified, and a synthetic peptide, designed to increase binding to HLA-A2 molecules, was used as a cancer vaccine to treat patients with metastatic melanoma [5].
• CTLp's recognizing MAGE-C2 and gp100 antigens were already present before vaccination, but new clonotypes appeared afterwards [6].
• We additionally show that melanosome-containing multivesicular bodies degranulate extracellularly and release FasL-bearing microvesicles, that coexpress both gp100 and CD63 and retain their functional activity in triggering Fas-dependent apoptosis of lymphoid cells [7].
• Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1 [8].
• To induce autoreactive T cells, we studied immune responses to gp100/pmel 17, an antigen naturally expressed by both normal melanocytes and melanoma cells [9].

Chemical compound and disease context of SILV

• Anti-Pmel17 immunoprecipitates from metabolically pulse labeled melanoma cells and melanocytes contain, in addition to full-length Pmel17, a glycoprotein that migrates with a lower relative molecular weight [10].
• We assessed the incidence of SI in offspring of Framingham Heart Study (FHS) patients following unrecognized myocardial infarction (UMI) and in controls without MI but who were matched for age, sex, hypertension, diabetes, smoking, and total cholesterol at entry into the FHS [11].
• This study was undertaken to determine whether patients with silent ischemia (SI) (a positive thallium stress test without chest pain) have nonchest-pain symptoms that might serve as "anginal equivalents." Two hundred ninety-four individuals on completing a stress test were requested to score ten symptoms on a questionnaire (0 absent; 3 severe) [12].
• These results show that administration of liposomes containing dexamethasone attenuated SI-induced pulmonary inflammation and fibrosis in rats, and that this protection is independent of some biochemical and functional parameters of damage [13].
• At Day 20, the DEX-LIP treatment significantly reduced the SI-induced increase in right lung/total body weight ratio and right lung hydroxyproline content, a biochemical index of fibrosis [13].

Biological context of SILV

• In this study, we have used biochemical and immunochemical approaches to more critically assess the synthesis, processing, glycosylation, and trafficking of gp100 [14].
• Polyvalent melanoma cell vaccine treatment enhanced anti-MAA antibody responses; however, only anti-TRP-2 and anti-gp100/pmel17 antibody response was enhanced [15].
• When we re-examined the products of wild-type and silver-mutant mouse si loci, RT-PCR of wild-type RNA and genomic DNA sequence accounted for gp87 but excluded the occurrence of Pmel17 [16].
• However, no sequence homology was found between either of the Pmel17 epitopes and the aforementioned proteins [17].
• We identified three previously unknown peptides processed from melanosomal proteins tyrosinase (presented by HLA-A(*)2601 and -B(*)3801) and gp100 (presented by HLA-B(*)07021) and five neoantigens generated by somatic point mutations in the patient's melanoma [18].

Anatomical context of SILV

• Heterogeneous expression of immunotherapy candidate proteins gp100, MART-1, and tyrosinase in human melanoma cell lines and in human melanocytic lesions [19].
• Tumor regression was thus correlated with the recognition of gp100 by the administered T cells (p = 0.0048) [20].
• Following its arrival, gp100 is cleaved at the amino and at the carboxyl termini in a series of specific steps that result in the reorganization of immature melanosomes to the fibrillar mature melanosomes [14].
• Four of ten HLA-A2-restricted melanoma specific CTL that were derived from tumor-infiltrating lymphocytes (TIL) and administered to patients recognized the gp100 melanoma Ag and nine of ten recognized the MART-1 Ag [20].
• Epitope mapping of the melanosomal matrix protein gp100 (PMEL17): rapid processing in the endoplasmic reticulum and glycosylation in the early Golgi compartment [14].

Associations of SILV with chemical compounds

• The internal proline/serine/threonine-rich repeat domain (called the RPT domain) of PMEL17 undergoes variable proteolytic cleavage [21].
• These mRNAs encode tyrosinase, the most essential enzyme for melanin synthesis, and gp100, a melanosomal matrix glycoprotein recognized by monoclonal antibody HMB-45 [22].
• While CLOT and CLIM are broad-spectrum antimycotics of the azole-type, SILV is a sulphonamide compound with antibacterial and antimycotic properties used topically in veterinary medicine [23].
• We performed Minimal Inhibitory Concentration (MIC)-testings of 40 clinical isolates of M. pachydermatis against climbazole (CLIM), clotrimazole (CLOT) and silver-sulphadiazine (SILV) [23].
• Replacement of either cysteine residue with alpha-amino butyric acid in the gp100 peptide, RLPRIFCSC, enhanced CTL recognition, suggesting that the peptide epitope naturally presented on the tumor cell surface may contain reduced cysteine residues [24].
• Analysis of Pmel17 processing in glycosylation-deficient mutant cells reveals that Pmel17 lacking the correct addition of sialic acid and galactose loses the ability to form fibrils [25].
• These results demonstrate that the release of the Pmel17 ectodomain, which is critical for melanin amyloidogenesis, is initiated by S2 cleavage at a juxtamembrane position [26].

Physical interactions of SILV

• We show that MART-1 forms a complex with Pmel17 and affects its expression, stability, trafficking, and the processing which is required for melanosome structure and maturation [27].
• The Marek's disease herpesvirus B antigen (MDHV-B) complex was previously immunologically identified and molecularly characterized as a set of three glycoproteins designated gp100, gp60, and gp49 on the basis of apparent molecular weight and immunoprecipitation with both polyclonal and monoclonal antibodies [28].

Regulatory relationships of SILV

• The full-length promoter, including a consensus binding site for MITF was found to contain sequences that suppressed gp100 expression [29].
• Retroviral transduction of primary human T lymphocytes with either one of the two sets of TCRalphabeta constructs enabled T lymphocytes to specifically kill and produce TNF-alpha when triggered by native gp100(pos)/HLA-A2(pos) tumor target cells as well as gp100 peptide-loaded HLA-A2(pos) tumor cells [30].
• PURPOSE: We examined in vivo particle-mediated epidermal delivery (PMED) of cDNAs for gp100 and granulocyte macrophage colony-stimulating factor (GM-CSF) into uninvolved skin of melanoma patients [31].

Other interactions of SILV

• MART-1 is required for the function of the melanosomal matrix protein PMEL17/GP100 and the maturation of melanosomes [27].
• Interestingly, gp100 and TRP-2 gene transcripts were detected in patients having recurrent and/or metastatic disease at the time of testing [32].
• To identify the epitopes recognized by these four gp100-reactive CTL, 169 peptides containing HLA-A2.1 binding motifs were synthesized and screened for their recognition by TIL using cytotoxicity and IFN-gamma release assays [20].
• Adoptive transfer of the four gp100-reactive CTL, but not the other TIL, resulted in tumor regression when infused into autologous patients along with IL-2 [20].
• Expression characteristics of four other MAAs-Tyr, Tyrp1, Dct, and gp100/Pmel17-were analyzed by RT-PCR [33].

Analytical, diagnostic and therapeutic context of SILV

• RESULTS: PCR tests for gp 100, Muc-18, and p97 reacted with RNA in blood from healthy subjects and were considered unsuitable for patient monitoring [34].
• In five of seven patients of the latter group, gp100 reverse transcriptase-polymerase chain reaction was carried out, showing also gp100 mRNA in nonsentinel lymph nodes only [35].
• Recognition of gp100 by HLA-A2 restricted TIL significantly correlated with clinical response to adoptive immunotherapy with TIL in 21 HLA-A2 melanoma patients (p = 0.024) [36].
• Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination [37].
• Especially where these peptides may be used in human clinical trials for the treatment or prevention of cancer, there is substantial need for direct evaluation of HLA-A*0201-associated peptides from MART-1 and gp100 that are naturally processed and presented [38].

References