Pemphigus vulgaris is a severe autoimmune disease caused by autoantibodies against the cutaneous adhesion molecule, desmoglein 3 (Dsg3). The aim of this study was to characterize the specificity of autoreactive Th cells, which presumably regulate Dsg3-specific autoantibody production. Ninety-seven Th1 and Th2 clones isolated from 16 pemphigus patients and 12 HLA-matched healthy donors recognized the Dsg3 peptides, DG3(78-94), DG3(96-112), DG3(189-205), DG3(205-221), and DG3(250-266). Peptide DG3(96-112), and to a lesser extent DG3(250-266), was recognized by the majority of T cells from patients and healthy donors in association with HLA-DRB1*0402 and DQB1*0503 which were prevalent in the pemphigus patients and Dsg3-responsive healthy donors. Analyzing the Vβ-chain of the TCR of the DG3(96-112)-specific T cells showed no restricted TCR usage. Peptides DG3(342-358) and DG3(376-392) were exclusively recognized by T cell clones (n = 13) from patients while DG3(483-499) was only recognized by T cell clones (n = 3) from a healthy donor. All Dsg3 peptides contained conserved amino acids at relative positions 1, 4, and 6; amino acids with a positive charge at position 4 presumably represent anchor motifs for DRB1*0402. These findings demonstrate that T cell recognition of distinct Dsg3 peptides is restricted by distinct HLA class II molecules and is independent from the development of pemphigus vulgaris.
The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated antigen by immunotherapeutical approaches based on HER2-directed monoclonal antibodies and cancer vaccines. We describe the adoptive transfer of autologous HER2-specific T-lymphocyte clones to a patient with metastatic HER2-overexpressing breast cancer. The HLA/multimer-based monitoring of the transferred T lymphocytes revealed that the T cells rapidly disappeared from the peripheral blood. The imaging studies indicated that the T cells accumulated in the bone marrow (BM) and migrated to the liver, but were unable to penetrate into the solid metastases. The disseminated tumor cells in the BM disappeared after the completion of adoptive T-cell therapy. This study suggests the therapeutic potential for HER2-specific T cells for eliminating disseminated HER2-positive tumor cells and proposes the combination of T cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors.
Numerous reports describe osteonecrosis after oral corticosteroid therapy. It is still uncertain if corticosteroid treatment alone or in combination with other factors leads to the development of this condition. The literature presents controversial clinical and experimental data. The most affected site for osteonecrosis is the femoral head and therefore our considerations are concentrated at this site. Oral corticosteroids are commonly used in dermatology, especially in the treatment of connective tissue diseases and hypersensitive diseases. This clinical review evaluates the relationship between and the onset of femoral head necrosis. Although osteonecrosis of the femoral head can be caused by various conditions such as trauma, excess alcohol and hemoglobinopathies, studies indicate that treatment with corticosteroids is the most common cause of the condition. There is some controversy on the role of underlying disease and total corticosteroid dose administered, in the development of osteonecrosis of the femoral head. MRI scans are used to establish an early diagnosis. There are several surgical and nonsurgical options for disease management, dependent on the stage of disease, the age of the patient and other risk factors. In general, the risk for osteonecrosis is considered to be low under oral corticosteroid therapy. So far, no data can establish a direct relationship, but data still strongly suggest an existing cause and effect relationship. Further investigations are necessary for example, a large controlled prospective long-term study, to further refine an association between the corticosteroid dose, the duration of treatment and other risk factors. Dermatologists who prescribe oral corticosteroids, should always be aware of the potential risk of avascular femoral head necrosis and the patients should be informed about this severe complication of oral coricosteroid therapy.
Pemphigus foliaceus (PF) is a severe autoimmune bullous disorder, characterized by autoantibodies (autoAb) against desmoglein 1 (Dsg1). As T cells may be critical in the pathology of PF, the aim of the present study was to identify and characterize autoaggressive T-helper cells reactive to Dsg1 in PF patients and healthy individuals. Eight patients with the clinical diagnosis of PF and six HLA class II-matched healthy individuals were examined. By magnetic cell-sorting (MACS) cytokine-secretion assay, Dsg1-responsive T-helper (Th) 1 and Th2 cells were isolated and cloned by limiting dilution. The generated T-cell clones (TCC) were characterized regarding proliferative response, TCR Vbeta-chain usage, and cytokine profile upon in vitro stimulation with Dsg1. Both Dsg1-reactive Th1 and Th2 cells were detected in PF patients and controls at similar frequencies. A total of 15 Th1 and Th2 clones were isolated from patients and 27 TCC from healthy controls. Analysis of TCR Vbeta-chain usage of autoreactive T cells from both groups revealed no predominance of a specific Vbeta chain. Noteworthy, the isolated TCC showed a polarized Th1- or Th2-like phenotype upon in vitro culture and stable expression of Th1 or Th2 cytokines during long-term in vitro culture. In summary, our data demonstrate that T-cell autoreactivity against Dsg1 is not restricted to patients with PF. Moreover, both Th1 and Th2 cells were present in patients and healthy donors, suggesting that the loss of B-cell tolerance against Dsg1 in PF is not exclusively determined by the presence of autoaggressive T cells.
The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated Ag by T cell-based immunotherapeutical strategies such as cancer vaccines and adoptive T cell transfer. The prerequisite for a successful T cell-based therapy is the induction of T cells capable of recognizing the HER2-expressing tumor cells. In this study, we generated human cytotoxic T cell clones directed against the HER2369–377 epitope known to be naturally presented with HLA-A*0201. Those HER2-reactive CTLs, which were also tumor lytic, exhibited a similar lysis pattern dividing the targets in lysable and nonlysable tumor cells. Several HER2-expressing tumor cells became susceptible to CTL-mediated lysis after IFN-γ treatment and, in parallel, up-regulated molecules of the Ag-presenting machinery, indicating that the tumor itself also contributes to the success of CTL-mediated killing. Some of the HER2369–377-reactive T cells specifically cross-reacted with the corresponding peptides derived from the family members HER3 and/or HER4 due to a high sequence homology. The epitopes HER3356–364 and HER4361–369 were endogenously processed and contributed to the susceptibility of cell lysis by HER cross-reacting CTLs. The principle of “double” or “triple targeting” the HER Ags by cross-reacting T cells will impact the further development of T cell-based therapies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.