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T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazol-induced skin reaction.

BACKGROUND: The incidence of skin rashes or erythema multiforme to sulfamethoxazole in exposed patients is about 3%. Among patients with acq … without interferon gamma pretreatment were used as target cells. Selective blockers of FasL/Fas and perforin-mediated killing and immunostaining for perforin were used to evaluate the involvement of the different cytolytic pathways. RESULTS: CD4+ and CD8+ sulfamethoxazole specific T-cell clones showed a drug-specific and MHC-restricted cytotoxicity agains …

Expression and function of synaptotagmin VII in CTLs.

The Ca(2+) sensor synaptotagmin (Syt) VII regulates the exocytosis of conventional lysosomes in several cell types. In CTLs, the Ca(2+)-regulated exocytosis of lytic granules/secretory lysosomes is responsible for the perforin/granzyme-mediated lysis of target cells. To investigate the role of Syt VII in CTL effector function, the expression and function of Syt VII were examined in wild-type and Syt VII-deficient mice. In comparison with Syt VII(+/+) controls, Syt VII(-/-) animals were impaired in their ability to clear an infection with the intracellular pathogen Listeria monocytogenes. When …

Granzyme A and B-deficient killer lymphocytes are defective in eliciting DNA fragmentation but retain potent in vivo anti-tumor capacity.

Recent studies have demonstrated that granzymes A and B make an important contribution to the clearance of the orthopoxvirus ectromelia, and in graft versus host disease. To test whether granzymes are generally necessary for lymphocyte-mediated cytotoxicity in vivo, we assessed the cytotoxic capacity of granzyme A and/or B-deficient lymphocytes in several perforin-dependent settings. Splenocytes and allogeneic CTL of granzyme A and/or B-deficient mice were defective for induction of DNA fragmentation, but induced significant membrane damage and target cell death. These results correlated well …

Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity.

Interactions between inducible co-stimulatory molecule (ICOS) and ICOS-ligand (ICOS-L) are crucial for T-cell co-stimulation, effector cell differentiation and memory CD8+ T-cell activation. Because in the muscle of patients with sporadic inclusion body myositis (sIBM) clonally expanded CD8+ T cells invade major histocompatibility complex (MHC) class I-expressing muscle fibres, we investigated ICOS.ICOS-L interactions and correlated their expression with perforin, a marker for cytotoxic effector function by autoinvasive CD8+ T cells. The mRNA from 20 muscle biopsies of sIBM, 20 non-inflammator…

Pathology of the liver in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis is a rare, rapidly progressive disorder characterized by an activation of the immune system resulting in a systemic proliferation of lymphocytes and histiocytes. The disease is genetically heterogeneous and maps to at least 4 loci including the gene encoding perforin, a protein critical for the cytotoxic and regulatory functions of T lymphocytes and natural killer (NK) cells. Hepatic dysfunction often occurs early in the clinical course, but the pathology of the liver is not well characterized. The clinical history, laboratory data, and pathologic ma…

Интерферон-гамма имеет важное значение для уничтожения бета-клеток и развития сахарного диабета с инсулиновой зависимостью.

Аутоиммунное разрушение бета-элементов островов Лангерхана ведет к инсулиннозависимому сахарному диабету (IDDM). Трансгенные мыши (LCMV), которые выражают нуклеопротеин (NP) или гликпротеин (GP) LCMV под контролем RIP в их бета-элементах, разрабатывают IDDM после инфекции с LCMV и служат моделью для IDDM с вирусом. Недавно Каги и др. (Каги, Д., Б. Одерматт, П. Охаши, Р.М. Зинкернагейл и Х. Хенгартнер, 1996, Дж. Эксп. Мед. 183:2143-2149 показал, используя RIP LCMV perforin-definente mice, что IDDM не происходит при отсутствии перфорина. Они пришли к выводу о том, что цитотоксичные лимфоциты (КТ…

The development of anti-PD-1 antibody-induced spinal cord injury in bone marrow transplant C57BL/6 Rag1-/- mouse model.

Aims: This paper was to scrutinize the toxicity mechanism of anti-programmed death 1 (anti-PD-1) therapy-caused spinal cord injury (SCI).Methods: Bone marrow transplant Rag1-/- mice were used to establish SCI model.Results: Anti-PD-1 results in SCI via CD8+ T-cells activation, while excessive activation of CD8+ T-cells further aggravated SCI. Both anti-PD-1 and the activation of CD8+ T-cells induced the expression of apoptosis-related perforin, GrB and FasL, but suppressed PI-9 level. The opposite results were observed in the effects of neuroserpin on these factors. CD8+ T-cells activation ind…

A knockout approach to understanding CD8+ cell effector mechanisms in adaptive immunity to Listeria monocytogenes.

In the described experimental approach, we use an attenuated LM strain to evoke LM specific CD8+ T cell responses. In this fashion, we can immunize immunocompromised gene knockout mice, that would succumb to low level infection with virulent LM. We then generate antigen matched, LM-specific CD8+ T cell lines from wild-type and gene knockout mice, and compare their capacity to provide immunity to LM infection in vivo. To date, our results demonstrate that CD8+ T cell-derived IFN-gamma and TNF are not required effector functions. Perforin deficiency has an impact on CD8+ T cell immunity but our …

Decreased DNA methyltransferase levels contribute to abnormal gene expression in "senescent" CD4(+)CD28(-) T cells.

A senescent CD4(+)CD28(-) T cell subset develops with aging and in chronic inflammatory diseases like rheumatoid arthritis, and is implicated in plaque rupture and myocardial infarctions. This subset is pro-inflammatory, cytotoxic for endothelial cells, and aberrantly expresses genes like CD70, perforin and killer cell immunoglobulin-like receptor (KIR) genes. Why CD4(+)CD28(-) cells overexpress these genes is unclear. We found that the CD70, perforin and KIR2DL4 promoters are demethylated in CD4(+)CD28(-) T cells, and that DNA methyltransferase 1 (Dnmt1) and Dnmt3a levels are decreased in thi…

Expression of granulysin in polymyositis and inclusion-body myositis.

BACKGROUND: Granulysin, a recently defined cytolytic molecule, is expressed in cytotoxic T cells and natural killer cells in a similar way to perforin, which is reported to have a major role in the pathogenesis of polymyositis and inclusion-body myositis (IBM). OBJECTIVE: To clarify the role of granulysin in polymyositis and IBM. METHODS: The expression of granulysin and perforin was examined by double staining with CD8, CD4 and CD56 in endomysial infiltrating cells and autoinvasive cells in muscle biopsy specimens of 17 patients with polymyositis (6 steroid resistant and 11 steroid responsi…

Altered pathological progression of diaphragm and quadriceps muscle in TNF-deficient, dystrophin-deficient mice.

We have previously demonstrated a role for T cells in Duchenne muscular dystrophy (DMD) using the mdx mouse and have shown that T cell killing of dystrophic muscle can occur through perforin-dependent and perforin-independent mechanisms. In this investigation, we explore the possibility that one perforin-independent mechanism utilized by the T cells is cytokine-based killing, specifically by tumor necrosis factor (TNF). We tested this hypothesis by generating mice that are TNF-deficient and dystrophin-deficient (TNF-/mdx). Body mass and muscle mass of the TNF-/mdx mice were significantly less …

Isolation and analysis of human natural killer cell subsets.

Natural killer (NK) cells were originally defined as mediators of spontaneous cytotoxicity against virus-infected and tumor cells. In human peripheral blood, the majority of NK cells can mediate cell lysis mainly through perforin and granzymes. It has been recently shown, however, that the majority of NK cells in human secondary lymphoid organs are primarily immunoregulatory by secreting cytokines immediately after activation and do not express perforin and granzymes. Because lymph nodes (LN) harbor 40% and peripheral blood only 2% of all lymphocytes in humans, this newly characterized NK cell…

Natural killer cell and gamma delta T cell alterations in enthesitis related arthritis category of juvenile idiopathic arthritis.

Enthesitis related arthritis (ERA) is associated with increased frequency of Th17 cells and synovial fluid (SF) IL-17 levels. Natural killer (NK) and gamma delta T cells have been recently shown to produce IL-17, thus we studied the NK and gamma delta-T cells in peripheral blood (PB) of 50 ERA, 16 other JIA patients and 19 healthy controls. We have analyzed the frequency of NK (total, CD56dim, CD56bright) and gamma delta-T cells, perforin and KIR3DL1/2 expression on NK cells and IL-17 and IFN-gamma production by them using flow cytometry. ERA patients had more NK cells with reduced perforin ex…

Pore-forming proteins share structural and functional homology with amyloid oligomers.

Degenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are believed to be causally related to the accumulation of amyloid oligomers that exhibit a common structure and may be toxic by a common mechanism involving permeabilization of membranes. We discovered that amyloid oligomers and the pore-forming bacterial toxin, alpha-hemolysin (alpha HL), as well as human perforin from cytotoxic T lymphocytes, share a structural and functional homology at the level of their common reactivity with a conformation-dependent antibody that is specific for amyloid oligomers, A11. The…

T-bet expression in CD8+ T cells associated with chronic hepatitis B virus infection.

BACKGROUND: The mechanisms leading to virus-specific CD8+ T cell dysfuction in chronic hepatitis B virus (HBV) infection remain to be elucidated. Our study focused on the role of transcription factor T-bet in HBV infection because it is a crucial regulator of T cell immunity. METHODS: We assessed the expression of T-bet along with PD-1, IFN-γ and perforin, in HBV-specific CD8+ T cells from resolved acute hepatitis B (rAHB) patients, chronic hepatitis B (CHB) patients, as well as asymptomatic HBV carriers (ASCs). We observed dynamic changes of T-bet, PD-1, IFN-γ and perforin in acute stage and…

Immunophenotyping of interstitial infiltrate does not distinguish between BK virus nephropathy and acute cellular rejection.

INTRODUCTION: BK virus nephropathy (BKVN) is a significant cause of late renal allograft loss. It is characterized histologically by an inte … ion serologically or histologically in these patients. Immunohistochemical staining with anti-CD20, perforin and granzyme B was performed on remaining tissue samples. RESULTS: Clustered B cells were demonstrated in both BKVN and ACR. Hence, the CD20-stained component within the interstitial infiltrate was not useful in distinguishing these biopsies. Perfo …

Distinct synovial immunopathology in Behçet disease and psoriatic arthritis.

INTRODUCTION: The aim of the study was to investigate synovial immunopathology differences between early Behçet disease (BD) and psoriatic arthritis (PsA). METHODS: Needle arthroscopy of an inflamed knee joint was performed in patients with early untreated BD (n = 8) and PsA (n = 9). Synovial fluid (SF) was collected for cytokines, perforin, and granzyme analysis. Eight synovial biopsies per patient were obtained for immunohistochemical analysis of the cellular infiltrate (T cells, natural killer cells, macrophages, B cells, plasma cells, mast cells, and neutrophils), blood vessels as well as…

Interferon gamma (IFN-γ) negative CD4+ and CD8+ T-cells can produce immune mediators in response to viral antigens.

Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-γ secreting cells. However, T-cells are capable of producing many more functions than just IFN-γ, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-γ secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive indi…

Functional study of peripheral blood CD8 + T cells in Epstein-Barr virus-associated infectious mononucleosis.

BACKGROUND: This study aimed to explore the function and clinical significance of peripheral blood CD8 + T cells in EBV-associated infectious mononucleosis (IM). METHODS: From June 2022 to May 2024, blood samples of 48 IM children and 24 healthy controls were collected. ELISA detected IFN-γ, IL-10, TGF-β1 levels, and RT-PCR measured perforin and granzyme B mRNA levels. RESULTS: results showed higher white blood cell, lymphocyte counts, etc. in the case group. Also, more CD3+, CD3 + CD8+ and NK cells, lower CD4+/CD8 + ratio were found in cases. IFN-γ, IL-10, perforin, granzyme B were higher, wh…

Сигнал Interleukin-1R необходим для впрыскивания проапопототических CD8 Т клеток, вирусной расчистки и патологии при лимфоцитном хориомингите в мышах.

Для борьбы с гепатотропическим лимфоцитным штаммом хориоменита WE (LCMV-WE) необходим траектория экзоцитоза в клетках Т (LCMV-WE), но также способствует наблюдаемой патологии у мышей. Хотя эффективный антивирусный иммунитет клеток Т и развитие вирусного гепатита строго зависят от перфорина и гранзимов, молекулярная основа, лежащая в основе индукции функционально компетентных к вирусу клеток Т, включая участие врожденной иммунной системы, еще далека от решения. Мы демонстрируем здесь, что LCMV-immune T клетки интерлейкина-1 рецептора (IL-1R)-дефицитных мышей легко резюмируют стенограммы перфори

Совпадение в аннотации оригинала
The T cell granule exocytosis pathway is essential to control hepatotropic lymphocytic choriomeningitis virus strain WE (LCMV-WE) but also contributes to the observed pathology in mice. Although effective antiviral T cell immunity and development of viral hepatitis are strictly dependent on perforin and granzymes, the molecular basis underlying induction of …