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Long-term persistence of clonally expanded T cells in patients with polymyositis.

Polymyositis is a CD8(+) T-cell-mediated disease. T-cell clonal expansions are observed at disease onset, but little is known about their persistence over time. Qualitative and quantitative spectratyping demonstrated that PM relapse features dramatically perturbed blood T-cell repertoires but is not associated with the emergence of new T-cell clones. It is striking that patients in remission also maintained all their T-cell repertoire abnormalities. The clonally expanded T-cells displayed a memory phenotype, expressed intracellular perforin, and dramatically responded to IL-2, showing a potent…

Granzyme A is critical for recovery of mice from infection with the natural cytopathic viral pathogen, ectromelia.

Cytolytic lymphocytes are of cardinal importance in the recovery from primary viral infections. Both natural killer cells and cytolytic T cells mediate at least part of their effector function by target cell lysis and DNA fragmentation. Two proteins, perforin and granzyme B, contained within the cytoplasmic granules of these cytolytic effector cells have been shown to be directly involved in these processes. A third protein contained within these granules, granzyme A, has so far not been attributed with any biological relevance. Using mice deficient for granzyme A, we show here that granzyme A…

Combined RNAscope and immunohistochemistry staining on duodenal paraffin sections as a new tool to reveal cytolytic potential of intraepithelial lymphocytes.

Immunohistochemistry (IHC) is a consolidated technique for the identification of surface and cytoplasmic antigens in cells or tissue sections using specific antibodies, yet simultaneous detection of two markers on the same cell may be difficult to achieve. Here we develop a protocol to perform a double staining using RNAscope, a new in-situ hybridization (ISH) technology, to visualize perforin transcripts, and classical IHC to visualize either CD8 or TcRγδ positive intraepithelial lymphocytes (IELs) in small intestinal paraffin sections of celiac disease (CD) patients. This double assay will a…

Inhibition of cytotoxic T lymphocyte-induced target cell DNA fragmentation, but not lysis, by inhibitors of DNA topoisomerases I and II.

Cytotoxic T lymphocytes (CTL) kill their target cells via a contact-dependent mechanism that results in the perturbation of the target cell's plasma membrane and the fragmentation of the target cell's DNA into nucleosomal particles. The membrane disruption is presumed to be due to the action of perforin, while the DNA fragmentation is thought to be by the activation of an endogenous nuclease(s). DNA topoisomerases I and II are nuclear enzymes with inherent endonuclease activities. We have investigated their role in the CTL-induced DNA fragmentation process. We report that in CTL killing assays…

Role of chemokines and their receptors in lesional CD8⁺ T cell homing in Indian Post-Kala-Azar Dermal Leishmaniasis.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis (VL) is considered as a reservoir that facilitates the transmission of VL. Although PKDL lesions demonstrate an overwhelming infiltration of CD8 ⁺ T cells, characterization of lesional CD8 ⁺ T cells, their tissue-homing chemokine receptors and corresponding ligands remains poorly defined, and was the aim of this study. METHODOLOGY: In patients with PKDL, CD8 ⁺ T cells were phenotyped in skin biopsies, in terms of senescence (CD8 ⁺ /CD57⁺), and cytotoxicity (expression of Perforin and Granzyme). T…

HLA-B*27 Heavy Chain Homo-Oligomers Promote the Cytotoxicity of NK Cells via Activation of PI3K/AKT Signaling.

Background and Objectives: Ankylosing spondylitis (AS) is a chronic inflammatory disease and is highly linked with the expression of the hum … d by NK-92MI cells. Results: Our results revealed that NK-92MI cells up-regulated the expression of perforin and enhanced the cytotoxic activity via augmentation of PI3K/AKT signaling after co-culturing with C1R-B*2704 cells. Suppression of the dimerized B*27-HC formation or treatment with an inhibitor of PI3K, LY294002, or with an anti-B*27-HC monoclonal …

Mass Cytometry Discovers Two Discrete Subsets of CD39-Treg Which Discriminate MGUS From Multiple Myeloma.

Multiple Myeloma (MM) is preceded by the clinically stable condition monoclonal gammopathy of undetermined significance (MGUS). Critical imm … ed at higher levels on BM-resident Treg than on activated Treg. Within BM, both subsets had limited Perforin and Granzyme B production, whilst activated Treg in PB acquired high Perforin and Granzyme B production. In conclusion, the use of mass cytometry and FlowSOM clustering discovered two discrete subsets of CD39-Treg which are discordant in MGUS and ND …

Potent immunotherapy against well-established thymoma using adoptively transferred transgene IL-6-engineered dendritic cell-stimulated CD8+ T-cells with prolonged survival and enhanced cytotoxicity.

BACKGROUND: Adoptive transfer of CD8(+) T-cells specific for tumor-antigens is an attractive strategy for anti-tumor therapy. In the present … mm in diameter). RESULTS: TA -cells displayed a higher level of expression of CD62 l, IL-7R, FasL, perforin and CCR6, and also exhibited more potent in vitro cytotoxicity to OVA-expressing EG7 thymoma cells via perforin- and Fas/FasL-mediated apoptosis than TB -cells. CD8(+) T-cell survival was kinetically analyzed in C57BL/6 mice transferred with TA - or …

Levels of CD56+TIM-3- effector CD8 T cells distinguish HIV natural virus suppressors from patients receiving antiretroviral therapy.

Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic e … of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receivin …

Comparison of human memory CD8 T cell responses to adenoviral early and late proteins in peripheral blood and lymphoid tissue.

Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific dono … his trend was reversed in PB. Tonsil epitope-specific CD8+ T cells expressed IFN-γ and IL-2 but not perforin or TNF-α, whereas PB T cells were positive for IFN-γ, TNF-α, and perforin. Tonsil epitope-specific T cells expressed lymphoid homing marker CCR7 and exhibited lower levels of the activation marker CD25 but higher proliferative potential than PB T ce …

γδ T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody.

BACKGROUND: Anti-CD20 monoclonal antibodies are major therapeutic agents for patients with follicular lymphoma and work through complement-m … ed GA101, the chimeric rituximab or the humanized ofatumumab. The ability of these cells to release perforin/granzyme and secrete interferon-γ when co-cultured with follicular lymphoma primary cells or cell lines in the presence or not of the three anti-CD20 monoclonal antibodies was also evaluated by CD107a staining and Elispot assays. RESULTS: Phosphost …

Immunologic Mediators in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of T-cell mediated immune disorders. While the contributory mechanisms leading to the apoptosis of epidermal cells in SJS/TEN remain unproven, the keratinocyte apoptosis seen in SJS/TEN is thought to occur through the T-cell mediated Fas-Fas ligand (FasL), perforin/granzyme B, and other immune mediators. Most recently, emphasis has been placed on the granulysin pathway as being the primary mediator of apoptosis and widespread epidermal necrosis in SJS/TEN. This article aims to review the proposed mechanisms by w…

Acquired Pure Red Cell Aplasia Secondary to Indolent Mature T-cell Lymphoid Malignancy.

Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by a marked decrease in reticulocytes and erythroid cells. For a long time up until today, PRCA has been clinically divided into idiopathic, thymoma-associated, and T-large granular lymphocytic leukemia (T-LGLL)-associated acquired PRCA (aPRCA). We herein report the case of a 90-year-old woman diagnosed with aPRCA secondary to an indolent mature T-cell malignancy atypical for T-LGLL. No apparent large granular lymphocytes were detected, tests for cytotoxic antigens, including granzyme B and perforin, were negative, and n…

Early Epcoritamab Administration Revives CAR-T Cells in Relapsed/Refractory B-Cell Lymphomas.

BACKGROUND: Bispecific antibodies are effective for relapsed/refractory B-cell lymphoma patients even after CAR-T therapy. METHODS: Peripheral blood CAR-T kinetics and functional analysis in vivo were carried out pre- and post-epcoritamab infusion in B-cell lymphoma patients relapsing after CAR-T therapy. RESULTS: CAR copy numbers spiked at relapse and rose again following epcoritamab administration. Expression levels of CAR-T exhaustion markers did not increase, whereas perforin and granzyme B expression increased after epcoritamab induction. CONCLUSION: Early epcoritamab administration wi…

Hepatosplenic gamma-delta T-cell lymphoma associated with Epstein-Barr virus.

Hepatosplenic gamma-delta T-cell lymphoma (HSTCL) is a rare, aggressive subset of peripheral T-cell lymphoma. It has been reported that Epstein-Barr virus (EBV) infection can cause HSTCL; however, such cases are extremely rare, with only a few cases having been reported to date. We herein report an autopsy case of HSTCL associated with EBV infection. The presence of EBV infection was confirmed in serum EBV DNA and on in-situ hybridization, and cytotoxic molecules, such as granzyme B, perforin and T-cell intracytoplasmic antigen (TIA)-1, were all positive in lymphoma cells. These findings indic…

CD8⁺CXCR5⁺ T cells regulate pathology in the genital tract.

We have identified a CD8⁺CXCR5⁺ T cell that prevents the development of oviduct dilation following C. muridarum genital infection. Phenotypic studies show that CD8⁺CXCR5⁺ cells express markers of T regulatory cells (FoxP3, CD25, and GITR) but do not express a necessary component of cytotoxic cells (perforin). Cxcr5⁻/⁻ mice have significantly lower numbers of CD8⁺ cells and lack the CD8⁺CXCR5⁺ population while the total number of CD4⁺ cells is equivalent between mouse strains. The transfer of CD8⁺ splenocytes from WT mice reduces the oviduct dilation seen in Cxcr5⁻/⁻ mice following C. muridarum…

Elranatamab: Роман B-клеточного созревания T-клеточного агента.

B-клеточное антигенное созревание (BCMA) — высоко выраженный трансмембранный рецептор на злокачественных плазменных клетках, который помогает выжить клеткам. Эти характеристики делают его привлекательной целью для новых клеточных и иммунотерапий. Elranatamab () — антитело, направленное против BCMA на плазменные клетки и CD3 на Т клетки. Это приводит к активации иммунных клеток и высвобождению гранзимов и перфоринов, что сопровождается убийством целевых клеток. Чрезмерная активация иммунной системы может привести к возникновению синдрома цитокина (CRS) и синдрома нейротоксичности иммунных клето

Совпадение в аннотации оригинала
B-cell maturation antigen (BCMA) is a highly expressed transmembrane receptor on malignant plasma cells, mediating cell survival. These char … sma cells and CD3 on T cells. This leads to immune cell activation and the release of granzymes and perforins, with attendant killing of target cells. Overactivation of the immune system can lead to cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Compared to similar agents, elranatamab has a favorable safety profi …

Recombinant live vaccine candidates against tuberculosis.

Tuberculosis (TB) remains among the most deadly health threats to humankind despite availability of several potent antibiotics and a vaccine … een genetically engineered to be attenuated, to overexpress TB antigens and/or to secrete bacterial perforins, ultimately seeking to trigger a robust immune response thereby providing long-lasting protection against TB.

[Aggressive NK/T cell leukemia/lymphoma associated with EBV].

The authors describe an unusual case of a young man presenting with fever, asthenia, anorexia and jaundice, associated to hepatosplenomegaly, evolving rapidly to multiorganic failure. Final diagnosis revealed an aggressive NK cell leukemia/lymphoma associated to the Epstein-Barr virus (EBV). The diagnosis, suggested clinically and after bone marrow immunophenotyping, was confirmed by morphologic and immunohistochemical findings on the post-mortem hepatic and splenic biopsy .The tumor cells were positive for CD3 and cytotoxic molecules, TIA, granzyme B and perforin. The herein reported case is …

CD8+ T-cell-mediated response to Listeria monocytogenes taken up in the liver and replicating within hepatocytes.

Like most other organisms that enter the bloodstream, the bulk of Listeria monocytogenes injected i.v. into mice is taken up by the liver. L … Ia- and class Ib-restricted CD8+ T cells in host resistance to Listeria. Evidence demonstrating the perforin- and/or Fas ligand-dependent induction of caspase activity and the resultant apoptosis of Listeria-infected hepatocytes is discussed.