Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells

Heusel, Jonathan W.; Wesselschmidt, Robin L.; Shresta, Sujan; Russell, John H.; Ley, Timothy J.

doi:10.1016/0092-8674(94)90376-x

Cited by 778 publications

(551 citation statements)

References 59 publications

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“…Subsequently, granzyme B-deficient cells were found to have defects in DNA fragmentation, thereby confirming a role for granzyme B in apoptosis [85]. Indeed, granzyme B has the same substrate specificity as caspases and cleaves caspase-3 as well as caspase-8, caspase-10 and Bid [86][87][88][89].…”

Section: Cell-mediated Cytotoxicitymentioning

confidence: 84%

How apoptosis got the immune system in shape

Feig

Marynen

2007

Eur. J. Immunol.

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Section: Cell-mediated Cytotoxicitymentioning

confidence: 84%

How apoptosis got the immune system in shape

Feig

Marynen

2007

Eur. J. Immunol.

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“…GzmA À / À , 32 GzmB À / À , 33 GzmA À / À B À / À 34 and Pfp À / À 35 mice were generated as previously described and maintained at the Peter MacCallum Cancer Centre. All mice were maintained under SPF conditions.…”

Section: Methodsmentioning

confidence: 99%

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

et al. 2013

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Human and mouse granzyme (Gzm)B both induce target cell apoptosis in concert with pore-forming perforin (Pfp); however the mechanisms by which other Gzms induce non-apoptotic death remain controversial and poorly characterised. We used timelapse microscopy to document, quantitatively and in real time, the death of target cells exposed to primary natural killer (NK) cells from mice deficient in key Gzms. We found that in the vast majority of cases, NK cells from wild-type mice induced classic apoptosis. However, NK cells from syngeneic Gzm B-deficient mice induced a novel form of cell death characterised by slower kinetics and a pronounced, writhing, 'worm-like' morphology. Dying cells initially contracted but did not undergo membrane blebbing, and annexin-V staining was delayed until the onset of secondary necrosis. As it is different from any cell death process previously reported, we tentatively termed this cell death 'athetosis'. Two independent lines of evidence showed this alternate form of death was due to Gzm A: first, cell death was revealed in the absence of Gzm B, but was completely lost when the NK cells were deficient in both Gzm A and B; second, the athetotic morphology was precisely reproduced when recombinant mouse Gzm A was delivered by an otherwise innocuous dose of recombinant Pfp. Gzm A-mediated athetosis did not require caspase activation, early mitochondrial disruption or generation of reactive oxygen species, but did require an intact actin cytoskeleton and was abolished by latrunculin B and mycalolide B. This work defines an authentic role for mouse Gzm A in granule-induced cell death by cytotoxic lymphocytes.

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“…On follow-up biopsies of responders cell death decreased consistently, specifically by 68% for cell necrosis and 86% for cell apoptosis, allowing cell repair and proliferation to become effective biological events for the improvement of cardiac function. Several mechanisms may have concurred to cell rescue including: (a) removal of natural killer cells and activated T-lymphocytes that with their perforins and granzymes produce damage of myocyte membrane inducing cell necrosis and DNA fragmentation leading to apoptosis; 16,17 (b) Inhibition of cytokine and free radical production (particularly TNF-a and IL-1) that can activate intracellular caspase cascade and ultimately myocyte apoptosis; 18 (c) reduction of reactive oxygen species production (including NO), that at high levels can induce necrosis while at lower levels can trigger apoptosis; 19 (d) reduction of left ventricular load due to the improvement of cardiac dimensions and contractility. 20 It is noteworthy that even severe degrees of cell death can be remarkably slowed or stopped if the treatment is really able to interfere with the underlying mechanism of damage.…”

Section: Role Of Cell Deathmentioning

confidence: 99%

Cell death, proliferation and repair in human myocarditis responding to immunosuppressive therapy

et al. 2006

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In this study, we evaluate cell death, proliferation and repair in left ventricular endomyocardial biopsies from 20 patients with active lymphocytic myocarditis worsening or recovering from cardiac dysfunction after 6-months immunosuppression. Apoptosis and necrosis were assessed by in situ ligation of hairpin probes, proliferation by Ki67 and MCM5 labelling of myocytes, repair by electron microscopy, morphometric study of percent myofibrillar area and real-time polymerase chain reaction of a-and b-Myosin Heavy Chain (MHC). Apoptosis and necrosis decreased in post-vs pretreatment biopsies by 85 and 62%, respectively in responders, while increased by 42 and 46% in nonresponders. Ki67 and MCM5-positive myocytes were higher vs controls at baseline and increased by 43 and 38% at follow-up in responders and by 75 and 63% in nonresponders. Myofibrillar area reduced in pretreatment samples, increased by 33% at follow-up in responders, correlated with percent enhancement of ejection fraction and was associated with increased a-MHC expression and a/b-MHC ratio. In follow-up biopsies of nonresponders, myofibrillar area diminished by 36% and correlated with percent decrease of ejection fraction. Our results suggest that recovery of cardiac function in myocarditis responding to immunosuppression is associated with inhibition of cell death, activation of cell proliferation and with newly synthesized contractile material. Keywords: myocarditis; heart failure; immunosuppressive therapy; apoptosis; myofibrillolysis; cell repair It has been recently shown that immunosuppression can be an effective therapeutic option in active lymphocytic myocarditis, 1,2 characterized by the presence of circulating serum cardiac autoantibodies and undetectable viral agents at the PCR evaluation of frozen endomyocardial samples. Cell mechanisms of cardiac recovery are, however, still speculative and may include halting of proteolysis and cell death, activation of cell proliferation and reconstitution of cell myofibrillar content. The contribution of each of these mechanisms has not yet been analyzed, while its definition may identify new strategies for the treatment of heart failure.The aim of this study is a morphologic, morphometric and molecular evaluation of cell death, cell proliferation and repair in sequential endomyocardial biopsies of patients with myocarditis and heart failure, deteriorating and recovering, respectively, after immunosuppressive therapy. Materials and methods Patient SelectionAmong 41 patients that at our Institution from January 1997 to July 2000 were treated for 6 months with immunosuppressive therapy (prednisone 1 mg kg À1 day À1 for 4 weeks followed by 0.33 mg kg À1 day À1 for 5 months and azathioprine 2 mg kg À1 day À1 for 6 months) in addition to full conventional therapy with digitalis, diuretics, ACE inhibitors and carvedilol because of active lymphocytic

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Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells

Cited by 778 publications

References 59 publications

How apoptosis got the immune system in shape

How apoptosis got the immune system in shape

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

Cell death, proliferation and repair in human myocarditis responding to immunosuppressive therapy

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