Cutting Edge: Granzyme B Proteolysis of a Neuronal Glutamate Receptor Generates an Autoantigen and Is Modulated by Glycosylation

Gahring, Lorise C.; Carlson, Noel G.; Meyer, Erin L.; Rogers, Scott W.

doi:10.4049/jimmunol.166.3.1433

Cited by 115 publications

(81 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our association of granzyme B immunoreactivity with advanced atherosclerotic disease, and localization of granzyme B to apoptotic cells, suggests that this cytotoxic immune factor may further contribute to acute coronary syndromes through a similar mechanism as FasL. Alternatively, because granzyme B proteolysis has been implicated in the generation of autoantigens in certain autoimmune diseases, granzyme B activity in atheromatous lesions could also lead to the generation of autoantigens in affected vessels (28).…”

Section: Discussionmentioning

confidence: 98%

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

et al. 2003

View full text Add to dashboard Cite

Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD).Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD. Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle ␣-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0 -5؉/5؉ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle ␣-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells. Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.

show abstract

Section: Discussionmentioning

confidence: 98%

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

et al. 2003

View full text Add to dashboard Cite

show abstract

“…In addition, GzmB can degrade cartilage proteoglycans potentially to exacerbate autoimmune or inflammatory arthritis (197,198). In the central nervous system, GzmB cleaves a glutamate receptor (GluR3), potentially contributing to immunoneurotoxicity, excitation, and autoimmunity in the brain (199,200). GzmB on its own causes death of neurons in a pertussis toxin-sensitive manner, suggesting possible cleavage or involvement of G protein-coupled receptors (201).…”

Section: Extracellular Roles Of Granzymesmentioning

confidence: 99%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

571

580

View full text Add to dashboard Cite

The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.

show abstract

“…One property that unifies most autoantigens targeted across the spectrum of autoimmunity, which is not shared by non-autoantigens, is susceptibility to cleavage by the cytotoxic lymphocyte granule protease, granzyme B (GB) (12)(13)(14)(15)(16)(17)(18). During cytotoxic lymphocyte granulemediated cell death, proteolysis by GB allows for the generation of autoantigen fragments not observed during other forms of cell death.…”

mentioning

confidence: 99%

Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: Insights into the association of specific autoantibodies with distinct disease phenotypes

Ulanet¹,

Flavahan²,

Casciola‐Rosen³

et al. 2004

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To investigate the association of specific autoantibodies with distinct disease phenotypes. The association of autoantibodies to nucleophosmin/ B23 with pulmonary hypertension in scleroderma, and the susceptibility of autoantigens to cleavage by granzyme B (GB), provided a focus for these studies.Methods. Intact cells were subjected to cytotoxic lymphocyte granule-induced death, and the susceptibility of autoantigens to cleavage by GB was addressed by immunoblotting and/or by a novel immunofluorescence assay.Results. B23 was cleaved efficiently by GB in vitro, but was highly resistant to cleavage by GB during cytotoxic lymphocyte granule-mediated death of many intact cell types. In contrast, this molecule was highly susceptible to GB-mediated proteolysis exclusively in differentiated vascular smooth muscle cells. Topoisomerase I and several other GB substrates did not show this striking change in cleavage susceptibility in different cell types.Conclusion. These data demonstrate that the cleavage of B23 by GB in intact cells is dependent upon both cell type and phenotype. The susceptibility of this autoantigen (which is associated with a distinct pulmonary vascular phenotype in scleroderma) to GBmediated proteolysis selectively in vascular smooth muscle cells suggests that the GB-cleavable conformation of autoantigens may occur selectively in the target tissue, and may play a role in shaping the phenotypespecific autoimmune response.

show abstract

Cutting Edge: Granzyme B Proteolysis of a Neuronal Glutamate Receptor Generates an Autoantigen and Is Modulated by Glycosylation

Cited by 115 publications

References 26 publications

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: Insights into the association of specific autoantibodies with distinct disease phenotypes

Contact Info

Product

Resources

About