Granzyme B: Evidence for a role in the origin of myasthenia gravis

Casciola‐Rosen, Livia; Miagkov, Alexei; Nagaraju, Kanneboyina; Askin, Frederic B.; Jacobson, Lisa P.; Rosen, Antony; Drachman, Daniel B.

doi:10.1016/j.jneuroim.2008.04.041

Cited by 28 publications

(21 citation statements)

References 41 publications

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“…Therefore, pDC may combine both regulatory effects on T cells and cytotoxic potential toward virus-infected or tumor cells. Very interesting in this context are recent reports indicating that GrB is not only involved in Ag uptake and cross-presentation (41,42) but also in the initiation of immune responses against autoantigens (42)(43)(44). Therefore, expression of GrB in pDC may allow this protease to cleave Ags in the early phase of an immune response so that they are optimally prepared for Ag loading and presentation on MHC I molecules.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

Fabricius

Nußbaum

Busch

et al. 2013

The Journal of Immunology

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Human plasmacytoid dendritic cells (pDC) are important modulators of adaptive T cell responses during viral infections. Recently, we found that human pDC produce the serine protease granzyme B (GrB), thereby regulating T cell proliferation in a GrB-dependent manner. In this study, we demonstrate that intrinsic GrB production by pDC is significantly inhibited in vitro and in vivo by clinically used vaccines against viral infections such as tick-borne encephalitis. We show that pDC GrB levels inversely correlate with the proliferative response of coincubated T cells and that GrB suppression by a specific Ab or a GrB substrate inhibitor results in enhanced T cell proliferation, suggesting a predominant role of GrB in pDC-dependent T cell licensing. Functionally, we demonstrate that GrBhigh but not GrBlow pDC transfer GrB to T cells and may degrade the ζ-chain of the TCR in a GrB-dependent fashion, thereby providing a possible explanation for the observed T cell suppression by GrB-expressing pDC. Modulation of pDC-derived GrB activity represents a previously unknown mechanism by which both antiviral and vaccine-induced T cell responses may be regulated in vivo. Our results provide novel insights into pDC biology during vaccinations and may contribute to an improvement of prophylactic and therapeutic vaccines.

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Section: Discussionmentioning

confidence: 99%

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

Fabricius

Nußbaum

Busch

et al. 2013

The Journal of Immunology

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“…Furthermore, GrB and the autoantigen fragments of AChR are observed in the thymus of MG patients but are not present in healthy controls. Casciola-Rosen et al 133 showed that GrB cleaves AChR, suggesting that GrB-mediated cleavage of this protein exposes cryptic antigens that facilitate an autoimmune response in the disease and results in a loss of functional AChR. G-protein-coupled receptors are also linked to GrB and neurotoxicity.…”

Section: Neurological Disordersmentioning

confidence: 99%

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

Boivin

Cooper

Hiebert

et al. 2009

Laboratory Investigation

259

290

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“…1,6,7 Many autoantigens across the spectrum of autoimmune diseases are susceptible to proteolysis by the serine protease granzyme B (GrB). 8,9 Cytotoxic T lymphocytes (CTLs) deploy GrB to kill virally infected and transformed cells, 10 and both infection and malignancy have been implicated as initiators of autoimmune diseases. 2,3 Although GrB and caspases induce cell death by cleaving intracellular proteins after aspartic acid residues, GrB often yields novel protein fragments not observed during caspase-mediated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis

et al. 2016

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Proteolysis of autoantigens can alter normal MHC class II antigen processing and has been implicated in the induction of autoimmune diseases. Many autoantigens are substrates for the protease granzyme B (GrB), but the mechanistic significance of this association is unknown. Peptidylarginine deiminase 4 (PAD4) is a frequent target of autoantibodies in patients with rheumatoid arthritis (RA) and a substrate for GrB. RA is strongly associated with specific MHC class II alleles, and elevated levels of GrB and PAD4 are found in the joints of RA patients, suggesting that GrB may alter the presentation of PAD4 by RA-associated class II alleles. In this study, complementary proteomic and immunologic approaches were utilized to define the effects of GrB cleavage on the structure, processing, and immunogenicity of PAD4. Hydrogen–deuterium exchange and a cell-free MHC class II antigen processing system revealed that proteolysis of PAD4 by GrB induced discrete structural changes in PAD4 that promoted enhanced presentation of several immunogenic peptides capable of stimulating PAD4-specific CD4+ T cells from patients with RA. This work demonstrates the existence of PAD4-specific T cells in patients with RA and supports a mechanistic role for GrB in enhancing the presentation of autoantigenic CD4+ T cell epitopes.

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Granzyme B: Evidence for a role in the origin of myasthenia gravis

Cited by 28 publications

References 41 publications

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis

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