Granzyme-B-Containing Lymphocyte Involvement in Epidermal Injury in Graft-versus-Host Disease

Abstract

Background: Skin lesions from graft-versus-host disease (GVHD) show histological features of epidermal cell death with lymphocyte infiltration. Perforin and granzyme B are involved in the process of apoptosis induced by cytotoxic T lymphocytes (CTL). Objective: To elucidate the role of CTL in the mechanism of epidermal injury in GVHD. Methods: We studied immunohistochemical staining for granzyme B and perforin in the skin lesions of 8 patients who developed GVHD after bone marrow transplantation. Results: Granzyme-B-positive lymphocytes were CD8 positive and were observed in the epidermis of 3 out of 6 specimens in acute GVHD, and of 5 specimens of chronic GVHD except for 1 sclerotic type in which it was negative. Perforin-positive lymphocytes were observed in the epidermis of the specimens from 1 acute and 1 chronic GVHD. Conclusions: Granzyme B derived from CTL may be involved in the mechanisms of epidermal injury in GVHD.

Genetic variations in T-cell activation and effector pathways modulate alloimmune responses after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies

“…Granzyme B, a unique effector protease for immune defense, is used by cytotoxic T lymphocytes and natural killer cells as a molecular weapon in their defense against alloantigens, virus-infect-haematologica | 2012; 97(12) 40 The importance of the granzyme B/perforin pathway in the pathogenesis of aGVHD is well established. 41,42 Increased gene expression of granzyme B was detected in patients with aGVHD 43 and an elevated serum level of granzyme B post-HSCT was highly predictive of the risk and severity of aGVHD. 44 However, inter-individual variability in the baseline expression and activity of granzyme B may result from variations in the granzyme B gene.…”

A triple-mutated allele of granzyme B incapable of inducing apoptosis

“…Like other cytotoxic granule contents, GzmB is involved in several pathologies including viral infections (13), graft rejection, graft-vs.-host disease (14)(15)(16)(17), and rheumatoid arthritis (18,19). GzmB is also likely to play an important role in antitumor immune responses.…”

Perforin: More than Just a Pore-Forming Protein

“…Serpins in CD8+ T cells may play a role to protect CTLs themselves from their own cytolytic mechanisms [67,101,102]. However, the number of CD8+ T cells is independent of persisting antigen and is programmed as an early event after activation during the contraction phase, and T cell elimination is apparently independent of perforin in this stage [67,[101][102][103][104][105][106][107][108][109].…”

“…Perforin also plays an important role in pathogenesis of GVHD and graft-versus-tumor (GVT) effects after bone-marrow-transplantation (BMT) [109,111,112,127]. GVHD is dependent on both donor T cell perforin and FasL-mediated pathways.…”