Perforin and lymphohistiocytic proliferative disorders

Abstract

Summary Perforin is critical for cytotoxicity mediated by granules present in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Perforin‐deficient mice have impaired cytotoxicity by NK cells and CTLs, resulting in failure to control infections with certain viruses or bacteria. Infection of perforin‐deficient mice with lymphocytic choriomeningitis virus results in haemophagocytic lymphohistiocytosis and elevated levels of pro‐inflammatory cytokines. Mutations throughout the perforin gene have been identified in patients with familial haemophagocytic lymphohistiocytosis (FHL) type 2. These patients present with fever, hepatosplenomegaly, pancytopenia, have marked elevations of T‐helper type 1 and type 2 cytokines, and have impaired NK cell and CTL cytotoxicity. A number of infectious pathogens have been implicated as triggering the onset of disease. Identification of mutations in perforin as the cause of FHL should allow prenatal diagnosis of the disorder. While stem cell transplantation is curative, gene therapy might be effective in the future.

Cutting Edge: Insufficient Perforin Expression in CD8+ T Cells in Response to Hemagglutinin from Avian Influenza (H5N1) Virus

“…The EBV-associated hypercytokinemia and hemophagocytosis has been suggested to be associated with excessive activation of EBV-infected T cells with the manifestation of hyperproduction of IFN-␥ and increased perforin expression in CD8 ϩ T cells (3,12). However, through a different mechanism, the hypercytokinemia and hemophagocytosis in severe human cases of H5N1 virus infection may be attributed to the insufficient expression of perforin in CD8 ϩ T cells, according to our data.…”

“…Viral infections of perforin-deficient mice or persons with perforin gene defect, such as familial hemophagocytic lymphohistiocytosis, may result in some characteristic presentations of dysregulated immune responses, including the hyperproduction of proinflammatory cytokines (including IFN-␥ and macrophage-derived cytokines) and hemophagocytic syndrome (3)(4)(5)(6). These presentations are similar to the clinical and laboratory findings from the severe human cases of H5N1 viral infection, especially those with acute respiratory distress syndrome and multiorgan failure (7)(8)(9)(10).…”

Novel function of perforin in negatively regulating CD4+ T cell activation by affecting calcium signaling

“…+ T cells are accumulated in the peripheral tissues [11][12][13]. The second possible mechanism might be that perforin acts in a cell-intrinsic manner to regulate CTL numbers by limiting proliferation or by contributing to the AICD of CTL.…”

“…Studies in perforindeficient (PKO) mice demonstrate that perforin has an important role in clearance of virus and elimination of tumor cells executed mainly by CD8 + T cells and NK cells [10]. In humans, mutations in the perforin gene result in familial hemophagocytic lymphohistiocytosis (FHL) [11][12][13] caused by the inability of activated CTLs to clear antigen-presenting targets. In FHL patients, CD8…”

Association of Monoclonal Expansion of Epstein-Barr Virus-Negative CD158a + NK Cells Secreting Large Amounts of Gamma Interferon with Hemophagocytic Lymphohistiocytosis

“…Among them, PRF1 is considered to be altered in 20 to 50% of cases worldwide (8,11). To confirm FHL diagnosis, NK cell counts, perforin expression, and NK cytolytic activity in PBMC were evaluated in all family members ( Fig.…”