Abstract
Natural killer (NK) cells and cytotoxic T lymphocytes (CTL) use a highly toxic pore-forming protein perforin (PFN) to destroy cells infected with intracellular pathogens and cells with pre-cancerous transformations. However, mutations of PFN and defects in its expression can cause an abnormal function of the immune system and difficulties in elimination of altered cells. As discussed in this chapter, deficiency of PFN due to the mutations of its gene, PFN1, can be associated with malignancies and severe immune disorders such as familial hemophagocytic lymphohistiocytosis (FHL) and macrophage activation syndrome. On the other hand, overactivity of PFN can turn the immune system against autologous cells resulting in other diseases such as systemic lupus erythematosus, polymyositis, rheumatoid arthritis and cutaneous inflammation. PFN also has a crucial role in the cellular rejection of solid organ allografts and destruction of pancreatic β-cells resulting in type 1 diabetes. These facts highlight the importance of understanding the biochemical characteristics of PFN.
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Abbreviations
- AD:
-
Atopic dermatitis
- CD4:
-
Cluster of differentiation 4
- CD8:
-
Cluster of differentiation 8
- CDC:
-
Cholesterol dependent cytolysin
- CIA:
-
Collagen-induced arthritis
- CL:
-
Cytotoxic lymphocytes
- CTL:
-
Cytotoxic T lymphocytes
- DM:
-
Dermatomyositis
- DMD:
-
Duchenne muscular dystrophy
- EGF:
-
Epidermal growth factor regulatory domain
- FasL:
-
Fas ligand, a type-II transmembrane protein that belongs to the TNF family
- FHL:
-
Familial hemophagocytic lymphohistiocytosis
- FHL-2:
-
Familial hemophagocytic lymphohistiocytosis type 2
- HGMD:
-
Human gene mutation database
- LCMV:
-
Lymphocytic choriomeningitis virus
- LCMV-GP:
-
Glycoprotein of lymphocytic choriomeningitis virus
- MACPF:
-
Membrane attack complex-PFN
- MHC:
-
Major histocompatibility complex
- NK:
-
Natural killer
- PFN:
-
Perforin
- PM:
-
Polymyositis
- SLE:
-
Systemic lupus erythematosus
- SLEDAI:
-
SLE disease activity index
- Tc1:
-
Type 1 CD8 T cells
- Tc2:
-
Type 2 CD8 T cells
- TNF:
-
Tumor necrosis factor
- WT:
-
Wild type
References
Abo-Elenein A, Shaaban D, Gheith O (2008) Flowcytometric study of expression of perforin and CD134 in patients with systemic lupus erythematosus. Egypt J Immunol 15:135–143
Amrani A, Verdaguer J, Anderson B, Utsugi T, Bou S, Santamaria P (1999) Perforin-independent beta-cell destruction by diabetogenic CD8(+) T lymphocytes in transgenic nonobese diabetic mice. J Clin Invest 103:1201–1209
An O, Gursoy A, Gurgey A, Keskin O (2013) Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients. Protein Sci 22:823–839
Badorff C, Noutsias M, Kühl U, Schultheiss H-P (1997) Cell-mediated cytotoxicity in hearts with dilated cardiomyopathy: correlation with interstitial fibrosis and foci of activated t lymphocytes. J Am Coll Cardiol 29:429–434
Badovinac VP (2000) Regulation of antigen-specific cd8+ t cell homeostasis by perforin and interferon-gamma. Science 290:1354–1357
Balasa B, Van Gunst K, Jung N, Balakrishna D, Santamaria P, Hanafusa T, Itoh N, Sarvetnick N (2000) Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules. J Immunol 165:2841–2849
Bauer K, Knipper A, Tu-Rapp H, Koczan D, Kreutzer H-J, Nizze H, Mix E, Thiesen H-J, Holmdahl R, Ibrahim SM (2005) Perforin deficiency attenuates collagen-induced arthritis. Arthritis Res Ther 7:R877–R884
Behrendt C, Gollnick H, Bonnekoh B (2000) Up-regulated perforin expression of CD8+ blood lymphocytes in generalized non-anaphylactic drug eruptions and exacerbated psoriasis. Eur J Dermatol 10:365–369
Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C (2005) Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood 105:1648–1651
Blanco P, Pitard V, Viallard J-F, Taupin J-L, Pellegrin J-L, Moreau J-F (2005) Increase in activated CD8+ T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 52:201–211
Blumenthal R, Millard PJ, Henkart MP, Reynolds CW, Henkart Pa (1984) Liposomes as targets for granule cytolysin from cytotoxic large granular lymphocyte tumors. Proc Natl Acad Sci USA 81:5551–5555
Brahn E, Peacock DJ, Banquerigo ML, Liu DY (1992) Effects of tumor necrosis factor alpha (TNF-alpha) on collagen arthritis. Lymphokine Cytokine Res 11:253–256
Brennan AJ, Chia J, Trapani JA, Voskoboinik I (2010) Perforin deficiency and susceptibility to cancer. Cell Death Differ 17:607–615
Brown DM, Lee S, Garcia-Hernandez MDLL, Swain SL (2012) Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol 86:6792–6803
Busiello R, Adriani M, Locatelli F, Galgani M, Fimiani G, Clementi R, Ursini MV, Racioppi L, Pignata C (2004) Atypical features of familial hemophagocytic lymphohistiocytosis. Blood 103:4610–4612
Busiello R, Fimiani G, Miano MG, Aricò M, Santoro A, Ursini MV, Pignata C (2006) A91V perforin variation in healthy subjects and FHLH patients. Int J Immunogenet 33:123–125
Chia J, Thia K, Brennan AJ, Little M, Williams B, Lopez JA, Trapani JA, Voskoboinik I (2012) Fatal immune dysregulation due to a gain of glycosylation mutation in lymphocyte perforin. Blood 119:1713–1716
Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I (2009) Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci USA 106:9809–9814
Choy JC (2010) Granzymes and perforin in solid organ transplant rejection. Cell Death Differ 17:567–576
Chun-yan G, Bo H, Hong C, Hong-lei J, Xiu-zhen H (2009) Anti-perforin neutralizing antibody reduces myocardial injury in viral myocarditis. Cardiol Young 19:601–607
Clementi R, Chiocchetti A, Cappellano G, Cerutti E, Ferretti M, Orilieri E, Dianzani I, Ferrarini M, Bregni M, Danesino C, Bozzi V, Putti MC, Cerutti F, Cometa A, Locatelli F, Maccario R, Ramenghi U, Dianzani U (2006) Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function. Blood 108:3079–3084
Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino C, Aricó M (2002) Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 100:2266–2267
Clementi R, Locatelli F, Dupré L, Garaventa A, Emmi L, Bregni M, Cefalo G, Moretta A, Danesino C, Comis M, Pession A, Ramenghi U, Maccario R, Aricò M, Roncarolo MG (2005) A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood 105:4424–4428
Côte M, Ménager MM, Burgess A, Mahlaoui N, Picard C, Schaffner C, Al-Manjomi F, Al-Harbi M, Alangari A, Le Deist F, Gennery AR, Prince N, Cariou A, Nitschke P, Blank U, El-Ghazali G, Ménasché G, Latour S, Fischer A, de Saint Basile G (2009) Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest 119:3765–3773
Egeler RM, Shapiro R, Loechelt B, Filipovich A (1996) Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 18:340–345
Enomoto N, Hyde E, Ma JZ-I, Yang J, Forbes-Blom E, Delahunt B, Le Gros G, Ronchese F (2012) Allergen-specific CTL require perforin expression to suppress allergic airway inflammation. J Immunol 188:1734–1741
Fang M, Siciliano NA, Hersperger AR, Roscoe F, Hu A, Ma X, Shamsedeen AR, Eisenlohr LC, Sigal LJ (2012) Perforin-dependent CD4+ T-cell cytotoxicity contributes to control a murine poxvirus infection. Proc Natl Acad Sci USA 109:9983–9988
Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, Lambert N, Ouachée-Chardin M, Chedeville G, Tamary H, Minard-Colin V, Vilmer E, Blanche S, Le Deist F, Fischer A, de Saint Basile G (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115:461–473
Feldmann J, Le Deist F, Ouachée-Chardin M, Certain S, Alexander S, Quartier P, Haddad E, Wulffraat N, Casanova JL, Blanche S, Fischer A, de Saint Basile G (2002) Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol 117:965–972
Fink TM, Zimmer M, Weitz S, Tschopp J, Jenne DE, Lichter P (1992) Human perforin (PRF1) maps to 10q22, a region that is syntenic with mouse chromosome 10. Genomics 13:1300–1302
Gebhard JR, Perry CM, Harkins S, Lane T, Mena I, Asensio VC, Campbell IL, Whitton JL (1998) Coxsackievirus B3-induced myocarditis: perforin exacerbates disease, but plays no detectable role in virus clearance. Am J Pathol 153:417–428
Gilbert RJC, Mikelj M, Dalla Serra M, Froelich CJ, Anderluh G (2013) Effects of MACPF/CDC proteins on lipid membranes. Cell Mol Life Sci 70:2083–2098
Goebels N, Michaelis D, Engelhardt M, Huber S, Bender A, Pongratz D, Johnson MA, Wekerle H, Tschopp J, Jenne D, Hohlfeld R (1996) Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. J Clin Invest 97:2905–2910
Gupta M, Greer P, Mahanty S, Shieh W-J, Zaki SR, Ahmed R, Rollin PE (2005) CD8-mediated protection against Ebola virus infection is perforin dependent. J Immunol 174:4198–4202
Gürgey A, Göğüş S, Özyürek E, Aslan D, Gümrük F, Çetin M, Yüce A, Ceyhan M, Seçmeer G, Yetgin S, Hiçsönmez G (2003) Primary hemophagocytic lymphohistiocytosis in Turkish children. Pediatr Hematol Oncol 20:367–371
Henkart PA, Millard PJ, Reynolds CW, Henkart MP (1984) Cytolytic activity of purified cytoplasmic granules from cytotoxic rat large granular lymphocyte tumors. J Exp Med 160:75–93
Henriques A, Teixeira L, Inês L, Carvalheiro T, Gonçalves A, Martinho A, Pais ML, da Silva JAP, Paiva A (2013) NK cells dysfunction in systemic lupus erythematosus: relation to disease activity. Clin Rheumatol 32:805–813
Henter J-I, Elinder G, Soder O, Hansson M, Andersson B, Andersson U (1991) Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 78:2918–2922
Henter J-I, Ehrnst A, Andersson J, Elinder G (1993) Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr 82:369–372
Henter J-I, Elinder G, Söder O, Ost A (1991) Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 80:428–435
Henter J-I, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G (2007) HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124–131
Hermsen C, van de Wiel T, Mommers E, Sauerwein R, Eling W (1997) Depletion of CD4+ or CD8+ T-cells prevents Plasmodium berghei induced cerebral malaria in end-stage disease. Parasitology 114:7–12
Herrera PL, Harlan DM, Vassalli P (2000) A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: possible role of membrane TNF. Proc Natl Acad Sci USA 97:279–284
Hom JT, Bendele AM, Carlson DG (1988) In vivo administration with IL-1 accelerates the development of collagen-induced arthritis in mice. J Immunol 141:834–841
Ishii E, Ohga S, Tanimura M, Imashuku S, Sako M, Mizutani S, Miyazaki S (1998) Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group. Med Pediatr Oncol 30:276–283
James JA, Harley JB, Scofield RH (2001) Role of viruses in systemic lupus erythematosus and Sjögren syndrome. Curr Opin Rheumatol 13:370–376
Janka GE (2012) Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 63:233–246
Kägi D (1996) Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity. J Exp Med 183:2143–2152
Kägi D, Ledermann B, Bürki K, Hengartner H, Zinkernagel RM (1994) CD8+ T cell-mediated protection against an intracellular bacterium by perforin-dependent cytotoxicity. Eur J Immunol 24:3068–3072
Kägi D, Ledermann B, Bürki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37
Kägi D, Odermatt B, Seiler P, Zinkernagel RM, Mak TW, Hengartner H (1997) Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med 186:989–997
Killar LM, Dunn CJ (1989) Interleukin-1 potentiates the development of collagen-induced arthritis in mice. Clin Sci 76:535–538
Kohyama K, Matsumoto Y (1999) C-protein in the skeletal muscle induces severe autoimmune polymyositis in Lewis rats. J Neuroimmunol 98:130–135
Koike H, Kanda T, Sumino H, Yokoyama T, Arai M, Motooka M, Suzuki T, Tamura J, Kobayashi I (2001) Reduction of viral myocarditis in mice lacking perforin. Res Commun Mol Pathol Pharmacol 110:229–237
Kozłowska A, Hrycaj P, Łącki JK, Jagodziński PP (2010) Perforin level in CD4+ T cells from patients with systemic lupus erythematosus. Rheumatol Int 30:1627–1633
Krupnick AS, Kreisel D, Popma SH, Balsara KR, Szeto WY, Krasinskas AM, Riha M, Wells AD, Turka LA, Rosengard BR (2002) Mechanism of T cell-mediated endothelial apoptosis. Transplantation 74:871–876
Law RHP, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, Dunstone MA, D’Angelo ME, Orlova EV, Coulibaly F, Verschoor S, Browne KA, Ciccone A, Kuiper MJ, Bird PI, Trapani JA, Saibil HR, Whisstock JC (2010) The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468:447–451
Lena G, Trapani JA, Sutton VR, Ciccone A, Browne KA, Smyth MJ, Denny WA, Spicer JA (2008) Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin. J Med Chem 51:7614–7624
Lichtenheld MG, Olsen KJ, Lu P, Lowrey DM, Hameed A, Hengartner H, Podack ER (1988) Structure and function of human perforin. Nature 335:448–451
Lopez JA, Susanto O, Jenkins MR, Lukoyanova N, Sutton VR, Law RHP, Johnston A, Bird CH, Bird PI, Whisstock JC, Trapani JA, Saibil HR, Voskoboinik I (2013) Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood 121:2659–2668
Luci C, Gaudy-Marqueste C, Rouzaire P, Audonnet S, Cognet C, Hennino A, Nicolas J-F, Grob J-J, Tomasello E (2012) Peripheral natural killer cells exhibit qualitative and quantitative changes in patients with psoriasis and atopic dermatitis. Br J Dermatol 166:789–796
Lyons DM, Huttunen KM, Browne KA, Ciccone A, Trapani JA, Denny WA, Spicer JA (2011) Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazoles. Bioorg Med Chem 19:4091–4100
Maglinao M, Klopfleisch R, Seeberger PH, Lepenies B (2013) The C-type lectin receptor DCIR is crucial for the development of experimental cerebral malaria. J Immunol 191:2551–2559
Mancebo E, Allende LM, Guzmán M, Paz-Artal E, Gil J, Urrea-Moreno R, Fernández-Cruz E, Gayà A, Calvo J, Arbós A, Durán MA, Canet R, Balanzat J, Udina MA, Vercher FJ (2006) Familial hemophagocytic lymphohistiocytosis in an adult patient homozygous for A91V in the perforin gene, with tuberculosis infection. Haematologica 91:1257–1260
Marsland BJ, Harris NL, Camberis M, Kopf M, Hook SM, Le Gros G (2004) Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells. Proc Natl Acad Sci USA 101:6116–6121
Mehta PA, Davies SM, Kumar A, Devidas M, Lee S, Zamzow T, Elliott J, Villanueva J, Pullen J, Zewge Y, Filipovich A (2006) Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Leukemia 20:1539–1541
Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, Kodama T, Dakhama A, Ott VL, Gelfand EW (2004) Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat Med 10:865–869
Moshous D, Feyen O, Lankisch P, Schwarz K, Schaper J, Schneider M, Dilloo D, Laws H-J, Schwahn BC, Niehues T (2007) Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four-year-old girl. Arthritis Rheum 56:995–999
Niece JA, Rogers ZR, Ahmad N, Langevin A, McClain KL (2010) Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer 54:424–428
Nitcheu J, Bonduelle O, Combadiere C, Tefit M, Seilhean D, Mazier D, Combadiere B (2003) Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis. J Immunol 170:2221–2228
Orilieri E, Cappellano G, Clementi R, Cometa A, Ferretti M, Cerutti E, Cadario F, Martinetti M, Larizza D, Calcaterra V, D’Annunzio G, Lorini R, Cerutti F, Bruno G, Chiocchetti A, Dianzani U (2008) Variations of the perforin gene in patients with type 1 diabetes. Diabetes 57:1078–1083
Piva L, Tetlak P, Claser C, Karjalainen K, Renia L, Ruedl C (2012) Cutting edge: Clec9A+ dendritic cells mediate the development of experimental cerebral malaria. J Immunol 189:1128–1132
Podack ER, Dennert G (1983) Assembly of two types of tubules with putative cytolytic function by cloned natural killer cells. Nature 302:442–445
Potter S, Chan-Ling T, Ball HJ, Mansour H, Mitchell A, Maluish L, Hunt NH (2006) Perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria. Int J Parasitol 36:485–496
Praper T, Beseničar MP, Istinič H, Podlesek Z, Metkar SS, Froelich CJ, Anderluh G (2010) Human perforin permeabilizing activity, but not binding to lipid membranes, is affected by pH. Mol Immunol 47:2492–2504
Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738
Sanapala S, Yu J-J, Murthy AK, Li W, Guentzel MN, Chambers JP, Klose KE, Arulanandam BP (2012) Perforin- and granzyme-mediated cytotoxic effector functions are essential for protection against Francisella tularensis following vaccination by the defined F. tularensis subsp. novicida ΔfopC vaccine strain. Infect Immun 80:2177–2185
Santoro A, Cannella S, Trizzino A, Lo Nigro L, Corsello G, Arico M (2005) A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica 90:697–698
Schneider EM, Lorenz I, Müller-Rosenberger M, Steinbach G, Kron M, Janka-Schaub GE (2002) Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood 100:2891–2898
Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA (2000) Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 192:755–760
Spencer MJ, Montecino-Rodriguez E, Dorshkind K, Tidball JG (2001) Helper (CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of dystrophin-deficient muscle. Clin Immunol 98:235–243
Spencer MJ, Walsh CM, Dorshkind KA, Rodriguez EM, Tidball JG (1997) Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity. J Clin Invest 99:2745–2751
Spicer JA, Huttunen KM, Miller CK, Denny WA, Ciccone A, Browne KA, Trapani JA (2012) Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones. Bioorg Med Chem 20:1319–1336
Spicer JA, Lena G, Lyons DM, Huttunen KM, Miller C, O’Connor PD, Bull M, Helsby N, Jamieson S, Denny WA, Ciccone A, Browne K, Lopez J, Rudd-Schmidt J, Voskoboinik I, Trapani JA (2013) Exploration of a series of 5-arylidene-2-thioxoimidazolidin-4-ones as inhibitors of the cytolytic protein perforin. J Med Chem. doi:10.1021/jm401604x
Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NST, Abeysinghe S, Krawczak M, Cooper DN (2003) Human gene mutation database (HGMD): 2003 update. Hum Mutat 21:577–581
Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint Basile G, Kumar V (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957–1959
Street SE, Cretney E, Smyth MJ (2001) Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood 97:192–197
Su MW-C, Pyarajan S, Chang J-H, Yu C-L, Jin Y-J, Stierhof Y-D, Walden P, Burakoff SJ (2004) Fratricide of CD8+ cytotoxic T lymphocytes is dependent on cellular activation and perforin-mediated killing. Eur J Immunol 34:2459–2470
Sugihara T, Okiyama N, Suzuki M, Kohyama K, Matsumoto Y, Miyasaka N, Kohsaka H (2010) Definitive engagement of cytotoxic CD8 T cells in C protein-induced myositis, a murine model of polymyositis. Arthritis Rheum 62:3088–3092
Sullivan KE, Delaat CA, Douglas SD, Filipovich AH (1998) Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first degree relatives. Pediatr Res 44:465–468
Tada Y, Ho A, Koh DR, Mak TW (1996) Collagen-induced arthritis in CD4- or CD8-deficient mice: CD8+ T cells play a role in initiation and regulate recovery phase of collagen-induced arthritis. J Immunol 156:4520–4526
Thomas HE, Trapani JA, Kay TWH (2010) The role of perforin and granzymes in diabetes. Cell Death Differ 17:577–585
Trambas C, Gallo F, Pende D, Marcenaro S, Moretta L, De Fusco C, Santoro A, Notarangelo L, Arico M, Griffiths GM (2005) A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. Blood 106:932–937
Trapani JA, Thia KYT, Andrews M, Davis ID, Gedye C, Parente P, Svobodova S, Chia J, Browne K, Campbell IG, Phillips WA, Voskoboinik I, Cebon JS (2013) Human perforin mutations and susceptibility to multiple primary cancers. Oncoimmunology 2:e24185
Trentham DE (1977) Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 146:857–868
Van den Broek ME, Kägi D, Ossendorp F, Toes R, Vamvakas S, Lutz WK, Melief CJ, Zinkernagel RM, Hengartner H (1996) Decreased tumor surveillance in perforin-deficient mice. J Exp Med 184:1781–1790
Vastert SJ, van Wijk R, D’Urbano LE, de Vooght KMK, de Jager W, Ravelli A, Magni-Manzoni S, Insalaco A, Cortis E, van Solinge WW, Prakken BJ, Wulffraat NM, de Benedetti F, Kuis W (2010) Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology 49:441–449
Voskoboinik I, Dunstone MA, Baran K, Whisstock JC, Trapani JA (2010) Perforin: structure, function, and role in human immunopathology. Immunol Rev 235:35–54
Voskoboinik I, Sutton VR, Ciccone A, House CM, Chia J, Darcy PK, Yagita H, Trapani JA (2007) Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood 110:1184–1190
Voskoboinik I, Thia M-C, Fletcher J, Ciccone A, Browne K, Smyth MJ, Trapani JA (2005) Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: a critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem 280:8426–8434
Wakeland EK, Liu K, Graham RR, Behrens TW (2001) Delineating the genetic basis of systemic lupus erythematosus. Immunity 15:397–408
Walsh CM, Matloubian M, Liu CC, Ueda R, Kurahara CG, Christensen JL, Huang MT, Young JD, Ahmed R, Clark WR (1994) Immune function in mice lacking the perforin gene. Proc Natl Acad Sci USA 91:10854–10858
Yañez DM, Manning DD, Cooley AJ, Weidanz WP, van der Heyde HC (1996) Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria. J Immunol 157:1620–1624
Yawalkar N, Schmid S, Braathen LR, Pichler WJ (2001) Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis. Br J Dermatol 144:1133–1139
Yoon J-W, Jun H-S (2005) Autoimmune destruction of pancreatic beta cells. Am J Ther 12:580–591
Young JD, Damiano A, DiNome MA, Leong LG, Cohn ZA (1987) Dissociation of membrane binding and lytic activities of the lymphocyte pore-forming protein (perforin). J Exp Med 165:1371–1382
Young LH, Joag SV, Zheng LM, Lee CP, Lee YS, Young JD (1990) Perforin-mediated myocardial damage in acute myocarditis. Lancet 336:1019–1021
Youssef A-R, Otley C, Mathieson PW, Smith RM (2004) Role of CD4+ and CD8+ T cells in murine skin and heart allograft rejection across different antigenic desparities. Transpl Immunol 13:297–304
Zhang Y (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9:40
Zur Stadt U, Beutel K, Weber B, Kabisch H, Schneppenheim R, Janka G (2004) A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. Blood 104:1909 (author reply 1910)
Zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, Strauss J, Kasper B, Nürnberg G, Becker C, Maul-Pavicic A, Beutel K, Janka G, Griffiths G, Ehl S, Hennies HC (2009) Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 85:482–492
Zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter J-I, Kabisch H, Schneppenheim R, Nürnberg P, Janka G, Hennies HC (2005) Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 14:827–834
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Naneh, O., Avčin, T., Bedina Zavec, A. (2014). Perforin and Human Diseases. In: Anderluh, G., Gilbert, R. (eds) MACPF/CDC Proteins - Agents of Defence, Attack and Invasion. Subcellular Biochemistry, vol 80. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8881-6_11
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