메뉴 건너뛰기




Volumn 116, Issue 3, 2010, Pages 217-226

Blood stage plasmodium falciparum antigens induce T cell independent immunoglobulin production via B cell activation factor of the TNF family (BAFF) pathway

Author keywords

B cells; BAFF; Hemozoin; Immunoglobulin; Plasmodium falciparum

Indexed keywords

B CELL ACTIVATING FACTOR; B CELL ACTIVATING FACTOR RECEPTOR; CELL NUCLEUS ANTIGEN; HEMOZOIN; IMMUNOGLOBULIN G; PARASITE ANTIGEN; TUMOR NECROSIS FACTOR;

EID: 77957752060     PISSN: 0001706X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.actatropica.2010.08.012     Document Type: Article
Times cited : (23)

References (70)
  • 3
    • 70649086102 scopus 로고    scopus 로고
    • Immunogenicity and antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf332
    • Balogun H.A., Vasconcelos N.M., Lindberg R., HaeggstrÖm M., Moll L., Chen Q., Wahlgren M., Berzins K. Immunogenicity and antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf332. Vaccine 2009, 28:90-97.
    • (2009) Vaccine , vol.28 , pp. 90-97
    • Balogun, H.A.1    Vasconcelos, N.M.2    Lindberg, R.3    HaeggstrÖm, M.4    Moll, L.5    Chen, Q.6    Wahlgren, M.7    Berzins, K.8
  • 4
    • 0025316726 scopus 로고
    • Malaria exoantigens induce T-independent antibody that blocks their ability to induce TNF
    • Bate C.A., Taverne J., Dave A., Playfair J.H. Malaria exoantigens induce T-independent antibody that blocks their ability to induce TNF. Immunology 1990, 70:315-320.
    • (1990) Immunology , vol.70 , pp. 315-320
    • Bate, C.A.1    Taverne, J.2    Dave, A.3    Playfair, J.H.4
  • 5
    • 55549094399 scopus 로고    scopus 로고
    • Recent insights into humoral and cellular immune responses against malaria
    • Beeson J.G., Osier F.H.A., Engwerda C.R. Recent insights into humoral and cellular immune responses against malaria. Trends Parasitol. 2008, 24:578-584.
    • (2008) Trends Parasitol. , vol.24 , pp. 578-584
    • Beeson, J.G.1    Osier, F.H.A.2    Engwerda, C.R.3
  • 6
    • 3042613829 scopus 로고    scopus 로고
    • Elevated anti-malarial IgE in asymptomatic individuals is associated with reduced risk for subsequent clinical malaria
    • Bereczky S., Montgomery S.M., Troye-Blomberg M., Rooth I., Shaw M.A., Farnert A. Elevated anti-malarial IgE in asymptomatic individuals is associated with reduced risk for subsequent clinical malaria. Int. J. Parasitol. 2004, 34:935-942.
    • (2004) Int. J. Parasitol. , vol.34 , pp. 935-942
    • Bereczky, S.1    Montgomery, S.M.2    Troye-Blomberg, M.3    Rooth, I.4    Shaw, M.A.5    Farnert, A.6
  • 8
    • 0014385564 scopus 로고
    • Isolation of mononuclear cells and granulocytes from human blood
    • Boyum A. Isolation of mononuclear cells and granulocytes from human blood. Scand J. Clin. Lab. Invest. Suppl. 1968, 97:77-89.
    • (1968) Scand J. Clin. Lab. Invest. Suppl. , vol.97 , pp. 77-89
    • Boyum, A.1
  • 9
    • 0036884414 scopus 로고    scopus 로고
    • Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells
    • Cerutti A., Zan H., Kim E.C., Shah S., Schattner E.J., Schaffer A., Casali P. Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells. J. Immunol. 2002, 169:6594-6603.
    • (2002) J. Immunol. , vol.169 , pp. 6594-6603
    • Cerutti, A.1    Zan, H.2    Kim, E.C.3    Shah, S.4    Schattner, E.J.5    Schaffer, A.6    Casali, P.7
  • 10
    • 29144479170 scopus 로고    scopus 로고
    • Plasmacytoid dendritic cells and the regulation of immunoglobulin heavy chain class switching
    • Cerutti A., Qiao X., He B. Plasmacytoid dendritic cells and the regulation of immunoglobulin heavy chain class switching. Immunol. Cell. Biol. 2005, 83:554-562.
    • (2005) Immunol. Cell. Biol. , vol.83 , pp. 554-562
    • Cerutti, A.1    Qiao, X.2    He, B.3
  • 11
    • 38449092157 scopus 로고    scopus 로고
    • In vitro and in vivo activation induces BAFF and APRIL expression in B cells
    • Chu V.T., Enghard P., Riemekasten G., Berek C. In vitro and in vivo activation induces BAFF and APRIL expression in B cells. J. Immunol. 2007, 179:5947-5957.
    • (2007) J. Immunol. , vol.179 , pp. 5947-5957
    • Chu, V.T.1    Enghard, P.2    Riemekasten, G.3    Berek, C.4
  • 12
    • 70350574196 scopus 로고    scopus 로고
    • Along a TNF-paved road from dead parasites in red cells to cerebral malaria, and beyond
    • Clark I.A. Along a TNF-paved road from dead parasites in red cells to cerebral malaria, and beyond. Parasitology 2009, 136:1457-1468.
    • (2009) Parasitology , vol.136 , pp. 1457-1468
    • Clark, I.A.1
  • 13
    • 0036084375 scopus 로고    scopus 로고
    • Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine
    • Coban C., Ishii K.J., Sullivan D.J., Kumar N. Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine. Infect. Immun. 2002, 70:3939-3943.
    • (2002) Infect. Immun. , vol.70 , pp. 3939-3943
    • Coban, C.1    Ishii, K.J.2    Sullivan, D.J.3    Kumar, N.4
  • 15
    • 0034307637 scopus 로고    scopus 로고
    • Falciparum malaria: sticking up, standing out and out-standing
    • Cooke B., Wahlgren M., Coppel R. Falciparum malaria: sticking up, standing out and out-standing. Parasitol. Today 2000, 16:416-420.
    • (2000) Parasitol. Today , vol.16 , pp. 416-420
    • Cooke, B.1    Wahlgren, M.2    Coppel, R.3
  • 17
    • 0038142395 scopus 로고    scopus 로고
    • Macrophage- and dendritic cell-dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF
    • Craxton A., Magaletti D., Ryan E.J., Clark E.A. Macrophage- and dendritic cell-dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF. Blood 2003, 101:4464-4471.
    • (2003) Blood , vol.101 , pp. 4464-4471
    • Craxton, A.1    Magaletti, D.2    Ryan, E.J.3    Clark, E.A.4
  • 19
    • 33747796656 scopus 로고    scopus 로고
    • Increased B cell survival and preferential activation of the memory compartment by a malaria polyclonal B cell activator
    • Donati D., Mok B., Chene A., Xu H., Thangarajh M., Glas R., Chen Q., Wahlgren M., Bejarano M.T. Increased B cell survival and preferential activation of the memory compartment by a malaria polyclonal B cell activator. J. Immunol. 2006, 177:3035-3044.
    • (2006) J. Immunol. , vol.177 , pp. 3035-3044
    • Donati, D.1    Mok, B.2    Chene, A.3    Xu, H.4    Thangarajh, M.5    Glas, R.6    Chen, Q.7    Wahlgren, M.8    Bejarano, M.T.9
  • 20
    • 13444269087 scopus 로고    scopus 로고
    • Human monocyte isolation methods influence cytokine production from in vitro generated dendritic cells
    • Elkord E., Williams P., Kynaston H., Rowbottom A. Human monocyte isolation methods influence cytokine production from in vitro generated dendritic cells. Immunology 2005, 114:204-212.
    • (2005) Immunology , vol.114 , pp. 204-212
    • Elkord, E.1    Williams, P.2    Kynaston, H.3    Rowbottom, A.4
  • 21
    • 0141672920 scopus 로고    scopus 로고
    • Normal B cell homeostasis requires B cell activation factor production by radiation-resistant cells
    • Gorelik L., Gilbride K., Dobles M., Kalled S.L., Zandman D., Scott M.L. Normal B cell homeostasis requires B cell activation factor production by radiation-resistant cells. J. Exp. Med. 2003, 198:937-945.
    • (2003) J. Exp. Med. , vol.198 , pp. 937-945
    • Gorelik, L.1    Gilbride, K.2    Dobles, M.3    Kalled, S.L.4    Zandman, D.5    Scott, M.L.6
  • 22
    • 39149107093 scopus 로고    scopus 로고
    • Increase in B-cell-activation factor (BAFF) and IFN-gamma productions by tonsillar mononuclear cells stimulated with deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN) in patients with IgA nephropathy
    • Goto T., Bandoh N., Yoshizaki T., Nozawa H., Takahara M., Ueda S., Hayashi T., Harabushi Y. Increase in B-cell-activation factor (BAFF) and IFN-gamma productions by tonsillar mononuclear cells stimulated with deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN) in patients with IgA nephropathy. Clin. Immunol. 2008, 126:260-269.
    • (2008) Clin. Immunol. , vol.126 , pp. 260-269
    • Goto, T.1    Bandoh, N.2    Yoshizaki, T.3    Nozawa, H.4    Takahara, M.5    Ueda, S.6    Hayashi, T.7    Harabushi, Y.8
  • 24
    • 0033937116 scopus 로고    scopus 로고
    • Flow cytometric cell division tracking using nuclei
    • Hasbold J., Hodgkin P.D. Flow cytometric cell division tracking using nuclei. Cytometry 2000, 40:230-237.
    • (2000) Cytometry , vol.40 , pp. 230-237
    • Hasbold, J.1    Hodgkin, P.D.2
  • 26
    • 70350612907 scopus 로고    scopus 로고
    • B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjogren's syndrome
    • Ittah M., Miceli-Richard C., Eric Gottenberg J., Lavie F., Lazure T., Ba N., Sellam J., Lepajolec C., Mariette X. B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjogren's syndrome. Arthritis Res. Ther. 2006, 8:R51.
    • (2006) Arthritis Res. Ther. , vol.8
    • Ittah, M.1    Miceli-Richard, C.2    Eric Gottenberg, J.3    Lavie, F.4    Lazure, T.5    Ba, N.6    Sellam, J.7    Lepajolec, C.8    Mariette, X.9
  • 29
    • 38149090131 scopus 로고    scopus 로고
    • B-cell activating factor of the tumour necrosis factor family expression in blood monocytes and T cells from patients with primary Sjogren's syndrome
    • Lavie F., Miceli-Richard C., Ittah M., Sellam J., Gottenberg J.E., Mariette X. B-cell activating factor of the tumour necrosis factor family expression in blood monocytes and T cells from patients with primary Sjogren's syndrome. Scand. J. Immunol. 2008, 67:185-192.
    • (2008) Scand. J. Immunol. , vol.67 , pp. 185-192
    • Lavie, F.1    Miceli-Richard, C.2    Ittah, M.3    Sellam, J.4    Gottenberg, J.E.5    Mariette, X.6
  • 32
    • 0037644586 scopus 로고    scopus 로고
    • The TNF family members BAFF and APRIL: the growing complexity
    • Mackay F., Ambrose C. The TNF family members BAFF and APRIL: the growing complexity. Cytokine Growth Factor Rev. 2003, 14:311-324.
    • (2003) Cytokine Growth Factor Rev. , vol.14 , pp. 311-324
    • Mackay, F.1    Ambrose, C.2
  • 33
    • 33747858998 scopus 로고    scopus 로고
    • The role of the BAFF/APRIL system on T cell function
    • Mackay F., Leung H. The role of the BAFF/APRIL system on T cell function. Semin. Immunol. 2006, 18:261-262.
    • (2006) Semin. Immunol. , vol.18 , pp. 261-262
    • Mackay, F.1    Leung, H.2
  • 34
    • 0036734407 scopus 로고    scopus 로고
    • BLySsful interactions between DCs and B cells
    • Macpherson A.J., Lamarre A. BLySsful interactions between DCs and B cells. Nat. Immunol. 2002, 3:798-800.
    • (2002) Nat. Immunol. , vol.3 , pp. 798-800
    • Macpherson, A.J.1    Lamarre, A.2
  • 36
    • 55049131371 scopus 로고    scopus 로고
    • Increased serum BAFF (B-cell activating factor of the TNF family) level is a peculiar feature associated with familial chronic lymphocytic leukemia
    • Molica S., Digiesi G., Mauro F., Mirabelli R., Cutrona G., Vitelli G., Morabito F., Iuliano F., Foa R., Ferrarini M. Increased serum BAFF (B-cell activating factor of the TNF family) level is a peculiar feature associated with familial chronic lymphocytic leukemia. Leuk. Res. 2009, 33:162-165.
    • (2009) Leuk. Res. , vol.33 , pp. 162-165
    • Molica, S.1    Digiesi, G.2    Mauro, F.3    Mirabelli, R.4    Cutrona, G.5    Vitelli, G.6    Morabito, F.7    Iuliano, F.8    Foa, R.9    Ferrarini, M.10
  • 37
    • 26244444307 scopus 로고    scopus 로고
    • Regulation of immune response by Plasmodium-infected red blood cells
    • Ndungu F.M., Urban B.C., Marsh K., Langhorne J. Regulation of immune response by Plasmodium-infected red blood cells. Parasite Immunol. 2005, 27:373-384.
    • (2005) Parasite Immunol. , vol.27 , pp. 373-384
    • Ndungu, F.M.1    Urban, B.C.2    Marsh, K.3    Langhorne, J.4
  • 40
    • 0030797568 scopus 로고    scopus 로고
    • A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens
    • Nicholson L.B., Murtaza A., Hafler B.P., Sette A., Kuchroo V.K. A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. Proc. Natl. Acad. Sci. U.S.A. 1997, 9279-9284.
    • (1997) Proc. Natl. Acad. Sci. U.S.A. , pp. 9279-9284
    • Nicholson, L.B.1    Murtaza, A.2    Hafler, B.P.3    Sette, A.4    Kuchroo, V.K.5
  • 45
    • 10344266963 scopus 로고    scopus 로고
    • Anti-CD3 antibodies OKT3 and hOKT3gamma1(Ala-Ala) induce proliferation of T cells but impair expansion of alloreactive T cells; aspecific T cell proliferation induced by anti-CD3 antibodies correlates with impaired expansion of alloreactive T cells
    • Popma S.H., Griswold D.E., Li L. Anti-CD3 antibodies OKT3 and hOKT3gamma1(Ala-Ala) induce proliferation of T cells but impair expansion of alloreactive T cells; aspecific T cell proliferation induced by anti-CD3 antibodies correlates with impaired expansion of alloreactive T cells. Int. Immunopharmacol. 2005, 5:155-162.
    • (2005) Int. Immunopharmacol. , vol.5 , pp. 155-162
    • Popma, S.H.1    Griswold, D.E.2    Li, L.3
  • 48
    • 67650074353 scopus 로고    scopus 로고
    • Cellular tumor necrosis factor, gamma interferon, and interleukin-6 responses as correlates of immunity and risk of clinical Plasmodium falciparum malaria in children from Papua New Guinea
    • Robinson L.J., D'Ombrain M.C., Stanisic D.I., Taraika J., Bernard N., Richards J.S., Beeson J.G., Tavul L., Michon P., Mueller I., Schofield L. Cellular tumor necrosis factor, gamma interferon, and interleukin-6 responses as correlates of immunity and risk of clinical Plasmodium falciparum malaria in children from Papua New Guinea. Infect. Immun. 2009, 77:3033-3043.
    • (2009) Infect. Immun. , vol.77 , pp. 3033-3043
    • Robinson, L.J.1    D'Ombrain, M.C.2    Stanisic, D.I.3    Taraika, J.4    Bernard, N.5    Richards, J.S.6    Beeson, J.G.7    Tavul, L.8    Michon, P.9    Mueller, I.10    Schofield, L.11
  • 49
    • 33947592601 scopus 로고    scopus 로고
    • TACI regulates IgA production by APRIL in collaboration with HSPG
    • Sakurai D., Hase H., Kanno Y., Kojima H., Okumura K., Kobata T. TACI regulates IgA production by APRIL in collaboration with HSPG. Blood 2007, 109:2961-2967.
    • (2007) Blood , vol.109 , pp. 2961-2967
    • Sakurai, D.1    Hase, H.2    Kanno, Y.3    Kojima, H.4    Okumura, K.5    Kobata, T.6
  • 51
    • 0026061995 scopus 로고
    • A gentle fixation and permeabilization method for combined cell surface and intracellular staining with improved precision in DNA quantification
    • Schmid I., Uittenbogaart C.H., Giorgi J.V. A gentle fixation and permeabilization method for combined cell surface and intracellular staining with improved precision in DNA quantification. Cytometry 1991, 12:279-285.
    • (1991) Cytometry , vol.12 , pp. 279-285
    • Schmid, I.1    Uittenbogaart, C.H.2    Giorgi, J.V.3
  • 53
    • 0025215802 scopus 로고
    • Lack of Ir gene control in the immune response to malaria. I. A thymus-independent antibody response to the repetitive surface protein of sporozoites
    • Schofield L., Uadia P. Lack of Ir gene control in the immune response to malaria. I. A thymus-independent antibody response to the repetitive surface protein of sporozoites. J. Immunol. 1990, 144:2781-2788.
    • (1990) J. Immunol. , vol.144 , pp. 2781-2788
    • Schofield, L.1    Uadia, P.2
  • 54
    • 4043146475 scopus 로고    scopus 로고
    • B cell-activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation
    • Shulga-Morskaya S., Dobles M., Walsh M.E., Ng L.G., MacKay F., Rao S.P., Kalled S.L., Scott M.L. B cell-activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation. J. Immunol. 2004, 173:2331-2341.
    • (2004) J. Immunol. , vol.173 , pp. 2331-2341
    • Shulga-Morskaya, S.1    Dobles, M.2    Walsh, M.E.3    Ng, L.G.4    MacKay, F.5    Rao, S.P.6    Kalled, S.L.7    Scott, M.L.8
  • 55
    • 33845573544 scopus 로고    scopus 로고
    • Hepatitis C virus-associated B-cell proliferation-the role of serum B lymphocyte stimulator (BLyS/BAFF)
    • Sene D., Limal N., Ghillani-Dalbin P., Saadoun D., Piette J.C., Cacoub P. Hepatitis C virus-associated B-cell proliferation-the role of serum B lymphocyte stimulator (BLyS/BAFF). Rheumatology (Oxford) 2007, 46:65-69.
    • (2007) Rheumatology (Oxford) , vol.46 , pp. 65-69
    • Sene, D.1    Limal, N.2    Ghillani-Dalbin, P.3    Saadoun, D.4    Piette, J.C.5    Cacoub, P.6
  • 57
    • 33644872674 scopus 로고    scopus 로고
    • Antigen presentation and dendritic cell biology in malaria
    • Stevenson M.M., Urban B.C. Antigen presentation and dendritic cell biology in malaria. Parasite Immunol. 2006, 28:5-14.
    • (2006) Parasite Immunol. , vol.28 , pp. 5-14
    • Stevenson, M.M.1    Urban, B.C.2
  • 58
    • 0037195272 scopus 로고    scopus 로고
    • Immunoglobulin genes: generating diversity with AID and UNG
    • Storb U., Stavnezer J. Immunoglobulin genes: generating diversity with AID and UNG. Curr. Biol. 2002, 12:R725-R727.
    • (2002) Curr. Biol. , vol.12
    • Storb, U.1    Stavnezer, J.2
  • 60
    • 0037108509 scopus 로고    scopus 로고
    • Isotype switching by human B cells is division-associated and regulated by cytokines
    • Tangye S.G., Ferguson A., Avery D.T., Ma C.S., Hodgkin P.D. Isotype switching by human B cells is division-associated and regulated by cytokines. J. Immunol. 2002, 169:4298-4306.
    • (2002) J. Immunol. , vol.169 , pp. 4298-4306
    • Tangye, S.G.1    Ferguson, A.2    Avery, D.T.3    Ma, C.S.4    Hodgkin, P.D.5
  • 62
    • 33749514258 scopus 로고    scopus 로고
    • Elevated serum B-lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity
    • Toubi E., Gordon S., Kessel A., Rosner I., Rozenbaum M., Shoenfeld Y., Zuckerman E. Elevated serum B-lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity. J. Autoimmun. 2006, 27:134-139.
    • (2006) J. Autoimmun. , vol.27 , pp. 134-139
    • Toubi, E.1    Gordon, S.2    Kessel, A.3    Rosner, I.4    Rozenbaum, M.5    Shoenfeld, Y.6    Zuckerman, E.7
  • 63
    • 0017311840 scopus 로고
    • Human malaria parasites in continuous cultures
    • Trager W., Jensen J.B. Human malaria parasites in continuous cultures. Science 1976, 193:673-675.
    • (1976) Science , vol.193 , pp. 673-675
    • Trager, W.1    Jensen, J.B.2
  • 64
    • 0033181890 scopus 로고    scopus 로고
    • Immune regulation of protection and pathogenesis in Plasmodium falciparum malaria
    • Troye-Blomberg M., Perlmann P., Mincheva Nilsson L., Perlmann H. Immune regulation of protection and pathogenesis in Plasmodium falciparum malaria. Parassitologia 1999, 41:131-138.
    • (1999) Parassitologia , vol.41 , pp. 131-138
    • Troye-Blomberg, M.1    Perlmann, P.2    Mincheva Nilsson, L.3    Perlmann, H.4
  • 65
    • 53549125796 scopus 로고    scopus 로고
    • Immune interactions in malaria co-infections with other endemic infectious diseases: implications for the development of improved disease interventions
    • Troye-Blomberg M., Berzins K. Immune interactions in malaria co-infections with other endemic infectious diseases: implications for the development of improved disease interventions. Microbes Infect. 2008, 10:948-952.
    • (2008) Microbes Infect. , vol.10 , pp. 948-952
    • Troye-Blomberg, M.1    Berzins, K.2
  • 66
    • 0029583248 scopus 로고
    • Adhesion of Plasmodium falciparum-infected erythrocytes to human cells and secretion of cytokines (IL-1-beta, IL-1RA, IL-6, IL-8, IL-10, TGF beta, TNF alpha, G-CSF, GM-CSF
    • Wahlgren M., Abrams J.S., Fernandez V., Bejarano M.T., Azuma M., Torii M., Aikawa M., Howard R.J. Adhesion of Plasmodium falciparum-infected erythrocytes to human cells and secretion of cytokines (IL-1-beta, IL-1RA, IL-6, IL-8, IL-10, TGF beta, TNF alpha, G-CSF, GM-CSF. Scand. J. Immunol. 1995, 42:626-636.
    • (1995) Scand. J. Immunol. , vol.42 , pp. 626-636
    • Wahlgren, M.1    Abrams, J.S.2    Fernandez, V.3    Bejarano, M.T.4    Azuma, M.5    Torii, M.6    Aikawa, M.7    Howard, R.J.8


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.