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Sigbjørn Berentsen - One of the best experts on this subject based on the ideXlab platform.
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new insights in the pathogenesis and therapy of cold Agglutinin mediated autoimmune hemolytic anemia
Frontiers in Immunology, 2020Co-Authors: Sigbjørn BerentsenAbstract:Autoimmune hemolytic anemias mediated by cold Agglutinins can be divided into cold Agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold Agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly Mycoplasma pneumoniae and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.
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prophylactic use of eculizumab during surgery in chronic cold Agglutinin disease
Case Reports, 2017Co-Authors: Eirik Tjonnfjord, Sigbjørn Berentsen, Oystein Vengen, Geir E. TjønnfjordAbstract:Primary chronic cold Agglutinin disease (CAD) is an autoimmune haemolytic anaemia in which a specific bone marrow lymphoproliferative disorder causes production of cold Agglutinins (CA). Binding of CA to erythrocyte surface antigens results in a predominantly extravascular haemolysis that is entirely complement dependent. Because of complement activation, exacerbations are common during febrile infections, trauma or major surgery. Involvement of the terminal complement pathway with C5-mediated intravascular haemolysis is probably not prominent in stable disease but is supposed to be of importance in exacerbations following acute phase reaction.We report on a patient with CAD prone to exacerbation of haemolysis during acute phase reactions who was scheduled for cardiac surgery. To prevent her having an exacerbation of haemolysis, we chose to treat her prophylactically with eculizumab along with the usual perioperative precautions. Aortic valve replacement was undertaken with full cardiopulmonary bypass at normothermia. The procedure was successful; no exacerbation of haemolysis was observed, and transfusion requirements did not exceed what could be expected.
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1871-529X/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. B-lymphocytes as Targets for Therapy in Chronic Cold Agglutinin Disease
2015Co-Authors: Sigbjørn Berentsen, Elling Ulvestad, Geir E. TjønnfjordAbstract:Abstract: Primary chronic cold Agglutinin disease (CAD) is an autoimmune hemolytic anemia induced by cold reactive autoantibodies (cold Agglutinins) against erythrocyte surface antigens. Corticosteroids or alkylating agents have been used in the treatment of CAD, but the results have been disappointing. The cold Agglutinins in CAD patients are monoclonal immunoglobulins, usually of the IgM type encoded by the VH4-34 gene segment. Flowcytometric assessment of lymphocytes from bone marrow aspirates and immunohistochemical as-sessment of biopsy samples have revealed a monoclonal CD20 ++ B lymphocyte population in 90 % of the patients. These pathogenetic features have provided a basis for novel therapies in primary CAD. Infusions of rituximab, a chimeric human-murine anti-CD20 antibody known to be effective in B-cell lymphoma, produced partial response rates of ap-proximately 50 % and occasional complete responses. Median response duration, however, was only 11 months. Comple-ment C3 and C4 depletion in many CAD patients, as well as Fc-RIIIa receptor polymorphism, have been proposed as ex-planations for the inconstant efficacy of rituximab therapy. In order to increase response rates and response duration, we are undertaking a phase 2 study of rituximab and fludarabine combination therapy. The preliminary results are encourag-ing, but further studies are required in order to allow firm conclusions. Key Words: B lymphocytes, cold Agglutinin disease, fludarabine, hemolytic anemia, lymphoproliferative, rituximab
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primary cold Agglutinin associated lymphoproliferative disease a b cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma
Haematologica, 2014Co-Authors: Ulla Randen, Sigbjørn Berentsen, Geir E. Tjønnfjord, Gunhild Troen, Anne Tierens, Chloe B Steen, Abdirashid Warsame, Klaus Beiske, Jan DelabieAbstract:Primary chronic cold Agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold Agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold Agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold Agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma.
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primary chronic cold Agglutinin disease an update on pathogenesis clinical features and therapy
Hematology, 2007Co-Authors: Sigbjørn Berentsen, Klaus Beiske, Geir E. TjønnfjordAbstract:Chronic cold Agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia. Primary CAD has traditionally been defined by the absence of any underlying or associated disease. The results of therapy with corticosteroids, alkylating agents and interferon-a have been poor. Cold reactive immunoglobulins against erythrocyte surface antigens are essential to pathogenesis of CAD. These cold Agglutinins are monoclonal, usually IgMκ auto antibodies with heavy chain variable regions encoded by the VH4-34 gene segment. By flowcytometric and immunohistochemical assessments, a monoclonal CD20+κ+B-lymphocyte population has been demonstrated in the bone marrow of 90% of the patients, and lymphoplasmacytic lymphoma is a frequent finding. Novel attempts at treatment for primary CAD have mostly been directed against the clonal B-lymphocytes. Phase 2 studies have shown that therapy with the chimeric anti-CD20 antibody rituximab produced partial response rates of more than 50% and occasional complete responses. Median response duration, however, was only 11 months. In this review, we discuss the clinical and pathogenetic features of primary CAD, emphasizing the more recent data on its close association with clonal lymphoproliferative bone marrow disorders and implications for therapy. We also review the management and outline some perspectives on new therapy modalities.
Geir E. Tjønnfjord - One of the best experts on this subject based on the ideXlab platform.
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prophylactic use of eculizumab during surgery in chronic cold Agglutinin disease
Case Reports, 2017Co-Authors: Eirik Tjonnfjord, Sigbjørn Berentsen, Oystein Vengen, Geir E. TjønnfjordAbstract:Primary chronic cold Agglutinin disease (CAD) is an autoimmune haemolytic anaemia in which a specific bone marrow lymphoproliferative disorder causes production of cold Agglutinins (CA). Binding of CA to erythrocyte surface antigens results in a predominantly extravascular haemolysis that is entirely complement dependent. Because of complement activation, exacerbations are common during febrile infections, trauma or major surgery. Involvement of the terminal complement pathway with C5-mediated intravascular haemolysis is probably not prominent in stable disease but is supposed to be of importance in exacerbations following acute phase reaction.We report on a patient with CAD prone to exacerbation of haemolysis during acute phase reactions who was scheduled for cardiac surgery. To prevent her having an exacerbation of haemolysis, we chose to treat her prophylactically with eculizumab along with the usual perioperative precautions. Aortic valve replacement was undertaken with full cardiopulmonary bypass at normothermia. The procedure was successful; no exacerbation of haemolysis was observed, and transfusion requirements did not exceed what could be expected.
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1871-529X/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. B-lymphocytes as Targets for Therapy in Chronic Cold Agglutinin Disease
2015Co-Authors: Sigbjørn Berentsen, Elling Ulvestad, Geir E. TjønnfjordAbstract:Abstract: Primary chronic cold Agglutinin disease (CAD) is an autoimmune hemolytic anemia induced by cold reactive autoantibodies (cold Agglutinins) against erythrocyte surface antigens. Corticosteroids or alkylating agents have been used in the treatment of CAD, but the results have been disappointing. The cold Agglutinins in CAD patients are monoclonal immunoglobulins, usually of the IgM type encoded by the VH4-34 gene segment. Flowcytometric assessment of lymphocytes from bone marrow aspirates and immunohistochemical as-sessment of biopsy samples have revealed a monoclonal CD20 ++ B lymphocyte population in 90 % of the patients. These pathogenetic features have provided a basis for novel therapies in primary CAD. Infusions of rituximab, a chimeric human-murine anti-CD20 antibody known to be effective in B-cell lymphoma, produced partial response rates of ap-proximately 50 % and occasional complete responses. Median response duration, however, was only 11 months. Comple-ment C3 and C4 depletion in many CAD patients, as well as Fc-RIIIa receptor polymorphism, have been proposed as ex-planations for the inconstant efficacy of rituximab therapy. In order to increase response rates and response duration, we are undertaking a phase 2 study of rituximab and fludarabine combination therapy. The preliminary results are encourag-ing, but further studies are required in order to allow firm conclusions. Key Words: B lymphocytes, cold Agglutinin disease, fludarabine, hemolytic anemia, lymphoproliferative, rituximab
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primary cold Agglutinin associated lymphoproliferative disease a b cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma
Haematologica, 2014Co-Authors: Ulla Randen, Sigbjørn Berentsen, Geir E. Tjønnfjord, Gunhild Troen, Anne Tierens, Chloe B Steen, Abdirashid Warsame, Klaus Beiske, Jan DelabieAbstract:Primary chronic cold Agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold Agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold Agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold Agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma.
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primary chronic cold Agglutinin disease an update on pathogenesis clinical features and therapy
Hematology, 2007Co-Authors: Sigbjørn Berentsen, Klaus Beiske, Geir E. TjønnfjordAbstract:Chronic cold Agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia. Primary CAD has traditionally been defined by the absence of any underlying or associated disease. The results of therapy with corticosteroids, alkylating agents and interferon-a have been poor. Cold reactive immunoglobulins against erythrocyte surface antigens are essential to pathogenesis of CAD. These cold Agglutinins are monoclonal, usually IgMκ auto antibodies with heavy chain variable regions encoded by the VH4-34 gene segment. By flowcytometric and immunohistochemical assessments, a monoclonal CD20+κ+B-lymphocyte population has been demonstrated in the bone marrow of 90% of the patients, and lymphoplasmacytic lymphoma is a frequent finding. Novel attempts at treatment for primary CAD have mostly been directed against the clonal B-lymphocytes. Phase 2 studies have shown that therapy with the chimeric anti-CD20 antibody rituximab produced partial response rates of more than 50% and occasional complete responses. Median response duration, however, was only 11 months. In this review, we discuss the clinical and pathogenetic features of primary CAD, emphasizing the more recent data on its close association with clonal lymphoproliferative bone marrow disorders and implications for therapy. We also review the management and outline some perspectives on new therapy modalities.
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b lymphocytes as targets for therapy in chronic cold Agglutinin disease
Cardiovascular and Hematological Disorders - Drug Targets, 2007Co-Authors: Sigbjørn Berentsen, Elling Ulvestad, Geir E. TjønnfjordAbstract:Primary chronic cold Agglutinin disease (CAD) is an autoimmune hemolytic anemia induced by cold reactive autoantibodies (cold Agglutinins) against erythrocyte surface antigens. Corticosteroids or alkylating agents have been used in the treatment of CAD, but the results have been disappointing. The cold Agglutinins in CAD patients are monoclonal immunoglobulins, usually of the IgMκ type encoded by the VH4-34 gene segment. Flowcytometric assessment of lymphocytes from bone marrow aspirates and immunohistochemical assessment of biopsy samples have revealed a monoclonal CD20+κ+ B lymphocyte population in 90% of the patients. These pathogenetic features have provided a basis for novel therapies in primary CAD. Infusions of rituximab, a chimeric human-murine anti-CD20 antibody known to be effective in B-cell lymphoma, produced partial response rates of approximately 50% and occasional complete responses. Median response duration, however, was only 11 months. Complement C3 and C4 depletion in many CAD patients, as well as Fcγ-RIIIa receptor polymorphism, have been proposed as explanations for the inconstant efficacy of rituximab therapy. In order to increase response rates and response duration, we are undertaking a phase 2 study of rituximab and fludarabine combination therapy. The preliminary results are encouraging, but further studies are required in order to allow firm conclusions.
Peter N Lipke - One of the best experts on this subject based on the ideXlab platform.
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glycosyl phosphatidylinositol dependent cross linking of alpha Agglutinin and beta 1 6 glucan in the saccharomyces cerevisiae cell wall
Journal of Cell Biology, 1995Co-Authors: Roy C Montijn, Janet Kurjan, Jeffrey L Brown, Frans M Klis, Howard Bussey, Peter N LipkeAbstract:The cell adhesion protein alpha-Agglutinin is bound to the outer surface of the Saccharomyces cerevisiae cell wall and mediates cell-cell contact in mating. alpha-Agglutinin is modified by addition of a glycosyl phosphatidylinositol (GPI) anchor as it traverses the secretory pathway. The presence of a GPI anchor is essential for cross-linking into the wall, but the fatty acid and inositol components of the anchor are lost before cell wall association (Lu, C.-F., J. Kurjan, and P. N. Lipke, 1994. A pathway for cell wall anchorage of Saccharomyces cerevisiae alpha-Agglutinin. Mol. Cell. Biol. 14:4825-4833). Cell wall association of alpha-Agglutinin was accompanied by an increase in size and a gain in reactivity to antibodies directed against beta 1,6-glucan. Several kre mutants, which have defects in synthesis of cell wall beta 1,6-glucan, had reduced molecular size of cell wall alpha-Agglutinin. These findings demonstrate that the cell wall form of alpha-Agglutinin is covalently associated with beta 1,6-glucan. The alpha-Agglutinin biosynthetic precursors did not react with antibody to beta 1,6-glucan, and the sizes of these forms were unaffected in kre mutants. A COOH-terminal truncated form of alpha-Agglutinin, which is not GPI anchored and is secreted into the medium, did not react with the anti-beta 1,6-glucan. We propose that extracellular cross-linkage to beta 1,6-glucan mediates covalent association of alpha-Agglutinin with the cell wall in a manner that is dependent on prior addition of a GPI anchor to alpha-Agglutinin.
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cell surface anchorage and ligand binding domains of the saccharomyces cerevisiae cell adhesion protein alpha Agglutinin a member of the immunoglobulin superfamily
Molecular and Cellular Biology, 1993Co-Authors: D Wojciechowicz, Chafen Lu, Janet Kurjan, Peter N LipkeAbstract:Abstract alpha-Agglutinin is a cell adhesion glycoprotein expressed on the cell wall of Saccharomyces cerevisiae alpha cells. Binding of alpha-Agglutinin to its ligand a-Agglutinin, expressed by a cells, mediates cell-cell contact during mating. Analysis of truncations of the 650-amino-acid alpha-Agglutinin structural gene AG alpha 1 delineated functional domains of alpha-Agglutinin. Removal of the C-terminal hydrophobic sequence allowed efficient secretion of the protein and loss of cell surface attachment. This cell surface anchorage domain was necessary for linkage to a glycosyl phosphatidylinositol anchor. A construct expressing the N-terminal 350 amino acid residues retained full a-Agglutinin-binding activity, localizing the binding domain to the N-terminal portion of alpha-Agglutinin. A 278-residue N-terminal peptide was inactive; therefore, the binding domain includes residues between 278 and 350. The segment of alpha-Agglutinin between amino acid residues 217 and 308 showed significant structural and sequence similarity to a consensus sequence for immunoglobulin superfamily variable-type domains. The similarity of the alpha-Agglutinin-binding domain to mammalian cell adhesion proteins suggests that this structure is a highly conserved feature of adhesion proteins in diverse eukaryotes.
Janet Kurjan - One of the best experts on this subject based on the ideXlab platform.
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glycosyl phosphatidylinositol dependent cross linking of alpha Agglutinin and beta 1 6 glucan in the saccharomyces cerevisiae cell wall
Journal of Cell Biology, 1995Co-Authors: Roy C Montijn, Janet Kurjan, Jeffrey L Brown, Frans M Klis, Howard Bussey, Peter N LipkeAbstract:The cell adhesion protein alpha-Agglutinin is bound to the outer surface of the Saccharomyces cerevisiae cell wall and mediates cell-cell contact in mating. alpha-Agglutinin is modified by addition of a glycosyl phosphatidylinositol (GPI) anchor as it traverses the secretory pathway. The presence of a GPI anchor is essential for cross-linking into the wall, but the fatty acid and inositol components of the anchor are lost before cell wall association (Lu, C.-F., J. Kurjan, and P. N. Lipke, 1994. A pathway for cell wall anchorage of Saccharomyces cerevisiae alpha-Agglutinin. Mol. Cell. Biol. 14:4825-4833). Cell wall association of alpha-Agglutinin was accompanied by an increase in size and a gain in reactivity to antibodies directed against beta 1,6-glucan. Several kre mutants, which have defects in synthesis of cell wall beta 1,6-glucan, had reduced molecular size of cell wall alpha-Agglutinin. These findings demonstrate that the cell wall form of alpha-Agglutinin is covalently associated with beta 1,6-glucan. The alpha-Agglutinin biosynthetic precursors did not react with antibody to beta 1,6-glucan, and the sizes of these forms were unaffected in kre mutants. A COOH-terminal truncated form of alpha-Agglutinin, which is not GPI anchored and is secreted into the medium, did not react with the anti-beta 1,6-glucan. We propose that extracellular cross-linkage to beta 1,6-glucan mediates covalent association of alpha-Agglutinin with the cell wall in a manner that is dependent on prior addition of a GPI anchor to alpha-Agglutinin.
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cell surface anchorage and ligand binding domains of the saccharomyces cerevisiae cell adhesion protein alpha Agglutinin a member of the immunoglobulin superfamily
Molecular and Cellular Biology, 1993Co-Authors: D Wojciechowicz, Chafen Lu, Janet Kurjan, Peter N LipkeAbstract:Abstract alpha-Agglutinin is a cell adhesion glycoprotein expressed on the cell wall of Saccharomyces cerevisiae alpha cells. Binding of alpha-Agglutinin to its ligand a-Agglutinin, expressed by a cells, mediates cell-cell contact during mating. Analysis of truncations of the 650-amino-acid alpha-Agglutinin structural gene AG alpha 1 delineated functional domains of alpha-Agglutinin. Removal of the C-terminal hydrophobic sequence allowed efficient secretion of the protein and loss of cell surface attachment. This cell surface anchorage domain was necessary for linkage to a glycosyl phosphatidylinositol anchor. A construct expressing the N-terminal 350 amino acid residues retained full a-Agglutinin-binding activity, localizing the binding domain to the N-terminal portion of alpha-Agglutinin. A 278-residue N-terminal peptide was inactive; therefore, the binding domain includes residues between 278 and 350. The segment of alpha-Agglutinin between amino acid residues 217 and 308 showed significant structural and sequence similarity to a consensus sequence for immunoglobulin superfamily variable-type domains. The similarity of the alpha-Agglutinin-binding domain to mammalian cell adhesion proteins suggests that this structure is a highly conserved feature of adhesion proteins in diverse eukaryotes.
Anjali A Karande - One of the best experts on this subject based on the ideXlab platform.
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structure function analysis and insights into the reduced toxicity of abrus precatorius Agglutinin i in relation to abrin
Journal of Biological Chemistry, 2006Co-Authors: A Bagaria, Kalpana Surendranath, U A Ramagopal, S Ramakumar, Anjali A KarandeAbstract:Abrin and Agglutinin-I from the seeds of Abrus precatorius are type II ribosome-inactivating proteins that inhibit protein synthesis in eukaryotic cells. The two toxins share a high degree of sequence similarity; however, Agglutinin-I is weaker in its activity. We compared the kinetics of protein synthesis inhibition by abrin and Agglutinin-I in two different cell lines and found that \sim 200-2000-fold higher concentration of Agglutinin-I is needed for the same degree of inhibition. Like abrin, Agglutinin-I also induced apoptosis in the cells by triggering the intrinsic mitochondrial pathway, although at higher concentrations as compared with abrin. The reason for the decreased toxicity of Agglutinin-I became apparent on the analysis of the crystal structure of Agglutinin-I obtained by us in comparison with that of the reported structure of abrin. The overall protein folding of Agglutinin-I is similar to that of abrin-a with a single disulfide bond holding the toxic A subunit and the lectin-like B-subunit together, constituting a heterodimer. However, there are significant differences in the secondary structural elements, mostly in the A chain. The substitution of Asn-200 in abrin-a with Pro-199 in Agglutinin-I seems to be a major cause for the decreased toxicity of Agglutinin-I. This perhaps is not a consequence of any kink formation by a proline residue in the helical segment, as reported by others earlier, but due to fewer interactions that proline can possibly have with the bound substrate.
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structure function analysis and insights into the reduced toxicity of abrus precatorius Agglutinin i in relation to abrin
Journal of Biological Chemistry, 2006Co-Authors: A Bagaria, Kalpana Surendranath, U A Ramagopal, S Ramakumar, Anjali A KarandeAbstract:Abrin and Agglutinin-I from the seeds of Abrus precatorius are type II ribosome-inactivating proteins that inhibit protein synthesis in eukaryotic cells. The two toxins share a high degree of sequence similarity; however, Agglutinin-I is weaker in its activity. We compared the kinetics of protein synthesis inhibition by abrin and Agglutinin-I in two different cell lines and found that approximately 200-2000-fold higher concentration of Agglutinin-I is needed for the same degree of inhibition. Like abrin, Agglutinin-I also induced apoptosis in the cells by triggering the intrinsic mitochondrial pathway, although at higher concentrations as compared with abrin. The reason for the decreased toxicity of Agglutinin-I became apparent on the analysis of the crystal structure of Agglutinin-I obtained by us in comparison with that of the reported structure of abrin. The overall protein folding of Agglutinin-I is similar to that of abrin-a with a single disulfide bond holding the toxic A subunit and the lectin-like B-subunit together, constituting a heterodimer. However, there are significant differences in the secondary structural elements, mostly in the A chain. The substitution of Asn-200 in abrin-a with Pro-199 in Agglutinin-I seems to be a major cause for the decreased toxicity of Agglutinin-I. This perhaps is not a consequence of any kink formation by a proline residue in the helical segment, as reported by others earlier, but due to fewer interactions that proline can possibly have with the bound substrate.