Superantigen-like interaction of IVIG with antibody Fab fragments cloned by phage display technologyAwuku Kwabena Osei, DEDICATION11.111.21.2.121.2.21.331.3.11.3.241.3.35542#7996560#2361.3.41.4781.591.6101.71.8112112.1122.22.3132.4142.52.5.1152.5.2162.617182.72.7.12.7.2192.8202.9212.9.12.9.2222.102.11232.122.12.12.12.22.12.2.12.12.2.2242.12.3252.132.142633.13.1.127262#2733.1.228567#26129566#18030522#2573.231566#3323.332333.434529#365542#4203.53536581#4523.637523#3983.738567#171567#139393.83.9403.10566#32041566#372423.1143542#35344.1434.2444.3454.446474.5484.6LIST OF ABBREVIATIONSDECLARATIONLIST OF PUBLICATIONSCURRICULUM VITAE ACKNOWLEDGEMENTCITED LITTERATUREenTable of contentsHelp CITED LITTERATURE Adey, N. B., Mataragnon, A. H., Rider, J. E., Carter, J. M., and Kay, B. K (1995). Characterization of phage that bind plastic from phage-derived random peptide libraries. Gene 156: 27-31 Arend, W. P., Smith, M. F., Janson, R. W., Joslin, and F. G (1991 ). IL-1 receptor antagonist and IL-1b production in human monocytes are regulated differently. J. Immunol147:1530-1536 Balow, J. E (1991). Kidney disease in system lupus erythematosus. Rheumatol. Int. 11: 113 Barbas, C. F (1995). Synthetic human antibodies. Nat Med. 8: 837-839. Barbas III, C. F., Kang, A. S., Lerner, R. A., and Benkovic, S. J (1991 ). Assembly of combinatorial antibody libraries on phage surfaces: The gene III site. Proc. Natl. Acad. Sci. U. S. A. 88: 7978-7982 Basta, M., and Dalakas, M. C (1994). High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J. Clin. Inv.94: 1729-1735 Basta, M., Fries, L. F., Frank, and M. M (1991). High-dose intravenous immunoglobulin inhibits in vitro uptake of C4 fragments onto sensitized erythrocytes. Blood 77: 376-380 Blasczyk, R., Westhoff, U., and Grossewilde, H (1993). Soluble CD4, CD8 and HLA molecules in commercial immunoglobulin preparations. Lancet 341: 789-790 Breitling, F., Dübel, S., Seehaus, T., Klewinghaus, I., and Litlle, M (1991). A surface expression vector for antibody screening. Gene. 104:147-153 Burton, D. R., and Barbas III, C. F (1994). Human antibodies from combinatorial libraries. Adv. Immunol. 57:191-280 Bussell, J., and Hilgartner, U. W (1986). Usage of intravenous gammaglobulins in the treatment of chronic idiopathic thrombocytopenic purpura. In ''Clinical use of Intravenous Immunoglobulins'' (A Morrell and U. E. Nydegger, Eds,), pp. 217-221, Academic Press,

Orlando

Cairns, E., Kwong, P. C., Misener, V., Ip, P., Bell, D. A., Siminovitch, K. A ( 1989 ). Analysis of variable region genes encoding a human anti-DNA antibody of normal origin. Implications for the molecular basis of human autoimmune responses. J Immunol. 143 : 685-691 . Cary, S. P., Lee, J., Wagenknecht, R., and Silverman, G. J ( 2000 ) . Characterization of superantigen-induced clonal deletion with a novel clan III-restricted avian monoclonal antibody: exploiting evolutionary distance to create antibodies specific for a conserved VH region surface. J. Immunol. 164. 4730-4741 Casali, P., and Notkins, A.L (1989). Probing the human B cell repertoire with EBV: Polyreactive antibodies and CD5+ B lymphocytes. Ann. Rev. Immunol 7: 513-535 Chang, C. N., Landolfi, N. F., and Queen, C (1991). Expression of antibody Fab domains on bacteriophage surfaces: Potential use for antibody selection. J. Immunol. 147 3610-3614 Clarkson, S. B., Bussel, J. B., Kimberly, R. P., Valinsky, J. E., Nachman, R. L., and Unkeless, J. C (1986). Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody. N. Engl. J. Med. 314: 1236-1239 Cold Spring Harbor Laboratory course on monoclonal antibodies from combinatorial libraries (1993). The Scripps Research Institute.

La Jolla, Ca. U. S. A.

Cook, G. P., and Tomlinson, I. M (1995). The human immunoglobulin VH repertoire. Immunol. Today. 16: 237–242 Courtney, B. C., Williams, K. C. , and Schlager, J. J (1995). A phage display vector with improved stability, applicability and ease of manipulation. Gene. 165: 139-140 Cox, D. W., Markovic, V. D., and Teshima, I. E (1982). Genes for immunoglobulin heavy chains and for  1-antitrypsin are localized to specific regions of chromosome 14q. Nature. 297: 428-430 Deckmyn, H., and De Reys, S (1995). Functional effects of human antiplatelet antibodies. Semin. Thromb. Hemost.21: 46-58 de la Chapelle, A., Lenoir, A., Boue, G., Gallano, P., Huerre, C., Szajnert, M. F., Jeanpierre, M., Lalouel, M., and Kaplan, J. C (1983). Lamda Ig constant region genes are translocated to chromosome 8 in a Burkitt's lymphoma Nucl. Acids. Res. 11; 1133-1142 De Wildt, R. M. T., Hoet, R. M. A., van Venrooij, W. J., Tomlinson, I. M., and Winter, G (1999). Analysis of heavy and light chain pairings indicates that receptor editing shapes the human antibody repertoire. J. Mol. Biol. 285: 895-901 Dersimonian, H., Schwartz, R. S., Barrett, K. J., and Stollar, B. D (1987). Relationship of human variable region heavy chain germ-line genes to genes encoding anti-DNA. J. Immunol. 139: 2496-2501 Domiati-Saad, R., and Lipsky, P. E (1997). B Cell Superantigens: Potential Modifiers of the Normal Human B Cell Repertoire. Intern. Rev. Immunol. 14: 309-324 Duchosal, M. A., Eming, S., Fischer, P., Leturcq, D., Barbas III, C.F., McConahey, P. J., Caothien, R. H., Thornton, G. B., Dixon, F. J., and Burton, D. R (1992). Immunization of hu-PBL-SCID mice and the rescue of human monoclonal Fab fragments through combinatorial libraries. Nature 355: 258-262 Fischer, P (1995). Expression des humanen Antikörperrepertoires mit Bakteriophagen: techniken, anwendungen, perspektiven. Biospektrum. 3: 26-29 Fischer, P (1998 ). Molekulare Charakterisierung humaner Autoantikörper durch Kombinatorische Phagen Display-Bibliotheken. Habilitation , Medizinischen Falkultät Charitè der Humboldt-Universität zu

Berlin

. pp143 Fischer, P., Jendreyko, N., Hoffmann, M., Lerch, H., Uttenreuther-Fischer, M. M., Chen, P. P., and Gaedicke, G (1999). Platelet reactive IgG antibodies cloned by phage display and panning with IVIG from patients with AITP. Br. J. Haematol. 105: 626-640 Fischer, P., Uttenreuther-Fischer, M. M., Naoe, S., and Gaedicke, G (1996 ). Kawasaki disease: update on diagnosis, treatment and a still controversial etiology. Pediatr. Hematol. Oncol. 13: 487-501 Gordon, J. M., Cohen, P., and Finlayson, J. S (1980). Levels of anti-A and anti-B in commercial immune globulins. Transfusion 26: 90-92 Graille, M., Stura, E. A., Corper, A. L., Sutton, B. J., Taussig, M. J., Charbonnier, J-B., and Silverman, G (2000). Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody: Structural basis for recognition of B-cell receptors and superantigen activity. Proc. Natl. Acad. Sci. U.S.A. 97: 5399-5404 Graus, Y. F., de Baets, M. H., Parren, P. W., Berrih-Aknin, S., Wokke, J., van Breda Vriesman, P. J., Burton, D. R (1997). Human anti-nicotinic acetylcholine receptor recombinant Fab fragments isolated from thymus-derived phage display libraries from myasthenia gravis patients reflect predominant specificities in serum and block the action of pathogenic serum antibodies. J Immunol.158: 1919-1929. Hillson, J. L., Karr, N. S., Oppliger, I. R., Mannik, M., and Sasso, E. H (1993). The structural basis of germline-encoded VH3 immunoglobulin binding to staphylococcal protein A. J. Exp. Med. 178: 331-336 Hoffmann, M., Uttenreuther-Fischer, M. M., Lerch, H., Gaedicke, G., and Fischer, P (2000). IVIG-bound IgG and IgM cloned by phage display from a healthy individual reveal the same restricted germ-line gene origin as in autoimmune thrombocytopenia. Clin. Exp. Immunol. 121:37-46 Honjo, T., and Matsuda, F (1995 ). Immunoglobulin heavy chain loci of mouse and human. In Immunoglobulin Genes. 2nd edition, ed. Honjo, T., and Alt, F. W. Academic Press.

New York

. P. 145-171 Hoogenboom, H. R (1997). Designing and optimizing library selection strategies for generating high-affinity antibodies. Trends Biotechnol. 15: 62-70 Huang, S. C., Jiang, R. H., Glas, A. M., and Milner, E. C. B (1996). Non-stochastic utilization of Ig V region genes in unselected human peripheral B cells. Mol. Immunol. 33: 553-560 Hurez, V., Kaveri, S. V., Mouhoub, A., Dietrich, G., Mani, J. C., Klatzmann, D., and Kazatchkine, M. D (1994). Anti-CD4 activity of normal human immunoglobulin G for therapeutic use (intravenous immunoglobulin, IVIG Therapeutic Immunol 1: 269-278 Huse, W. D., Sastry, L., Iverson, S. A., Kang, A. S., Alting-Meers, M., Burton, D. R., Benkovic, S. J., and Lerner, R. A (1989). Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda. Science. 246: 1275-1281 Imbach, P., Wagner, H. P., Berchtold, W., Gaedicke, G., Hirt, A., Joller, P., Mueller-Eckhardt, C., Muller, B., Rossi, E (1985). Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet. 2: 464-468 James, K., and Bell, G. T (1987). Human monoclonal antibody production. Current status and future prospects. J Immunol Methods. 100: 5-40. Jansson, B., Uhlèn, M., and Nygre, P-A (1998). All individual domains of staphylococcal protein A show Fab binding. FEMS Immunol. Med. Mirobiol. 20: 69-78 Jendreyko, N., Uttenreuther-Fischer, M. M., Lerch, H., Gaedicke, G., and Fischer, P (1998). Genetic origin of IgG antibodies cloned by phage display and antiidiotypic panning from three patients with autoimmune thrombocytopenia. Eur. J. Immunol. 28: 4236-4247 Jerne, N. K (1974). Towards a network theory of the immune system. Ann Immunol. (Inst. Pasteur) 125c: 373-389 Jones, T. D (1944). Diagnosis of rheumatic fever. JAMA 126: 481 Kabat, E. A., Wu, T. T., Reid-Miller, M., Perry, H. M., Gottesman, K. S., and Foeller, C (1991). Sequences of proteins of immunological interest . U.S. Dept. of Health and Human Services,

Bethesda, MD, U.S.A

Kang, AS., Barbas III, C. F., Janda, K. D., Benkovic, S. J., and Lerner, R. A (1991a). Linkage of recognition and replication functions by assemblying combinatorial antibody Fab libraries along phage surfaces. Proc. Natl. Acad. Sci. U. S. A. 88: 4363 - 4366 Kang, A. S., Burton, D. R., and Lerner, R. A (1991b). Combinatorial immunoglobulin libraries in phage  . Methods. Companion Methods Enzymol. 2: 111-118 Karpatkin, S (1997). Autoimmune (idiopathic) thrombocytopenic purpura. Lancet 349: 1531-1536. Karray, S., Juompan, L., Maroun, R. C., Isenberg, D., Silverman, G. J., and Zouali, M (1998). Structural basis of the gp120 superantigen-binding site on human immunoglobulins. J. Immunol. 161: 6681-6688 Kearney, J. F., and Vakil, M (1986). Idiotype-directed interactions during ontogeny play a major role in the establishment of the adult B cell repertoire. Immunol. Rev. 94: 39-50 Kiefel, V., Santoso, S., Kaufmann, E., and Mueller-Eckhardt, C (1991). Autoantibodies against against platelet glycoprotein Ib/IX: a frequent finding in autoimmune thrombocytopenic purpura. Br. J. Hematol. 79: 256 - 262 Kimberly, R. P., Salmon, J. E., Bussel, J. B., Crow, M. K., and Hilgartner, M. W (1984). Modulation of mononuclear phagocyte function by intravenous gamma globulin. J. Immunol 132: 745-750 Kincade, P. W (1987). Experimental models for understanding B lymphocyte formation. Adv. Immunol. 41: 181-267 Kirkham, P. M., and Schroeder, H. W., Jr (1994). Antibody structure and the evolution of immunoglobulin V gene segments. Semin. Immunol. 6: 347-360 Köhler, G., and Milstein, C (1975). Continous cultures of fused cells secreting antibody of pre-defined specificity. Nature. 256: 495-497 Kondo, N., Kasahara, K., Kameyama, T., Suzuki, Y., Shimozawa, N., Tomatsu S., Nakashima Y., and Hori, T (1994). Intravenous immunoglobulins suppress immunoglobulin production by suppressing Ca2+-dependent signal transduction through Fcg receptors in B lymphocytes. Scand. J. Immunol 40: 37-42 Kondo, N., Ozawa, T., Mushiake, K., Motoyoshi, F., Kameyama, T., Kasahara, K., Kaneko, H, Yamashina M., Kato, Y., and Orii, T (1991). Suppression of immunoglobulin production of lymphocytes by intravenous immunoglobulin.J. Clin. Immunol. 11: 152-158 Kotzin, B. L (1996). Systemic lupus erythematosus. Cell. 85: 303-306 Kraj, P., Rao, S. P., Glas, A. M., Hardy, R. R., Milner, E. C. B., and Silberstein, L. E (1997). The human heavy chain Ig V region gene repertoire is biased at all stages of B cell ontogeny, including early pre-B cells. J. Immunol. 158: 5824-5832 Kuby, J (1997). Immunology. 3rd Edition. pp664. W. H. Freeman and Company.

New York

Lam, L., Whitsett, C. F., McNicholl, J. M., Hodge, T. W., and Hooper, J (1993). Immunologically active proteins in intravenous immunoglobulin. Lancet 342: 678 Leffell, M. S (1997). The molecular basis for immune responses. In: Handbook of Human Immunology. Ed. Leffell, M. S., Donnenberg, A. D., Bias, W. B., and Rose, N. R. pp 660. CRC Press Leucht, S., Uttenreuther-Fischer, M. M., Gaedicke, G., and Fischer, P (2001). The B cell superantigen-like interaction of intravenous immunoglobulin (IVIG) with Fab fragments of VH 3-23 and 3-30/3-30.5 germ-line gene origin cloned from a patient with Kawasaki disease is enhanced after IVIG therapy. Clin. Immunol. 99: 18-29 Leung, D. Y., Gately, M., Trumble, A., Ferguson-Darnell, B., Schlievert, P. M., and Picker, L. J (1995). Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin-12 production. J. Exp. Med 181: 747-753 Little, M., Breitling, F., Dübel, S., Fuchs, P., and Braunagel, M (1995 ). Human antibody libraries in Escherichia coli. J. Biotechnol. 41. 187 – 195 Little, M., Dübel, S., and Breitling, F (1997). Recent developments in antibody engineering. In: “Molecular Diagnosis of Infectious Diseases” in the series “Methods in Molecular Medicine. Vol 13, p. 555-580” ed. U. Reischl, Humana Press Inc

.

Totowa, N. Y.

Macchi, L., Rispal, P., Clofent-Sanchez, G., Pellegrin, J. -L., Nurden, P., Leng, B., and Nurden, A (1997). Anti-platelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody syndrome: their relationship with the observed thrombocytopenia. Br. J. Haematol. 98: 336-341 Malcolm, S., Barton, P., Murphy, C., Ferguson-Smith, M., A., Bentley, D. L., and Rabbits, T. H (1982). Localization of human immunoglobulin kappa light chain variable region genes to the short arm of chromosome 2 by in situ hybridization. Proc. Natl. Acad. Sci. USA. 79: 4957-4961 Marchalonis, J. J., Kaymaz, H., Dedeoglu, F., Schluter, S. F., Yocum, D. E., and Edmundson, A. B (1992). Human autoantibodies reactive with synthetic autoantigens from T-cell receptor  chain. Proc. Natl. Acad. Sci. U.S.A 89: 3325-3329 Matsuda, F., Ishii, K., Bourvagnet, P., Kuma, K., Hayashida, H, Miyata, T., and Honjo, T (1998). The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. J. Exp. Med. 188: 2151-2162 Matsuda, F., Shin, E. K., Nagoka, H., Matsumara, R., Haino, M., Fukita, Y., Takaishi, S., Imai, T., Riley, J. H., Anand, R., and Honjo, T (1993 ). Structure and physical map of 64 variable segments in the 3' 0.8-megabase region of the human immunoglobulin heavy-chain locus. Nature Genet. 3: 88-94 McCafferty, J., Griffiths, A. D., Winter, G., and Chiswell, D. J (1990). Phage antibodies: Filamentous phage displaying antibody variable domains. Nature 348: 552-554 Melchers, F., Karasuyama, H., Hassner, D., Bauer, S., Kudo, A., Sakaguchi, N., Jameson, B., and Rolink, A (1993). The surrogate light chain in B-cell development. Immunol. Today. 14: 60 - 68 Mouthon, L., Kaveri, S. V., Spalter, S. H., Lacroix-Desmazes, S., Lefranc, C., Desai, R., and Kazatchkine, M. D (1996). Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol. 104 (Suppl. 1): 3-9 Neshat, M. N., Goodglick, L., Lim, K., and Braun, J (2000). Mapping the B cell superantigen binding site for HIV-1 gp120 on a V(H)3 Ig. Int Immunol. 12: 305-312 Olee, T., Yang, P-M., Siminovitch, K. A., Olsen, N. J., Hillson, J., Wu, J., Kozin, F., Carson, D. A., and Chen, P. P (1991). Molecular Basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases. J. Clin. Invest. 88: 193-203 Osei, A., Uttenreuther-Fischer, M. M., Lerch, H., Gaedicke, G., Fischer, P (2000). Restricted VH3 gene use in phage displayed Fab that are selected by IVIG. Arthritis Rheum. 43: 2722-2732 Pascual, V., Randen, I., Thompson, K., Sioud, M., Forre, O., Natvig, J., and Capra, J. D (1990). The complete nucleotide sequences of the heavy chain variable regions of six monospecific rheumatoid factors derived from Epstein-Barr virus-transformed B cells isolated from the synovial tissue of patients with rheumatoid arthritis. Further evidence that some autoantibodies are unmutated copies of germ line genes. J Clin Invest. 86: 1320 - 1328. Persson, M. A (1993). Combinatorial libraries. Intern. Rev. Immunol. 10: 153 - 163 Persson, M. A., Caothien, R. H., and Burton, D. R (1991). Generation of diverse high-affinity human monoclonal antibodies by repertoire cloning.Proc. Natl. Acad. Sci. U. S. A. 86: 2432-2436 Potter, K. N., and Capra, J. D (1995 ). Immunoglobulin variable region gene segments in human autoantibodies. In Immunoglobulin Genes. 2nd edition, ed. Honjo, T., and Alt, F. W. Academic Press.

New York

. P. 379-396 Potter, K. N., Li, Y., Mageed, R. A., Jefferis, R., and Capra, J. D (1998). Anti-idiotypic antibody D12 and superantigen SpA both interact with human V(H)3-encoded antibodies on the external face of the heavy chain involving FR3. Mol. Immunol. 35: 1179-1187 Potter, K. N., Li, Y., Pascual, V., and Capra, J. D (1997). Staphylococcal Protein A Binding to VH3 Encoded Immunoglobulins. Intern. Rev. Immunol.14: 291-308 Quinti, I., Papetti, C., Paganelli, R., D'Amelio, R., Nisini, R., D'Offizi, G., and Aiuto, F (1987). Evaluation of the presence of RF-like activities in immunoglobulin preparations for intravenous use. IgG anti-IgE in intravenous Ig.J. Clin. Lab. Immunol. 24: 135-138 Rader, C., and Barbas III, C. F (1997). Phage display of combinatorial antibody libraries. Curr. Opin. Biotechnol. 8: 503-508 Rao, S. P., Riggs, J. M., Friedman, D. F., Scully, M. S., LeBien, T. W., and Silberstein, L. E (1999). Biased VH gene usage in early lineage human B cells: evidence for preferential Ig gene rearragement in the absence of selection. J. Immunol. 163: 2732-2740 Retter, M. W., and Nemazee, D (1998). Receptor Editing occurs frequently during normal B cell Development. J. Exp. Med. 7: 1231-1238 Rolink, A. and Melchers, F (1991). Molecular and cellular origins of B lymphocyte diversity. Cell. 66: 1081-1094 Rondot, S., Koch, J., Breitling, F., and Dubel, S (2001). A helper phage to improve single-chain antibody presentation in phage display. Nat. Biotechnol. 1 : 75-78 Sambrook, J., Fritsch, E. F., and Maniatis, T (1989). Molecular Cloning: A Laboratory Manual. 2nd Edition. Cold Spring Harbor Laboratory Press.

Cold Spring Harbor

. Sanz, I., Dang, H., Takei, M., Talal, N., and Capra, J. D (1989 ). VH sequence of a human anti-Sm autoantibody. J. Immunol. 142: 883 - 887. Sasano , M., Burton, D. R., and Silverman, G. J (1993). Molecular selection of human antibodies with an unconventional bacterial B cell superantigen. J. Immunol. 151 : 5822-5839 Sastry, L., Alting-Meers, M., Huse, W. D., Short, J. M., Sorge, J. A., Hay B. N., Janda, K. D., Benkovic, S. J., and Lerner, R. A (1989). Cloning of the immunoglobulin repertoire in Escherichia coli for generation of monoclonal catalytic antibodies: Construction of a heavy chain variable region-specific cDNA library. Proc. Natl. Acad. Sci. U. S. A. 86: 5728-5732 Schroeder, H., and Wang, J. Y (1990). Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc. Natl. Aca. Sci. USA 87: 6164-6150 Schroeder, H. W., Hillson, J. L., and Perlmutter, R. M (1990 ). Structure and evolution of mammalian VH families. Int. Immunol. 20: 41-50. Shimozato, T., Iwata, M., Kawada, H., and Tamura, N (1991). Human immunoglobulin preparation for intravenous use induces elevation of cellular cyclic adenosine 3´:5´-monophosphate levels, resulting in suppression of tumor necrosis factor alpha and interleukin-1 production. Immunology 72: 497-501 Siegel, D. L., Chang, T. Y., Russell, S. L., and Bunya, V. Y (1997). Isolation of cell surface-specific human monoclonal antibodies using phage display and magnetically-activated cell sorting: applications in immunohematology. J. Immunol. Methods 206: 73-85 Silverman, G. J (1997). B-cell superantigens. Immunol. Today 18: 379-386 Silverman, G. J (1998). B cell superantigens: possible roles in immunodeficiency and autoimmunity. Semin. Immunol. 1: 43 - 55 Smith, G. P (1985). Filamentous fusion phage: Novel expression vectors that display cloned antigens on the virion surface. Science. 228: 1315-1316 Stollar, B. D (1989). Immunochemistry of DNA. Int Rev Immunol. 5: 1-22. Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., McShane, D. J., Rothfield, N. F., Schaller, J. G., Talal, N., and Winchester, R. J (1982). The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25: 1271 Tomer, Y., Buskila, D., and Shoenfeld, Y (1993). Pathogenic significance and diagnostic value of lupus autoantibodies. Int. Arch. Allergy Immunol. 100: 293-306 Tomlinson, I. M., Walter, G., Marks, J. D., Llewelyn, M. B ., and Winter, G (1992 ). The repertoire of human germline VH sequences reveals about fifty groups of VH segments with different hypervariable loops. J. Mol. Biol. 227: 776-798 Tomlinson, I. M (1997). V Base sequence directory. M. R. C. Center for Protein Engineering.

Cambridge, U. K

Townsley-Fuchs, J., Neshat, M. S., Margolin, D. H., Braun, J. H., and Goodglick, L (1997). HIV-1 gp120: A Novel Viral B cell Superantigen. Int. Rev. Immunol. 14: 325-338 van Dijk, K. W., Mortari, F., Kirkham, P. M., Schroeder, H. W., and Milner, E. C (1993). The human immunoglobulin VH7 segment gene family consists of a small, polymorphic group of six to eight gene segments dispersed throughout the VH locus. Eur. J. Immunol. 23: 832-839 Vassilev, T., Gelin, C., Kaveri, S. V., Zilber, M-T., Boumsell, L., Kazatchkine, and M. D (1993). Antibodies to the CD5 molecule in normal human immunoglobulins for therapeutic use (intravenous immunoglobulin, IVIG). Clin. Exp. Immunol. 92: 369-372 Verhoeyen, M. E., and Windust, J. H. C (1996). Advances in antibody engineering. In Molecular Immunology. 2nd edition, p 283-325. Editors: Hames, B. D., and Glover, D. M. IRL Press, Oxford Univ. Press,

New York, U. S. A

White, J., Herman, A., Pullen, A. M., Kubo, R., Kappler, J. W., and Marrack, P (1989). The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell 56: 27-35 Williams, S. C., Frippiat, J-P., Tomlinson, I. M., Ignatovich, O., Lefranc, M-P., and Winter, G (1996). Sequence and evolution of the human germline V lambda repetoire. J. Mol. Biol. 264: 220-232 Wolf, H. M., and Eibl, M. M (1996). Immunomodulatory effect of immunoglobulins. Clin. Exp Rheumatol 14 (Suppl. 15): S17-S25. Woods, V. L., Oh, E. H., Mason, D., and McMillan, R ( 1984 ). Autoantibodies against the platelet glycoprotein IIb/IIIa complex in patients with chronic ITP. Blood. 63: 368 – 375 Xu, H., Frojmovic, M. M., Wong, T., and Rauch, J (1995). Inhibition of platelet aggregation by an SLE-derived human hybridoma autoantibody against an activation-dependent antigen. Thromb Haemos 74: 1152-1162 Yang, Y.-Y., Fischer, P., Leu, S.-Y., Zhu, M., Woods, V. L., and Chen, P. P (1999 ). Possible presence of enhancing antibodies in idiopathic thrombocytopenic purpura. Br. J. Haematol. 104: 69–80