, Unité Mixte de Recherche en Santé (UMR S) 1138, Centre de Recherche des Cordeliers, Equipe Immunopathology and Therapeutic Immunointervention

, Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Equipe Immunopathology and Therapeutic Immunointervention

, UMR S 1138, Centre de Recherche des Cordeliers, Equipe Immunopathology and Therapeutic Immunointervention, vol.5

, AP-HP

, BAS

C. Laboratoire-de-génétique-moléculaire and . Ch,

C. Laboratoire-d'immunologie-and-d'immunopathologie and . Caen,

. Laboratoire-d'immunologie and . Histocompatibilité, AP-HP

H. Département-d'immunologie-clinique and . Saint-louis, AP-HP

H. Service-d'hématologie-biologique and . Lariboisière, International Associated Laboratory IMPACT, vol.12

. Institute-of-biology, . Technologies, . Simopro, L. Labex, and V. Labex,

, Service d'Hématologie, Hôpital Saint Antoine, AP-HP

H. M. Tsai and E. C. Lian, Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura, N Engl J Med, vol.339, issue.22, pp.1585-1594, 1998.

M. Furlan, R. Robles, and M. Solenthaler, Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura, Blood, vol.91, issue.8, pp.2839-2846, 1998.

G. G. Levy, W. C. Nichols, and E. C. Lian, Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura, Nature, vol.413, issue.6855, pp.488-494, 2001.

Y. Lone, Bagirath Gangadharan, vol.5, p.3

B. Michard, , vol.1, p.3

Y. Kherabi, , vol.1, 2006.

J. Latouche,

O. Toutirais, , vol.8

P. Loiseau, 9 Lionel Galicier, 10 Agnès Veyradier, 11 Srini Kaveri, vol.1, p.12

B. Maillère, , p.13

, Paul Coppo 4,14 and Sébastien Lacroix-Desmazes, vol.1, p.12

, Unité Mixte de Recherche en Santé (UMR S) 1138, Centre de Recherche des Cordeliers, 1 Institut National de la Santé et de la Recherche Médicale (INSERM), vol.75010

, BAS, vol.6

. Laboratoire-d'immunologie, H. Histocompatibilité, . Saint-louis, and . Ap-hp, Département d'Immunologie Clinique, Hôpital Saint-Louis, International Associated Laboratory IMPACT, vol.10

. Institute-of-biology, . Technologies, . Simopro, L. Labex, V. Labex et al., Commissariat à l'énergie Atomique (CEA) Saclay, Gif sur Yvette, France and 14 Service d'Hématologie, Hôpital Saint Antoine, N Engl J Med, vol.339, issue.22, pp.1585-1594, 1998.

G. G. Levy, W. C. Nichols, and E. C. Lian, Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura, Nature, vol.413, issue.6855, pp.488-494, 2001.

P. Coppo, D. Bengoufa, and A. Veyradier, Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement, Medicine (Baltimore), vol.83, issue.4, pp.233-244, 2004.
URL : https://hal.archives-ouvertes.fr/hal-02414908

X. L. Zheng, H. M. Wu, and D. Shang, Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura

, Haematologica, vol.95, issue.9, pp.1555-1562, 2010.

S. Ferrari, K. Palavra, and B. Gruber, Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura, Haematologica, vol.99, issue.4, pp.779-787, 2014.

M. R. Thomas, R. De-groot, and M. A. Scully, Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura, EBioMedicine, vol.2, issue.8, pp.942-952, 2015.

W. Pos, J. Crawley, and R. Fijnheer, An autoantibody epitope comprising residues R660, Y661, and Y665 in the ADAMTS13 spacer domain identifies a binding site for the A2 domain of VWF, Blood, vol.115, issue.8, pp.1640-1649, 2010.

W. Pos, B. M. Luken, and N. Sorvillo, Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura, J Thromb Haemost, vol.9, issue.7, pp.1285-1291, 2011.

P. Coppo, M. Busson, and A. Veyradier, HLA-DRB1*11: a strong risk factor for acquired severe ADAMTS13 deficiency-related idiopathic thrombotic thrombocytopenic purpura in Caucasians, J Thromb Haemost JTH, vol.8, issue.4, pp.856-859, 2010.

M. Scully, J. Brown, and R. Patel, Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link, J Thromb Haemost, vol.8, issue.2, pp.257-262, 2010.

M. John, W. Hitzler, and I. Scharrer, The role of human leukocyte antigens as predisposing and/or protective factors in patients with idiopathic thrombotic thrombocytopenic purpura, Ann Hematol, vol.91, issue.4, pp.507-510, 2012.

N. Sorvillo, S. D. Van-haren, and P. H. Kaijen, Preferential HLA-DRB1*11-dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells, Blood, vol.121, issue.17, pp.3502-3510, 2013.

F. C. Verbij, A. W. Turksma, and F. De-heij, CD4+ T cells from patients with acquired thrombotic thrombocytopenic purpura recognize CUB2 domain-derived peptides, Blood, vol.127, issue.12, pp.1606-1609, 2016.

P. Wang, J. Sidney, and C. Dow, A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach, PLoS Comput Biol, vol.4, issue.4, p.1000048, 2008.

P. Wang, J. Sidney, and Y. Kim, Peptide binding predictions for HLA DR, DP and DQ molecules, BMC Bioinformatics, vol.11, p.568, 2010.

R. Vita, J. A. Overton, and J. A. Greenbaum, The immune epitope database

P. M. Mannucci and E. G. Tuddenham, The hemophilias-from royal genes to gene therapy, N Engl J Med, vol.344, pp.1773-1782, 2001.

J. Graw, H. H. Brackmann, J. Oldenburg, R. Schneppenheim, M. Spannagl et al., Haemophilia A: from mutation analysis to new therapies, Nat Rev Genet, vol.6, pp.488-501, 2005.

S. Ehrenforth, W. Kreuz, and I. Scharrer, Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs, Lancet, vol.339, pp.594-602, 1992.

A. Gringeri, L. G. Mantovani, L. Scalone, and P. M. Mannucci, Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group, Blood, vol.102, pp.2358-63, 2003.

M. Algiman, G. Dietrich, U. Nydegger, D. Boieldieu, Y. Sultan et al., Natural antibodies to factor VIII (anti-hemophilic factor) in healthy individuals, Proc Natl Acad Sci, vol.89, pp.3795-3804, 1992.

A. Moreau, S. Lacroix-desmazes, and N. Stieltjes, Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity, are present in the plasma of non-responder patients with severe hemophilia A and healthy blood donors, Blood, vol.95, pp.3435-3476, 2000.

M. T. Reding, D. K. Okita, B. M. Diethelm-okita, T. A. Anderson, and B. M. Conti-fine, Human CD4 + T-cell epitope repertoire on the C2 domain of coagulation factor VIII, J Thromb Haemost, vol.1, pp.1777-84, 2003.

M. T. Reding, D. K. Okita, B. M. Diethelm-okita, T. A. Anderson, and B. M. Conti-fine, Epitope repertoire of human CD4(+) T cells on the A3 domain of coagulation factor VIII, J Thromb Haemost, vol.2, pp.1385-94, 2004.

M. T. Reding, H. Wu, and M. Krampf, CD4 + T cell response to factor VIII in hemophilia A, acquired hemophilia, and healthy subjects, Thromb Haemost, vol.82, pp.509-524, 1999.

F. Rossi, G. Dietrich, and M. D. Kazatchkine, Anti-idiotypes against autoantibodies in normal immunoglobulins: evidence for network regulation of human autoimmune responses, Immunol Rev, vol.110, pp.135-184, 1989.

F. Rossi, Y. Sultan, and M. D. Kazatchkine, Anti-idiotypes against autoantibodies and alloantibodies to factor VIII:C (anti-haemophilic factor) are present in therapeutic polyspecific normal immunoglobulins, Clin Exp Immunol, vol.74, pp.311-317, 1988.

C. Kamate, P. J. Lenting, H. M. Van-den-berg, and T. Mutis, Depletion of CD4(+)CD25(high) regulatory T cells may enhance or uncover factor VIII-specific T cell responses in healthy individuals, J Thromb Haemost, vol.5, pp.611-614, 2007.

S. Lacroix-desmazes, A. M. Navarrete, S. Andre, J. Bayry, S. V. Kaveri et al., Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A, Blood, vol.112, pp.240-249, 2008.

P. W. Collins, S. Hirsch, and T. P. Baglin, Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation, Blood, vol.109, pp.1870-1877, 2007.

S. C. Gouw, H. M. Van-den-berg, and J. Oldenburg, F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis, Blood, vol.119, pp.2922-2956, 2012.

R. Schwaab, H. Brackmann, and C. Meyer, Haemophilia A: mutation type determines risk of inhibitor formation, Thromb Haemost, vol.74, pp.1402-1408, 1995.

K. R. Viel, A. Ameri, and T. C. Abshire, Inhibitors of factor VIII in black patients with hemophilia, N Engl J Med, vol.360, pp.1618-1645, 2009.

J. Schwarz, J. Astermark, and E. D. Menius, F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study, vol.19, pp.113-121, 2013.

J. Oldenburg and O. El-maarri, New insight into the molecular basis of hemophilia A, Int J Hematol, vol.83, pp.96-102, 2006.

J. Astermark, J. Oldenburg, and J. Carlson, Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A, Blood, vol.108, pp.3739-3784, 2006.

J. Astermark, J. Oldenburg, A. Pavlova, E. Berntorp, and A. K. Lefvert, Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A, Blood, vol.107, pp.3167-72, 2006.

J. Astermark, X. Wang, J. Oldenburg, E. Berntorp, and A. K. Lefvert, Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A, J Thromb Haemost, vol.5, pp.263-268, 2007.

A. Pavlova, D. Delev, and S. Lacroix-desmazes, Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A, J Thromb Haemost, vol.7, pp.2006-2021, 2009.

J. Oldenburg, J. K. Picard, R. Schwaab, H. H. Brackmann, E. G. Tuddenham et al., HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII, Thromb Haemost, vol.77, pp.238-280, 1997.

C. R. Hay, W. Ollier, and L. Pepper, HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party, Thromb Haemost, vol.77, pp.234-241, 1997.

J. Astermark, S. M. Donfield, and E. D. Gomperts, The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort, Blood, vol.121, pp.1446-54, 2013.

C. L. Eckhardt, L. A. Menke, and C. H. Van-ommen, Intensive peri-operative use of factor VIII and the Arg593->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A, J Thromb Haemost, vol.7, pp.930-937, 2009.

W. S. Bril, P. E. Maclean, and P. H. Kaijen, HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg593 to Cys mutation, Haemophilia, vol.10, pp.509-523, 2004.

G. Kemball-cook, E. G. Tuddenham, and A. I. Wacey, The factor VIII structure and mutation resource site: HAMSTeRS version 4, Nucleic Acids Res, vol.26, pp.216-225, 1998.

R. Vita, L. Zarebski, and J. A. Greenbaum, The immune epitope database 2.0, Nucleic Acids Res, vol.38, pp.854-62, 2010.

M. Nielsen and O. Lund, NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction, BMC Bioinformatics, vol.10, p.296, 2009.

M. Nielsen, C. Lundegaard, and T. Blicher, NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence, PLoS ONE, vol.2, p.796, 2007.

H. H. Bui, J. Sidney, and B. Peters, Automated generation and evaluation of specific MHC binding predictive tools: ARB matrix applications, Immunogenetics, vol.57, pp.304-318, 2005.

M. Nielsen, C. Lundegaard, and T. Blicher, Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan, PLoS Comput Biol, vol.4, p.1000107, 2008.

T. Sturniolo, E. Bono, and J. Ding, Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices, Nat Biotechnol, vol.17, pp.555-61, 1999.

P. Wang, J. Sidney, C. Dow, B. Mothe, A. Sette et al., A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach, PLoS Comput Biol, vol.4, p.1000048, 2008.

H. H. Lin, G. L. Zhang, S. Tongchusak, E. L. Reinherz, and V. Brusic, Evaluation of MHC-II peptide binding prediction servers: applications for vaccine research, BMC Bioinformatics, vol.9, p.22, 2008.

S. Delluc, G. Ravot, and B. Maillere, Quantification of the preexisting CD4 T-cell repertoire specific for human erythropoietin reveals its immunogenicity potential, Blood, vol.116, pp.4542-4547, 2010.

P. Wang, J. Sidney, and Y. Kim, Peptide binding predictions for HLA DR, DP and DQ molecules, BMC Bioinformatics, vol.11, p.568, 2010.

P. M. Green, R. D. Bagnall, N. H. Waseem, and F. Giannelli, Haemophilia A mutations in the UK: results of screening one-third of the population, Br J Haematol, vol.143, pp.115-143, 2008.

C. Yanover, N. Jain, G. Pierce, T. E. Howard, and Z. E. Sauna, Pharmacogenetics and the immunogenicity of protein therapeutics, Nat Biotechnol, vol.29, pp.870-873, 2011.

A. D. Pashov, S. V. Kaveri, and S. Lacroix-desmazes, Missense Mutations Disrupting Promiscuous Class II Self-Epitopes are Associated with Development of Inhibitory Antibodies to Factor VIII, 2010.

S. D. Van-haren, E. Herczenik, A. Ten-brinke, K. Mertens, J. Voorberg et al., HLA-DR-presented peptide repertoires derived from human monocyte-derived dendritic cells pulsed with blood coagulation factor VIII, Mol Cell Proteomics, vol.10, 2011.

K. N. Steinitz, P. M. Van-helden, and B. Binder, CD4 + T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1* 1501 mice, Blood, vol.119, pp.4073-82, 2012.

J. D. Dimitrov, L. T. Roumenina, and J. L. Plantier, A human FVIII inhibitor modulates FVIII surface electrostatics at a VWF-binding site distant from its epitope, J Thromb Haemost, vol.8, pp.1524-1555, 2010.

A. J. Vlot, S. J. Koppelman, and J. Meijers, Kinetics of factor VIII-von Willebrand factor association, Blood, vol.87, pp.1809-1825, 1996.

P. J. Lenting, J. A. Van-mourik, and K. Mertens, The life cycle of coagulation factor VIII in view of its structure and function, Blood, vol.92, pp.3983-96, 1998.

K. N. Steinitz, P. M. Van-helden, and B. Binder, CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice, Blood, vol.119, issue.17, pp.4073-4082, 2012.

S. Lacroix-desmazes, A. M. Navarrete, S. Andre, J. Bayry, S. V. Kaveri et al., Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A, Blood, vol.112, issue.2, pp.240-249, 2008.

R. Vita, L. Zarebski, and J. A. Greenbaum, The immune epitope database 2.0, Nucleic Acids Res, vol.38, pp.854-862, 2010.

A. Sette, W. Fleri, B. Peters, M. Sathiamurthy, H. H. Bui et al., A roadmap for the immunomics of category A-C pathogens, Immunity, vol.22, issue.2, pp.155-161, 2005.

Y. Kim, A. Sette, and B. Peters, Applications for T-cell epitope queries and tools in the Immune Epitope Database and Analysis Resource, J Immunol Methods, vol.374, issue.1-2, pp.62-69, 2010.

S. Delignat, *. Repess-e, §. L. Gilardi-n, *. D. Di-mitrov, and *. C. Lone,

S. V. Kav-eri-*-?-?-** and S. Lacr-oix-desmaz-es*-?-?-**,

, *Institut National de la Sant e et de la Recherche M edicale (INSERM), Unit e Mixte de Recherche en Sant e (UMR S), vol.6

J. Graw, H. H. Brackmann, and J. Oldenburg, from mutation analysis to new therapies, Nat Rev Genet, vol.6, pp.488-501, 2005.

J. Astermark, J. Oldenburg, and J. Carlson, Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A, Blood, vol.108, pp.3739-3784, 2006.

J. Goudemand, C. Rothschild, and V. Demiguel, Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A, Blood, vol.107, pp.46-51, 2006.

S. C. Gouw, J. G. Van-der-bom, G. Auerswald, E. Ettinghausen, C. Tedgard et al., Recombinant versus plasmaderived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study, Blood, vol.109, pp.4693-4700, 2007.

S. C. Gouw, J. G. Van-der-bom, and R. Ljung, Factor VIII products and inhibitor development in severe hemophilia A, N Engl J Med, vol.368, pp.231-240, 2013.

C. M. Kessler and A. Iorio, The Rodin (Research Of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters, Haemophilia, vol.19, pp.351-355, 2013.

L. M. Aledort, R. J. Navickis, and M. M. Wilkes, Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies, J Thromb Haemost, vol.9, pp.2180-92, 2011.

A. Iorio, M. Marcucci, and M. Makris, Concentrate-related inhibitor risk: is a difference always real?, J Thromb Haemost, vol.9, pp.2176-2185, 2011.

S. Delignat, S. Dasgupta, and A. S. , Comparison of the immunogenicity of different therapeutic preparations of human factor VIII in the murine model of hemophilia A, Haematologica, vol.92, pp.1423-1429, 2007.

Y. Repesse, S. Dasgupta, A. M. Navarrete, S. Delignat, S. V. Kaveri et al., Mannose-sensitive receptors mediate the uptake of factor VIII therapeutics by human dendritic cells, J Allergy Clin Immunol, vol.129, pp.1172-1175, 2012.

B. Kelley, M. Jankowski, and J. Booth, An improved manufacturing process for Xyntha/ReFacto AF, Haemophilia, vol.16, pp.717-742, 2010.

J. Bayry, S. Lacroix-desmazes, and C. Carbonneil, Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin, Blood, vol.101, pp.758-65, 2003.

A. Pajot, M. L. Michel, and N. Fazilleau, A mouse model of human adaptive immune functions: HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice, Eur J Immunol, vol.34, pp.3060-3069, 2004.

L. Bi, A. M. Lawler, S. E. Antonarakis, K. A. High, J. D. Gearhart et al., Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A

, Nat Genet, vol.10, pp.119-140, 1995.

J. Qian, M. Borokov, L. Bi, H. H. Kazazian, and L. W. Hoyer, Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A, Thromb Haemost, vol.81, pp.240-244, 1999.

S. Dasgupta, A. M. Navarrete, and J. Bayry, A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4 + T lymphocytes, Proc Natl Acad Sci U S A, vol.104, pp.8965-70, 2007.

Y. Kim, A. Sette, and B. Peters, Applications for T-cell epitope queries and tools in the Immune Epitope Database and Analysis Resource, J Immunol Methods, vol.374, pp.62-71, 2010.

R. Vita, L. Zarebski, and J. A. Greenbaum, The immune epitope database 2.0, Nucleic Acids Res, vol.38, pp.854-62, 2010.

S. Lacroix-desmazes, A. M. Navarrete, S. Andre, J. Bayry, S. V. Kaveri et al., Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A, Blood, vol.112, pp.240-249, 2008.

E. A. James, W. W. Kwok, R. A. Ettinger, A. R. Thompson, and K. P. Pratt, T-cell responses over time in a mild hemophilia A inhibitor subject: epitope identification and transient immunogenicity of the corresponding self-peptide, J Thromb Haemost, vol.5, pp.2399-407, 2007.

R. A. Ettinger, E. A. James, W. W. Kwok, A. R. Thompson, and K. P. Pratt, HLA-DRrestricted T-cell responses to factor VIII epitopes in a mild haemophilia A family with missense substitution A2201P, Haemophilia, vol.16, pp.44-55, 2010.

P. J. Lenting, J. A. Van-mourik, and K. Mertens, The life cycle of coagulation factor VIII in view of its structure and function, Blood, vol.92, pp.3983-96, 1998.

M. A. Cunningham, S. W. Pipe, B. Zhang, H. P. Hauri, D. Ginsburg et al., LMAN1 is a molecular chaperone for the secretion of coagulation factor VIII, J Thromb Haemost, vol.1, pp.2360-2367, 2003.

S. Pipe, J. Morris, J. Shah, and R. Kaufman, Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin, J Biol Chem, vol.273, pp.8537-8581, 1998.

N. Bovenschen, D. C. Rijken, L. M. Havekes, B. J. Vlijmen, and K. Mertens, The B domain of coagulation factor VIII interacts with the asialoglycoprotein receptor, J Thromb Haemost, vol.3, pp.1257-65, 2005.

, Véronique Frémeaux-Bacchi, 1,2,3,6 Srinivas V, vol.1, p.3

T. Lubka, Roumenina 1,2,3 and Sébastien Lacroix-Desmazes 1, vol.2, p.3

U. Inserm, T. X. Comptech, U. ). , and M. Millipore, Recombinant human A disintegrin and metalloprotease with thrombospondin type I repeats-13 (ADAMTS-13) was a kind gift from Baxter. Complement human proteins Factor B, Factor D, C3, C3b and C3-depleted serum were purchased from Complement Technology, Antibodies against CD1a, CD3, CD14, CD40, CD83, CD86, HLA-DR, CD206, low density lipoprotein receptor-related protein (LRP, CD91), CD209, CD68 and APClabeled Annexin V were purchased from BD Pharmingen, vol.4, pp.594-598, 1138.

J. Skupsky, A. H. Zhang, Y. Su, and D. W. Scott, A role for thrombin in the initiation of the immune response to therapeutic factor VIII, Blood, vol.114, issue.21, pp.4741-4748, 2009.

J. D. Dimitrov, S. Dasgupta, and A. M. Navarrete, Induction of heme oxygenase-1 in factor VIII-deficient mice reduces the immune response to therapeutic factor VIII, Blood, vol.115, issue.13, pp.2682-2685, 2010.
URL : https://hal.archives-ouvertes.fr/inserm-02455593

K. Kurnik, G. Auerswald, and W. Kreuz, Inhibitors and prophylaxis in paediatric haemophilia patients: focus on the German experience, Thromb Res, vol.134, issue.1, pp.27-32, 2014.

L. Castro-nunez, I. Dienava-verdoold, E. Herczenik, K. Mertens, and A. B. Meijer, Shear stress is required for the endocytic uptake of the factor VIII-von Willebrand factor complex by macrophages, J Thromb Haemost, vol.10, issue.9, pp.1929-1937, 2012.

S. Dasgupta, A. M. Navarrete, and J. Bayry, A role for exposed mannosylations in presentation of human therapeutic self-proteins to CD4+ T lymphocytes, Proc Natl Acad Sci, vol.104, issue.21, pp.8965-8970, 2007.

S. Dasgupta, Y. Repesse, and J. Bayry, VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors, Blood, vol.109, issue.2, pp.610-612, 2007.

E. Herczenik, S. D. Van-haren, and A. Wroblewska, Uptake of blood coagulation factor VIII by dendritic cells is mediated via its C1 domain, J Allergy Clin Immunol, vol.129, issue.2, pp.501-509, 2012.

N. Sorvillo, R. B. Hartholt, and E. Bloem, Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII, Haematologica, vol.101, issue.3, pp.309-318, 2016.

N. Merle, S. Church, V. Fremeaux-bacchi, and L. Roumenina, Complement system part Imolecular mechanisms of activation and regulation, Front Immunol, vol.6, p.262, 2015.

F. Bexborn, P. O. Andersson, H. Chen, B. Nilsson, and K. N. Ekdahl, The tick-over theory revisited: formation and regulation of the soluble alternative complement C3 convertase (C3(H2O)Bb), Mol Immunol, 2008.

N. Zewde, R. D. Gorham, A. Dorado, and D. Morikis, Quantitative Modeling of the Alternative Pathway of the Complement System, PLoS One, vol.11, issue.3, p.152337, 2016.

E. Ballanti, C. Perricone, and E. Greco, Complement and autoimmunity. Immunol Res, vol.56, issue.2-3, pp.477-491, 2013.

R. M. Horton, S. N. Ho, J. K. Pullen, H. D. Hunt, Z. Cai et al., Gene splicing by overlap extension, Methods Enzymol, vol.217, pp.270-279, 1993.

C. B. Doering, J. F. Healey, E. T. Parker, R. T. Barrow, and P. Lollar, High level expression of recombinant porcine coagulation factor VIII, J Biol Chem, vol.277, issue.41, pp.38345-38349, 2002.

D. C. Fritzinger, B. E. Hew, and M. Thorne, Functional characterization of human C3/cobra venom factor hybrid proteins for therapeutic complement depletion, Dev Comp Immunol, vol.33, issue.1, pp.105-116, 2009.

S. Delignat, Y. Repesse, and L. Gilardin, Predictive immunogenicity of Refacto AF, Haemophilia, vol.20, issue.4, pp.486-492, 2014.

C. W. Vogel, P. W. Finnegan, and D. C. Fritzinger, Humanized cobra venom factor: structure, activity, and therapeutic efficacy in preclinical disease models, Mol Immunol, vol.61, issue.2, pp.191-203, 2014.

G. E. Gilbert, B. C. Furie, and B. Furie, Binding of human factor VIII to phospholipid vesicles, J Biol Chem, vol.265, issue.2, pp.815-822, 1990.

C. W. Vogel and D. C. Fritzinger, Cobra venom factor: Structure, function, and humanization for therapeutic complement depletion, Toxicon, vol.56, issue.7, pp.1198-1222, 2010.

M. R. Jacquier-sarlin, F. M. Gabert, M. B. Villiers, and M. G. Colomb, Modulation of antigen processing and presentation by covalently linked complement C3b fragment, Immunology, vol.84, issue.1, pp.164-170, 1995.

N. Sorvillo, W. Pos, and L. M. Van-den-berg, The macrophage mannose receptor promotes uptake of ADAMTS13 by dendritic cells, Blood, vol.119, issue.16, pp.3828-3835, 2012.

P. Lenting, J. Neels, and B. Van-den-berg, The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein, J Biol Chem, vol.274, pp.23734-23739, 1999.

E. Saenko, A. Yakhyaev, I. Mikhailenko, D. Strickland, and A. Sarafanov, Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism, J Biol Chem, vol.274, pp.37685-37692, 1999.

A. Wroblewska, S. D. Van-haren, and E. Herczenik, Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice, Blood, vol.119, issue.22, pp.5294-5300, 2012.

B. Gangadharan, M. Ing, and S. Delignat, The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells, Haematologica, vol.102, issue.2, pp.271-281, 2017.

L. Bi, R. Sarkar, and T. Naas, Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies, Blood, vol.88, pp.3446-3450, 1996.

P. J. Lachmann and L. Halbwachs, The influence of C3b inactivator (KAF) concentration on the ability of serum to support complement activation, Clin Exp Immunol, 1975.

M. K. Pangburn, R. D. Schreiber, and H. J. Muller-eberhard, Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3, J Exp Med, vol.154, issue.3, pp.856-867, 1981.

J. H. Foley and E. M. Conway, Cross Talk Pathways Between Coagulation and Inflammation, Circ Res, vol.118, issue.9, pp.1392-1408, 2016.

J. Rayes, L. T. Roumenina, and J. D. Dimitrov, The interaction between factor H and VWF increases factor H cofactor activity and regulates VWF prothrombotic status, Blood, vol.123, issue.1, pp.121-125, 2014.

S. Feng, X. Liang, M. H. Kroll, and D. W. Chung, Afshar-Kharghan V. von Willebrand factor is a cofactor in complement regulation, Blood, vol.125, issue.6, pp.1034-1037, 2015.

D. G. Noone, M. Riedl, and F. G. Pluthero, Von Willebrand factor regulates complement on endothelial cells, Kidney Int, 2016.

X. Zheng, D. Chung, T. K. Takayama, E. M. Majerus, J. E. Sadler et al., Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura, J Biol Chem, vol.276, issue.44, pp.41059-41063, 2001.

H. M. Tsai, Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion, Blood, vol.87, issue.10, pp.4235-4244, 1996.

M. Furlan, R. Robles, and B. Lämmle, Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis, Blood, vol.87, issue.10, pp.4223-4234, 1996.

E. M. Ostertag, S. Kacir, and M. Thiboutot, ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: 1. Structural and functional characterization in vitro, Transfusion, vol.56, issue.07, pp.1763-1774, 2016.

M. Schaller, M. Vogel, K. Kentouche, and B. Lämmle, Kremer Hovinga JA. The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs, Blood, vol.124, issue.23, pp.3469-3479, 2014.

W. Pos, B. M. Luken, K. Hovinga, and J. A. , VH1-69 germline encoded antibodies directed towards ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura, J Thromb Haemost, vol.7, issue.03, pp.421-428, 2009.

B. M. Luken, P. Kaijen, and E. Turenhout, Multiple B-cell clones producing antibodies directed to the spacer and disintegrin/thrombospondin type-1 repeat 1 (TSP1) of ADAMTS13 in a patient with acquired thrombotic thrombocytopenic purpura, J Thromb Haemost, vol.4, issue.11, pp.2355-2364, 2006.

A. L. Foreman, J. Van-de-water, M. L. Gougeon, and M. E. Gershwin, B cells in autoimmune diseases: insights from analyses of immunoglobulin variable (Ig V) gene usage, Autoimmun Rev, vol.6, issue.06, pp.387-401, 2007.

D. L. Siegel, Translational applications of antibody phage display, Immunol Res, vol.42, issue.1-3, pp.118-131, 2008.

M. Schaller, J. D. Studt, J. Voorberg, K. Hovinga, and J. A. , Acquired thrombotic thrombocytopenic purpura. Development of an autoimmune response, Hamostaseologie, vol.33, issue.02, pp.121-130, 2013.

C. Klaus, B. Plaimauer, and J. D. Studt, Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura, Blood, vol.103, issue.12, pp.4514-4519, 2004.

X. L. Zheng, H. M. Wu, and D. Shang, Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura, Haematologica, vol.95, issue.09, pp.1555-1562, 2010.

B. M. Luken, E. A. Turenhout, J. Hulstein, J. A. Van-mourik, R. Fijnheer et al., The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura, Thromb Haemost, vol.93, issue.02, pp.267-274, 2005.

W. Pos, N. Sorvillo, and R. Fijnheer, Residues Arg568 and Phe592 contribute to an antigenic surface for anti-ADAMTS13 antibodies in the spacer domain, Haematologica, vol.96, issue.11, pp.1670-1677, 2011.

B. M. Luken, E. A. Turenhout, and P. Kaijen, Amino acid regions 572-579 and 657-666 of the spacer domain of ADAMTS13 provide a common antigenic core required for binding of antibodies in patients with acquired TTP, Thromb Haemost, vol.96, issue.03, pp.295-301, 2006.

W. Pos, J. Crawley, R. Fijnheer, J. Voorberg, D. A. Lane et al., An autoantibody epitope comprising residues R660, Y661, and Y665 in the ADAMTS13 spacer domain identifies a binding site for the A2 domain of VWF, Blood, vol.115, issue.08, pp.1640-1649, 2010.

K. Soejima, M. Matsumoto, and K. Kokame, ADAMTS-13 cysteinerich/spacer domains are functionally essential for von Willebrand factor cleavage, Blood, vol.102, issue.09, pp.3232-3237, 2003.

M. R. Thomas, R. De-groot, M. A. Scully, and J. Crawley, Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura, EBioMedicine, vol.2, issue.08, pp.942-952, 2015.

J. Muia, J. Zhu, and G. Gupta, Allosteric activation of ADAMTS13 by von Willebrand factor, Proc Natl Acad Sci U S A, vol.111, issue.52, pp.18584-18589, 2014.

K. South, B. M. Luken, and J. Crawley, Conformational activation of ADAMTS13, Proc Natl Acad Sci U S A, vol.111, issue.52, pp.18578-18583, 2014.

L. Deforche, E. Roose, and A. Vandenbulcke, Linker regions and flexibility around the metalloprotease domain account for conformational activation of ADAMTS-13, J Thromb Haemost, 2015.

E. Roose, A. Schelpe, and B. S. Joly, An open conformation of ADAMTS-13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura, J Thromb Haemost, vol.16, issue.02, pp.378-388, 2018.

S. E. Dohmen, A. Mulder, O. Verhagen, C. Eijsink, M. Franke-van-dijk et al., Production of recombinant Ig molecules from antigen-selected single B cells and restricted usage of Iggene segments by anti-D antibodies, J Immunol Methods, vol.298, issue.1-2, pp.9-20, 2005.

H. B. Feys, J. Roodt, and N. Vandeputte, Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus), Blood, vol.116, issue.12, pp.2005-2010, 2010.

H. B. Feys, M. T. Canciani, F. Peyvandi, H. Deckmyn, K. Vanhoorelbeke et al., ADAMTS13 activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis, Br J Haematol, vol.138, issue.04, pp.534-540, 2007.

H. B. Feys, N. Vandeputte, and R. Palla, Inactivation of ADAMTS13 by plasmin as a potential cause of thrombotic thrombocytopenic purpura, J Thromb Haemost, vol.8, issue.09, pp.2053-2062, 2010.

H. B. Feys, P. J. Anderson, K. Vanhoorelbeke, E. M. Majerus, and J. E. Sadler, Multistep binding of ADAMTS-13 to von Willebrand factor, J Thromb Haemost, vol.7, issue.12, pp.2088-2095, 2009.

L. A. Lotta, C. Valsecchi, and S. Pontiggia, Measurement and prevalence of circulating ADAMTS13-specific immune complexes in autoimmune thrombotic thrombocytopenic purpura, J Thromb Haemost, vol.12, issue.03, pp.329-336, 2014.

I. Mancini, B. Ferrari, and C. Valsecchi, Italian Group of TTP Investigators. ADAMTS13-specific circulating immune complexes as potential predictors of relapse in patients with acquired thrombotic thrombocytopenic purpura, Eur J Intern Med, vol.39, pp.79-83, 2017.

A. Mulder, M. J. Kardol, and J. Kamp, Determination of the frequency of HLA antibody secreting B-lymphocytes in alloantigen sensitized individuals, Clin Exp Immunol, vol.124, issue.01, pp.9-15, 2001.

D. Valle, L. Dohmen, S. E. Verhagen, O. Berkowska, M. A. Vidarsson et al., Ellen van der Schoot C. The majority of human memory B cells recognizing RhD and tetanus resides in IgMþ B cells, J Immunol, vol.193, issue.03, pp.1071-1079, 2014.

S. Fath, A. P. Bauer, and M. Liss, Multiparameter RNA and codon optimization: a standardized tool to assess and enhance, Thrombosis and Haemostasis, vol.118, issue.10, 2018.

, Antibodies against Cryptic Epitopes in ADAMTS13 Roose et al. 1741

, Downloaded by: INSERM. Copyrighted material

, autologous mammalian gene expression, PLoS One, vol.6, issue.03, p.17596, 2011.

D. Raab, M. Graf, F. Notka, T. Schödl, and R. Wagner, The GeneOptimizer Algorithm: using a sliding window approach to cope with the vast sequence space in multiparameter DNA sequence optimization, Syst Synth Biol, vol.4, issue.03, pp.215-225, 2010.

C. Gustafsson, S. Govindarajan, and J. Minshull, Codon bias and heterologous protein expression, Trends Biotechnol, vol.22, issue.07, pp.346-353, 2004.

J. B. Plotkin, H. Robins, and A. J. Levine, Tissue-specific codon usage and the expression of human genes, Proc Natl Acad Sci U S A, vol.101, issue.34, pp.12588-12591, 2004.

T. Vink, M. Oudshoorn-dickmann, M. Roza, J. J. Reitsma, and R. N. De-jong, A simple, robust and highly efficient transient expression system for producing antibodies, Methods, vol.65, issue.01, pp.5-10, 2014.

K. Kokame, Y. Nobe, Y. Kokubo, A. Okayama, and T. Miyata, FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay, Br J Haematol, 2005.

O. L. Rojas, C. F. Narváez, H. B. Greenberg, J. Angel, and M. A. Franco, Characterization of rotavirus specific B cells and their relation with serological memory, Virology, vol.380, issue.02, pp.234-242, 2008.

S. Ferrari, F. Scheiflinger, and M. Rieger, French Clinical and Biological Network on Adult Thrombotic Microangiopathies. Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity, Blood, vol.109, issue.07, pp.2815-2822, 2007.

M. Rieger, P. M. Mannucci, K. Hovinga, and J. A. , ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases, Blood, vol.106, issue.04, pp.1262-1267, 2005.

E. M. Majerus, P. J. Anderson, and J. E. Sadler, Binding of ADAMTS13 to von Willebrand factor, J Biol Chem, vol.280, issue.23, pp.21773-21778, 2005.

I. Dogan, B. Bertocci, and V. Vilmont, Multiple layers of B cell memory with different effector functions, Nat Immunol, vol.10, issue.12, pp.1292-1299, 2009.

R. Froehlich-zahnd, J. N. George, and S. K. Vesely, Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura, Haematologica, vol.97, issue.02, pp.297-303, 2012.

M. I. Underwood, M. R. Thomas, M. A. Scully, and J. Crawley, Autoantibodies binding to "open" and "closed" ADAMTS13 in patients with acquired immune thrombotic thrombocytopenic purpura, RPTH, vol.1, issue.01, p.255, 2017.

F. Alwan, C. Vendramin, and K. Vanhoorelbeke, Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura, Blood, vol.130, issue.04, pp.466-471, 2017.