Anti-ADAMTS13 IgG autoantibodies present in healthy individuals share linear epitopes with those in patients with thrombotic thrombocytopenic purpura

Grillberger, Rana; Casina, Veronica C.; Turecek, Peter L.; Zheng, X. Long; Rottensteiner, Hanspeter; Scheiflinger, Friedrich

doi:10.3324/haematol.2013.100685

Cited by 32 publications

(24 citation statements)

References 19 publications

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“…by guest www.bloodjournal.org From antibodies as serving as a template for pathogenic antibodies, but the trigger to set off the maturation process still needs to be elucidated. 58 For the first time, we show that an antibody repertoire selected by 2 techniques, phage display and EBV transformation of memory B cells, contains very similar antibodies regarding the V H gene use, V H CDR3 regions, functionality (ADAMTS13 inhibitory potential), and epitope recognition, indicating that both techniques reflect the in vivo situation. Pairing of H-and L-chain in whole IgG derived from EBV-transformed switched memory B cells was, however, more uniform and restricted than in the phage display Fabs.…”

Section: Discussionmentioning

confidence: 76%

The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs

Schaller¹,

Vogel

Kentouche

et al. 2014

Blood

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Key Points• The spleen harbors ADAMTS13-specific memory B cells following acute acquired TTP.• The splenic anti-ADAMTS13 antibody repertoire is characterized by a set of unique and novel CDR3 motifs, 4 shared by 2 patients.Acquired thrombotic thrombocytopenic purpura (TTP) is the consequence of a severe ADAMTS13 deficiency resulting from autoantibodies inhibiting ADAMTS13 or accelerating its clearance. Despite the success of plasma exchange the risk of relapse is high. From 2 patients (A and B), splenectomized for recurrent episodes of acquired TTP, the splenic B-cell response against ADAMTS13 was characterized through generation of human monoclonal anti-ADAMTS13 autoantibodies (mAbs) by cloning an immunoglobulin G (IgG) 4 k-and IgG 4 l-Fab library using phage display technology and by Epstein-Barr virus transformation of switched memory B cells (CD19 1 /CD27 1 /IgG 1 ). Sequence analysis of the anti-ADAMTS13 IgGs of both patients revealed that the V H gene use was limited in our patients to V H 1-3 (55%), V H 1-69 (17%), V H 3-30 (7%), and V H 4-28 (21%) and contained 8 unique and thus far not reported heavy-chain complementarity determining region 3 motifs, of which 4 were shared by the 2 patients. The discovery of several highly similar anti-ADAMTS13 autoantibodies in 2 unrelated TTP patients suggests that the autoimmune response is antigen driven, because the probability that such similar immunoglobulin rearrangements happen by chance is very low (<10 29). (Blood. 2014;124(23):3469-3479)

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Section: Discussionmentioning

confidence: 76%

The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs

Schaller¹,

Vogel

Kentouche

et al. 2014

Blood

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“…49 However, autoantibodies against the enzyme are present in up to 5% of healthy individuals, 50,51 and might become problematic under VEGF inhibition. In addition, certain patient groups such as those suffering from immunomediated diseases like SLE and the antiphospholipid antibody syndrome can be far more susceptible to the development of inhibitory autoantibodies.…”

Section: /2mentioning

confidence: 99%

ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor–Induced Thrombotic Microangiopathy

Erpenbeck

Demers

Zsengellér

et al. 2016

Journal of the American Society of Nephrology

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Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor-related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor-related TMA. ADAMTS13 2/2 mice overexpressing sFlt-1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor-related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13 2/2 mice overexpressing sFlt-1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition.

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“…Notably, low levels of ADAMTS‐13‐specific ICs were also observed in the control samples with the three highest IgG concentrations. These ICs were probably generated by naturally occurring binding anti‐ADAMTS‐13 antibodies purified from naive goat plasma, similar to those present in healthy human individuals .…”

Section: Resultsmentioning

confidence: 97%

Neutralization of inhibitory antibodies and restoration of therapeutic ADAMTS‐13 activity levels in inhibitor‐treated rats by the use of defined doses of recombinant ADAMTS‐13

Plaimauer¹,

Schiviz²,

Kaufmann³

et al. 2015

Journal of Thrombosis and Haemostasis

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restoration of therapeutic ADAMTS-13 activity levels in inhibitor-treated rats by the use of defined doses of recombinant ADAMTS-13. 2015; 13: 2053-62. Summary. Background: Acquired thrombotic thrombocytopenic purpura (TTP) is caused by an autoantibody-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS-13. Acute episodes of the disease are treated with a combination of immunosuppression and repeated cycles of plasma exchange to remove anti-ADAMTS-13 autoantibodies and, at the same time, replenish functional ADAMTS-13. Although this is often effective, the mortality rate has remained between 10% and 20%, highlighting the need for safer treatment options. Objectives: We previously showed that, in vitro, human recombinant ADAMTS-13 (rADAMTS-13) is able to override neutralizing antibodies and restore ADAMTS-13 activity in plasma from patients with acquired TTP. In the present study, we assessed the in vivo feasibility of this strategy by using a rat model. Methods: Wild-type rats were adjusted to an ADAMTS-13 inhibitor (inhibitor) titer of~10 BU mL À1 with goat anti-ADAMTS-13 IgG, and treated with increasing doses of rADAMTS-13. Blood samples were drawn and analyzed for ADAMTS-13-specific parameters, including FRETS-VWF73 activity, inhibitor, and ADAMTS-13-specific immune complexes (ICs). The pharmacokinetics of ADAMTS-13 activity and inhibitors were evaluated. Results: Administration of inhibitor titer-adjusted doses of rADAMTS-13 to inhibitor-treated rats predictably restored activity. Inhibitors were readily neutralized through formation of ADAMTS-13-specific ICs, which were cleared at a higher rate than the free inhibitor. Surplus protease was enzymatically active in plasma, and showed similar pharmacokinetics to ADAMTS-13 in not inhibitor-treated rats. Conclusions: Defined doses of rADAMTS-13 neutralized circulating anti-ADAMTS-13 antibodies and enabled reconstitution of ADAMTS-13 activity in plasma in our model, indicating that the protease may be a promising candidate for further exploration in treating acute episodes of acquired TTP. J Thromb Haemost

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Anti-ADAMTS13 IgG autoantibodies present in healthy individuals share linear epitopes with those in patients with thrombotic thrombocytopenic purpura

Abstract: LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o n

Cited by 32 publications

References 19 publications

The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs

The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs

ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor–Induced Thrombotic Microangiopathy

Neutralization of inhibitory antibodies and restoration of therapeutic ADAMTS‐13 activity levels in inhibitor‐treated rats by the use of defined doses of recombinant ADAMTS‐13

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