scholarly journals Anti-cysteine/spacer antibodies that open ADAMTS13 are a common feature in iTTP

2021 ◽  
Author(s):  
Laure De Waele ◽  
Alexandre Curie ◽  
Kadri Kangro ◽  
Edwige Tellier ◽  
Gilles Kaplanski ◽  
...  
Keyword(s):  
Affinity Chromatography ◽  
The Other ◽  
Autoimmune Response ◽  
Healthy Individuals ◽  
Thrombocytopenic Purpura ◽  
Open Conformation ◽  
Immune Mediated ◽  
Almost All ◽  
Thrombospondin Type 1 Repeats

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency of ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats member 13). In healthy individuals, ADAMTS13 has a folded conformation where the central spacer domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G's (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in iTTP patients are directed against the different ADAMTS13 domains but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13 thereby opening ADAMTS13. Therefore, we purified anti-CS and anti-CUB autoantibodies from 13 acute iTTP patients by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were further tested in our ADAMTS13 conformation ELISA to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP.

scholarly journals A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Sandrine Luce ◽  
Sophie Guinoiseau ◽  
Alexis Gadault ◽  
Franck Letourneur ◽  
Patrick Nitschke ◽  
...  
Keyword(s):  
Autoimmune Response ◽  
Preclinical Model ◽  
Humanized Mouse ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Human Insulin Gene ◽  
Immune Mediated ◽  
Insulin Secreting Cells

To circumvent the limitations of available preclinical models for the study of type 1 diabetes (T1D), we developed a new humanized model, the YES-RIP-hB7.1 mouse. This mouse is deficient of murine major histocompatibility complex class I and class II, the murine insulin genes, and expresses as transgenes the HLA-A*02:01 allele, the diabetes high-susceptibility HLA-DQ8A and B alleles, the human insulin gene, and the human co-stimulatory molecule B7.1 in insulin-secreting cells. It develops spontaneous T1D along with CD4+ and CD8+ T-cell responses to human preproinsulin epitopes. Most of the responses identified in these mice were validated in T1D patients. This model is amenable to characterization of hPPI-specific epitopes involved in T1D and to the identification of factors that may trigger autoimmune response to insulin-secreting cells in human T1D. It will allow evaluating peptide-based immunotherapy that may directly apply to T1D in human and complete preclinical model availability to address the issue of clinical heterogeneity of human disease.

scholarly journals Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura

Blood ◽  
2020 ◽  
Author(s):  
Elien Roose ◽  
An-Sofie Schelpe ◽  
Edwige Tellier ◽  
György Sinkovits ◽  
Bérangère S Joly ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Follow Up Study ◽  
Open Conformation ◽  
Immune Mediated ◽  
Long Term Follow Up ◽  
Donor Plasma

Recently, we showed that during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP), ADAMTS13 circulates in an open conformation. Although the cause of this conformational change in acute iTTP remains elusive, ADAMTS13 is mainly closed in iTTP patients (i) in remission with an ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, and (ii) after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, IgGs from 18 acute iTTP patients were purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14/18 (78%) samples, proving that indeed anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n=197) that also included plasma samples of iTTP patients in remission where ADAMTS13 activity was <50%. The open ADAMTS13 conformation was not only found during acute iTTP but also in patients in remission with an ADAMTS13 activity <50% and in half of the patients with an ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus open ADAMTS13 is not only a hallmark of acute iTTP, but also a novel biomarker to detect subclinical iTTP in patients in remission. Finally, a long term follow-up study in one iTTP patient showed that the open conformation precedes a severe drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.

scholarly journals Open ADAMTS13 Conformation in Immune-Mediated Thrombotic Thrombocytopenic Purpura Is Induced By Anti-ADAMTS13 Autoantibodies and Corresponds with an Ongoing ADAMTS13 Pathology

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 222-222
Author(s):  
Elien Roose ◽  
An-Sofie Schelpe ◽  
Edwige Tellier ◽  
György Sinkovits ◽  
Gilles Kaplanski ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Conformational Changes ◽  
Clinical Signs ◽  
Advisory Board ◽  
Close Monitoring ◽  
Plasma Samples ◽  
Chi Square ◽  
Thrombocytopenic Purpura ◽  
Open Conformation ◽  
Immune Mediated

Abstract Background. Deficient ADAMTS13 activity (TS13:act <10%) induced by anti-ADAMTS13 autoantibodies (autoAbs) causes immune-mediated thrombotic thrombocytopenic purpura (iTTP). Recently we showed that an open ADAMTS13 conformation is characteristic for acute iTTP patients, while folded ADAMTS13 was found in 78% of iTTP patients in remission with an TS13:act >50%. However, also iTTP patients in remission with a persistent (<10%) or moderately restored (10-50%) TS13:act have been described, but their ADAMTS13 conformation is unknown. Intriguingly, the factor responsible for inducing open ADAMTS13 in iTTP patients remains elusive. Identifying the cause of open ADAMTS13 in iTTP will help better understand the pathophysiology of iTTP and could help appreciate the prognosis and better manage the prevention of subsequent relapses. Aim. Determine ADAMTS13 conformation in plasma of iTTP patients during acute TTP and remission when TS13:act is <10%, moderately restored (10-50%) or >50% and investigate if anti-ADAMTS13 autoAbs induce conformational changes in ADAMTS13. Methods. TS13:act was determined in 120 iTTP plasma samples from 4 different centers (Marseille, Milan, Budapest, Utrecht). Samples were categorized according to the presence of clinical symptoms (acute versusremission) and their TS13:act in remission (>50%, 10-50%,<10%). Next, ADAMTS13 conformation was determined in all samples using our ADAMTS13 conformation ELISA. Additionally, presence of anti-ADAMTS13 autoAbs was also determined via ELISA. Finally, IgG's from 18 acute iTTP plasma samples were purified and added to folded ADAMTS13 from healthy donor (HD) plasma to test whether iTTP IgG's are able to induce the open HD ADAMTS13 conformation. Results. Of the 120 iTTP plasma samples, 46 were obtained during the acute (clinical signs present) and 74 during the remission phase (clinical signs absent). Further subdividing remission samples showed that TS13:act was >50% in 41, 10-50% in 14 and <10% in 19 samples. ADAMTS13 was open in 98% (45/46) of the acute samples and folded in 71% (29/41) of the remission samples with TS13:act >50%, confirming our previous results. Interestingly, ADAMTS13 was open in 93% and 89% of remission samples with TS13:act 10-50% and <10%, respectively (chi square, P<0.0001). Since anti-ADAMTS13 autoAbs influence TS13:act in iTTP patients, we next could demonstrate that open ADAMTS13 conformation was linked with presence of anti-ADAMTS13 autoAbs (chi square, P<0.0001) suggesting that anti-ADAMTS13 autoAbs could be a factor able to induce an open ADAMTS13 conformation in iTTP patients. To further test this hypothesis, we purified IgG's from 18 acute iTTP plasma's with open ADAMTS13 and added them to HD plasma containing closed ADAMTS13, where 14 of the 18 patient IgG pools (78%) did induce the open conformation in HD ADAMTS13, indicating that patient anti-ADAMTS13 autoAbs indeed can induce conformational changes in ADAMTS13. Conclusion. We show that ADAMTS13 is not only in the open conformation in iTTP patient plasma during the acute phase but also in remission when TS13:act is <10% or 10-50%. Hence, the presence of open ADAMTS13 in those remission patients indicates that the underlying pathophysiology is still ongoing, emphasizing the need for a close monitoring of those patients. In addition, anti-ADAMTS13 autoAbs were identified as a factor responsible for the change in conformation in ADAMTS13 in iTTP. Disclosures Peyvandi: Octapharma US: Honoraria; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Kedrion: Consultancy; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Roche: Speakers Bureau; Grifols: Speakers Bureau; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Octapharma US: Honoraria. Coppo:Ablynx: Consultancy. Veyradier:LFB: Other: Investigator. Vanhoorelbeke:Shire: Consultancy; Ablynx: Consultancy.

scholarly journals Narcolepsy type 1: what have we learned from immunology?

SLEEP ◽  
2020 ◽  
Vol 43 (10) ◽  
Author(s):  
Birgitte R Kornum
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Adaptive Immune Response ◽  
Autoimmune Response ◽  
Healthy Individuals ◽  
Epidemiological Evidence ◽  
Autoreactive T Cells ◽  
Blood Samples ◽  
Adaptive Immune

Abstract Narcolepsy type 1 is hypothesized to be an autoimmune disease targeting the hypocretin/orexin neurons in the hypothalamus. Ample genetic and epidemiological evidence points in the direction of a pathogenesis involving the immune system, but this is not considered proof of autoimmunity. In fact, it remains a matter of debate how to prove that a given disease is indeed an autoimmune disease. In this review, a set of commonly used criteria for autoimmunity is described and applied to narcolepsy type 1. In favor of the autoimmune hypothesis are data showing that in narcolepsy type 1 a specific adaptive immune response is directed to hypocretin/orexin neurons. Autoreactive T cells and autoantibodies have been detected in blood samples from patients, but it remains to be seen if these T cells or antibodies are in fact present in the hypothalamus. It is also unclear if the autoreactive T cells and/or autoantibodies can transfer the disease to healthy individuals or animals or if immunization with the proposed autoantigens can induce the disease in animal models. Most importantly, it is still controversial whether suppression of the autoimmune response can prevent disease progression. In conclusion, narcolepsy type 1 does still not fully meet the criteria for being classified as a genuine autoimmune disease, but more and more results are pointing in that direction.

scholarly journals Clinical experience in treatment of thrombotic thrombocytopenic purpura - hemolytic uremic syndrome with 28 patients

2013 ◽  
Vol 60 (1) ◽  
pp. 29-38
Author(s):  
Dragica Vucelic ◽  
Zoran Rajic ◽  
Nebojsa Savic ◽  
Danijela Mikovic ◽  
Zivko Budisin ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Response Rate ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Severe Deficiency ◽  
Uremic Syndrome ◽  
Design And Methods ◽  
Thrombospondin Type 1 Repeats

Background: Neither optimal treatment nor significance of ADAMTS13 (A Desintegrin And Metalloprotease with ThromboSpondin type 1 repeats) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have not been defined yet. The aim of the report is to analyze response to different volumes of plasma exchange (PE), and relationship to ADAMTS13. Design and methods: 28 patients clinically diagnosed with idiopathic TTP (n=18), secondary TTP (n=4), atypical HUS (n=3) and typical HUS (n=3) manifested 31 acute episodes. Patients were treated with PE in 26, and with plasma transfusion in 5 episodes with additional different therapies. Results: PE volumes were as follows: 1 in 7, 1.5 in 3, 2 in 14, and intensifying schedule (1 to 1.5) in 2 episodes. Procedure number was lower in patients treated with 2 and 1.5 (p=0.019) than in those treated with 1 volume exchange and PE intensifying, respectively (p=0.010). PE response rate was 25/26 (96.15%). Exacerbation frequency was higher in idiopathic TTP patients (3/19) treated with 1 compared with patients treated with >1 volume exchange (p=0.003). Survival rate was 25/28 (89.29%). ADAMTS13 activity was reduced in 22 with severe deficiency in 14 patients. Conclusion: Patients responded to different treatments regardless of ADAMTS13 activity, requiring less PEs with larger volume exchanges.

scholarly journals Thrombotic thrombocytopenic purpura after ChAdOx1 nCoV-19 vaccine

2021 ◽  
Vol 14 (10) ◽  
pp. e246049
Author(s):  
Hui Ping Lee ◽  
Veena Selvaratnam ◽  
Jay Suriar Rajasuriar
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Blood Film ◽  
Indian Woman ◽  
Thrombocytopenic Purpura ◽  
First Case ◽  
Immune Mediated ◽  
Peripheral Blood Film ◽  
A Disintegrin And Metalloproteinase ◽  
The Brain

A 50-year-old Indian woman presented with acute dysphasia, left upper limb numbness and thrombocytopenia 12 days after receiving the ChAdOx1 nCoV-19 vaccine (AstraZeneca/Vaxzevria). MRI of the brain was unremarkable. Microangiopathic haemolytic anaemia with thrombocytopenia was noted on her peripheral blood film. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was confirmed through the findings of absent ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity and markedly raised titre of ADAMTS13 autoantibodies. Prompt treatment with plasma exchange, adjunctive steroids and rituximab was commenced. A remission of TTP was achieved and she was discharged 3 weeks after admission. While other immune-mediated conditions have been documented after receipt of the vaccine, this report highlights the first case of immune-mediated TTP diagnosed after administration of the ChAdOx1 nCoV-19 vaccine.

scholarly journals Severely Deficient ADAMTS13 Activity Predicts Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Pregnancy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1098-1098
Author(s):  
Camila Masias ◽  
Krista Carter ◽  
Haiwa Wu ◽  
Shangbin Yang ◽  
Alcinda Flowers ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Research Funding ◽  
The Other ◽  
Clinical Relapse ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Second Hit ◽  
Immune Mediated ◽  
Risk Of Relapse ◽  
In Pregnancy

Background: It is commonly accepted that severely deficient ADAMTS13 activity in remission increases the risk for relapse, but relapse in severely deficient ADAMTS13 activity in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) is not uniform. Mouse models and published studies have suggested that a "second hit" is required in addition to severely deficient ADAMTS13 activity to lead to clinical relapse. Our initial published experience led us to preliminarily conclude that pregnancy could serve as the second hit in addition to severely deficient ADAMTS13 activity and lead to relapse. The aim of this study was to evaluate the risk of relapse and outcomes of pregnant patients with a diagnosis of iTTP. Methods: Since the initiation of the Ohio State University TTP Research Program in 2003, patients were consented at enrollment and followed longitudinally in our IRB approved iTTP registry, usually every three to six months. During pregnancy, patients were seen and CBC, LDH and ADAMTS13 activity were obtained monthly. Due to prior reports of iTTP relapses during pregnancy, it is our practice to offer prophylaxis with cyclosporine to pregnant patients with a diagnosis of iTTP and severely deficient ADAMTS13 activity. The clinical diagnosis of iTTP (defined as thrombocytopenia, microangiopathic hemolytic anemia, without an alternative explanation was confirmed by severely deficient ADAMTS13 activity (<10%) in all cases. ADAMTS13 activity was determined using a SELDI-TOF mass-spectrometer-based method. Results: During the study time, we have followed 11 pregnancies from eight patients with iTTP. Two pregnancies occurred at the time of their initial diagnosis, and nine pregnancies occurred during follow up. Two patients were black, nine were white. Median age was 26 ( range 20-36). Of the nine pregnancies in patients with a previous diagnosis of iTTP, three resulted in relapses, two in the same patient; one at 23 weeks that resulted in fetal demise, and the next one occurred one week after delivery at 36 weeks. The other patient relapsed at 35 weeks and the baby was delivered early at 36 weeks. All relapses were preceded by a documented ADAMTS13 <10%, with a normal platelet count, LDH and no associated symptoms, while none of the other pregnancies had a documented ADAMTS13 <10% (Figure 1). Interestingly, one of the relapses occurred while the patient was taking cyclosporine during pregnancy as preemptive therapy to prevent relapses. She initially responded to therapy with an increase in her ADAMTS13 activity but subsequently lost the response which preceded her relapse post-partum. Conclusions: Pregnancy in patients with a diagnosis of iTTP is a risk factor for iTTP relapse. To our knowledge, this is the first report of the relationship between ADAMTS13 and the risk of relapse during pregnancy. Our results demonstrate that severely deficient ADATMS13 activity uniformly leads to relapse in pregnancy. It also highlights the clinical relevance of monitoring ADAMTS13 activity closely in patients with a history of iTTP that become pregnant. Figure 1 Disclosures Masias: Rigel Pharmaceuticals: Consultancy. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. OffLabel Disclosure: the use of cyclosporine for prevention of TTP relapses

scholarly journals Anti-ADAMTS13 autoantibody profiling in patients with immune-mediated thrombotic thrombocytopenic purpura

2021 ◽  
Vol 5 (17) ◽  
pp. 3427-3435 ◽  
Author(s):  
Kadri Kangro ◽  
Elien Roose ◽  
Bérangère S. Joly ◽  
György Sinkovits ◽  
Tanja Falter ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Clinical Data ◽  
Epitope Mapping ◽  
Thrombocytopenic Purpura ◽  
Immune Mediated ◽  
Number Of Patients ◽  
Large Cohort Study ◽  
A Disintegrin And Metalloproteinase

Abstract Anti-A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) autoantibodies cause a severe ADAMTS13 deficiency in immune-mediated thrombotic thrombocytopenic purpura (iTTP). ADAMTS13 consists of a metalloprotease (M), a disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). We recently developed a high-throughput epitope mapping assay based on small, nonoverlapping ADAMTS13 fragments (M, DT, CS, T2-T5, T6-T8, CUB1-2). With this assay, we performed a comprehensive epitope mapping using 131 acute-phase samples and for the first time a large group of remission samples (n = 50). Next, samples were stratified according to their immunoprofiles, a field that is largely unexplored in iTTP. Three dominant immunoprofiles were found in acute-phase samples: profile 1: only anti-CS autoantibodies (26.7%); profile 2: both anti-CS and anti-CUB1-2 autoantibodies (12.2%); and profile 3: anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, and anti-CUB1-2 autoantibodies (8.4%). Interestingly, profile 1 was the only dominant immunoprofile in remission samples (52.0%). Clinical data were available for a relatively small number of patients with acute iTTP (&gt;68), and no correlation was found between immunoprofiles and disease severity. Nevertheless, profile 1 was linked with younger and anti-T2-T5 autoantibodies with older age and the absence of anti-CUB1-2 autoantibodies with cerebral involvement. In conclusion, identifying acute phase and remission immunoprofiles in iTTP revealed that anti-CS autoantibodies seem to persist or reappear during remission providing further support for the clinical development of a targeted anti-CS autoantibody therapy. A large cohort study with acute iTTP samples will validate possible links between immunoprofiles or anti-domain autoantibodies and clinical data.

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