The role of human leukocyte antigens as predisposing and/or protective factors in patients with idiopathic thrombotic thrombocytopenic purpura

John, M.-L.; Hitzler, W; Scharrer, I.

doi:10.1007/s00277-011-1384-z

Cited by 51 publications

(57 citation statements)

References 17 publications

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“…Together with previous reports, our findings suggest that, HLA-DRB1*11 is related to syndromes of thrombotic microangiopathy, including TTP, [22][23][24] haemolytic uraemic syndrome 33 and TA-TMA. The observed association of HLA-DRB1*11 and TA-TMA indicate that the role of HLA-DRB1*11 in the pathogenesis of thrombotic microangiopathies might be complex and extend beyond susceptibility to autoantibody formation against ADAMTS13.…”

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy

Balassa

Andrikovics

Reményi

et al. 2015

Bone Marrow Transplant

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Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) with high mortality rate. We retrospectively studied the frequency, clinical and genetic associations and prognostic effect of TA-TMA, in a total of 425 consecutive adult patients, who underwent allo-HSCT for a malignant haematological condition between 2007 and 2013 at our single centre. TA-TMA developed in 19% of the patients. Unrelated donor type (P o 0.001), acute GvHD grades II-IV (P o0.001), myeloablative conditioning regimens (P = 0.003), tacrolimus-based GvHD prophylaxis (P = 0.003), CMV infection (P = 0.003) and carriership for HLA-DRB1*11 (P = 0.034) were associated with the development of TA-TMA. Survival was adversely affected by the presence of TA-TMA (P o 0.001). Among patients with TA-TMA, the outcome of HLA-DRB1*11 carriers was significantly better compared with non-carriers (P = 0.003). As a new finding, our observations suggest that the presence of HLA-DRB1*11 antigen contributes to the development of TA-TMA and affects the outcome.

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Section: Discussionsupporting

confidence: 87%

“…In recent years, an association of HLA-DRB1*11 and idiopathic TTP has been recognised by independent groups. [22][23][24] Our hypothesis was that in view of the correlations between the two conditions, HLA-DRB1*11 might have a role in the pathogenesis of TA-TMA, as well.…”

Section: Introductionmentioning

confidence: 99%

The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy

Balassa

Andrikovics

Reményi

et al. 2015

Bone Marrow Transplant

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“…Three independent studies have shown that HLA-DRB1*11 is a risk factor for acquired TTP, which further implicates CD4 1 T cells in the pathogenesis of this disease. [13][14][15] We have previously shown that ADAMTS13 is endocytosed by antigen-presenting cells such as dendritic cells (DCs) by the macrophage mannose receptor (MMR). 16 After its intracellular processing, a restricted set of ADAMTS13-derived peptides is presented on major histocompatibility complex class II for presentation to CD4…”

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confidence: 99%

The class I scavenger receptor CD163 promotes internalization of ADAMTS13 by macrophages

et al. 2017

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Key Points• Uptake of ADAMTS13 by macrophages is not dependent on the macrophage mannose receptor.• CD163 promotes internalization of ADAMTS13 by macrophages.Internalization of ADAMTS13 by macrophages may contribute to its clearance from the circulation. Here we investigated endocytic mechanisms that contribute to the uptake of ADAMTS13 by macrophages. Human monocyte-derived macrophages were used to monitor the uptake of fluorescently labeled recombinant ADAMTS13 by flow cytometry.Internalization of ADAMTS13 was blocked upon addition of the cell-permeable dynamin inhibitor dynasore. Partial blocking of ADAMTS13 uptake was observed by using mannan;however, uptake was not affected by an antibody that blocked binding to the macrophage mannose receptor CD206, which suggests that other endocytic receptors contribute to the internalization of ADAMTS13 by macrophages. A pull-down with ADAMTS13 and subsequent mass spectrometric analysis identified the class I scavenger receptor CD163 as a candidate receptor for ADAMTS13. Blocking experiments with monoclonal anti-CD163 antibody EDHu-1 resulted in decreased ADAMTS13 internalization by macrophages. Pronounced inhibition of ADAMTS13 uptake by EDHu-1 was observed in CD163 high-expressing macrophages. In agreement with these findings, CD163-expressing Chinese hamster ovary cells were capable of rapidly internalizing ADAMTS13. Surface plasmon resonance revealed binding of ADAMTS13 to scavenger receptor cysteine-rich domains 1-9 and 1-5 of CD163. Taken together, our data identify CD163 as a major endocytic receptor for ADAMTS13 on macrophages.

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“…It has been observed that the HLA-DRB1*11 is more frequent in patients with acquired TTP when compared with a control population. [29][30][31] These findings indicate that presentation of ADAMTS13-derived peptides on MHC II molecules by APC is necessary to activate ADAMTS13-specific CD41 T cells. We have recently shown that ADAMTS13 is efficiently internalized by immature dendritic cells (iDCs) through the macrophage mannose receptor.…”

Section: Introductionmentioning

confidence: 84%

“…Four of the donors were heterozygous for DRB1*11, which was recently identified as a risk factor for the development of acquired TTP (Table 1). [29][30][31] DCs derived from 4 DRB1*11-negative donors are also included ( Table 1). The total number of HLA-DR-presented peptides meeting our criteria ranged between 100 and 360 unique presented peptides (supplemental Figure 1A).…”

Section: Analysis Of Adamts13-presented Peptides On Mhc Class II Molementioning

confidence: 99%

Preferential HLA-DRB1*11–dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

Sorvillo

Haren

Kaijen

et al. 2013

Blood

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Key Points• ADAMTS13 derived peptides presented on HLA-DR; implications for acquired TTP.• CUB2 domain peptide binds to risk-allele HLA-DRB1*11.Autoantibodies directed against ADAMTS13 prohibit the processing of von Willebrand factor multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13-derived peptides presented on MHC class II alleles from 17 healthy donors. Dendritic cells from a panel of both HLA-DRB1*11-positive and -negative donors were pulsed with ADAMTS13, and the HLA-DR-presented peptide repertoire was analyzed by mass spectrometry. Interestingly, at low antigen concentrations, HLA-DRB1*11-or DRB1*03-positive donors presented a limited number of CUB2-derived peptides. Pulsing of dendritic cells using higher concentrations of ADAMTS13 resulted in the presentation of larger numbers of ADAMTS13-derived peptides by both HLA-DRB1*11-positive and -negative donors. Although the presented peptides were derived from several ADAMTS13 domains, inspection of the peptide profiles revealed that CUB2 domainderived peptides were presented with a higher efficiency when compared with other peptides. Remarkably, dendritic cells from DRB1*11 donors pulsed with higher concentrations of ADAMTS13-present derivatives of a single CUB2-derived peptide. We hypothesize that functional presentation of CUB2-derived peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low-affinity, self-reactive CD41 T cells. (Blood. 2013;121(17):3502-3510) Introduction Acquired thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disorder characterized by the production of autoantibodies directed toward ADAMTS13, a plasma metalloprotease responsible for the cleavage of ultra-large von Willebrand factor (UL-VWF) multimers.1-3 Deficiency of ADAMTS13 causes the accumulation of UL-VWF strings on the surface of endothelial cells of the vessel wall and in the circulation. 4 Prolonged exposure of UL-VWF strings on the surface of endothelial cells promotes platelet adhesion, leading to low platelet counts and microvascular thrombosis. 5,6 The majority of the inhibitory anti-ADAMTS13 antibodies that develop in patients affected by acquired TTP targets a single epitope composed of Arg568, Phe592, Arg660, Tyr661, and Tyr665 on the outer surface of the spacer domain. This exposed region is crucial for binding of ADAMTS13 to unfolded VWF A2 domain.7-9 Antibodies targeting the CUB 1-2 and TSP2-8 regions of ADAMTS13 have also been detected in the plasma of several patients with acquired TTP. 10,11 The pathogenic role of anti-TSP2-8 and anti-CUB1-2 is still unclear. The carboxy-terminal ADAMTS13 TSP2-8 and CUB 1-2 regions not only modulate processing of VWF under flow 12-14 but are also necessary for the binding of ADAMTS13 to endothelial cells. 15A number of studies have shown that anti-ADAMTS13 antibodies detected in the plasma ...

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The role of human leukocyte antigens as predisposing and/or protective factors in patients with idiopathic thrombotic thrombocytopenic purpura

Cited by 51 publications

References 17 publications

The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy

The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy

The class I scavenger receptor CD163 promotes internalization of ADAMTS13 by macrophages

Preferential HLA-DRB1*11–dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

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