CD8+ T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia

Qiu, Jianxiu; Liu, Xuena; Li, Xiaoqing; Zhang, Xu; Han, Panpan; Zhou, Hai; Shao, Liming; Hou, Yu; Min, Yanan; Kong, Zhangyuan; Wang, Yawen; Wei, Yu; Liu, Xinguang; Ni, Heyu; Peng, Jun; Hou, Ming

doi:10.1038/srep27445

Cited by 67 publications

(59 citation statements)

References 52 publications

(96 reference statements)

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“…First, it is known that a proportion of patients initially diagnosed as ITP may have other, non-immune causes of thrombocytopenia 35 . Previous work by our group and others has indicated that treatment-refractory patients may not have any detectable anti-platelet antibodies in the first place 5,36 , and CD8-T cell mediated platelet clearance could be an alternative mechanism that maintains thrombocytopenia 37,38 .…”

Section: Discussionmentioning

confidence: 88%

IgG-Fc glycosylation before and after rituximab treatment in immune thrombocytopenia

Schmidt

Haan

Sonneveld

et al. 2020

Sci Rep

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the interactions of antibodies with myeloid fcγ receptors and the complement system are regulated by an Asn297-linked glycan in the Fc portion of IgG. Alterations of serum IgG-Fc glycosylation have been reported in various autoimmune diseases, and correlate with treatment response and disease activity. We hypothesized that igG-fc glycosylation is altered in immune thrombocytopenia (itp) and associates with response to anti-CD20 monoclonal antibody treatment (rituximab). IgG-Fc glycosylation was analyzed by liquid chromatography-mass spectrometry. We found that igG-fc glycosylation was identical between refractory ITP patients (HOVON64 trial; N = 108) and healthy controls (N = 120). Two months after rituximab treatment, we observed a shift in Fc glycosylation, with a mean 1.7% reduction in galactosylation for IgG1 and IgG4 and a mean 1.5% increase for bisection in IgG1, IgG2/3 and IgG4 (adjusted p < 1.7 × 10 −3 and p < 2 × 10 −4 , respectively). Neither baseline nor longitudinal changes in igG-fc glycosylation after rituximab were associated with clinical treatment response. We conclude that igG-fc glycosylation in refractory itp is similar to healthy controls and does not predict treatment responses to rituximab. the observed changes two months after treatment suggest that rituximab may influence total serum IgG-Fc glycosylation. Overall, our study suggests that the pathophysiology of refractory ITP may differ from other autoimmune diseases.Immune thrombocytopenia (ITP) is an autoimmune bleeding disease characterized by self-reactive cellular and humoral anti-platelet responses that result in platelet clearance. A hallmark of ITP in adults are IgG-anti-platelet autoantibodies 1 . The diagnosis of ITP is established clinically by exclusion of alternative causes of thrombocytopenia 2 , which is thought to result in diagnostic heterogeneity. Rituximab, an anti-CD20 antibody targeting B cells, represents an important second-line treatment, with about 60% of patients responding. The underlying working mechanisms remain incompletely understood 3-5 .The Fc portion of each heavy chain of an IgG molecule has a single glycosylation site at Asn297. The exact composition of the attached N-glycan affects effector functions through modification of the Fc-tail affinity for Fcγ receptors and C1q-mediated complement activation 6 . The total serum IgG-Fc glycosylation is skewed in multiple autoimmune diseases, such as rheumatoid arthritis 7,8 , autoimmune hemolytic anemia 9 , systemic lupus erythematosus 10 , Guillain-Barre syndrome 11 , vasculitis 12,13 and inflammatory bowel disease 14 . Across these studies, the strongest association with autoimmune diseases is a reduction in Asn-297 galactosylation, followed by sialylation, which are linked because galactosylated glycan structures are substrates for sialyltransferases 6 . Moreover, GWAS-identified loci that regulate Fc N-glycosylation are strongly associated with susceptibility to autoimmune diseases 15 .In rheumatoid arthritis, extensive data indicate that a low total IgG-Fc ...

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Section: Discussionmentioning

confidence: 88%

IgG-Fc glycosylation before and after rituximab treatment in immune thrombocytopenia

Schmidt

Haan

Sonneveld

et al. 2020

Sci Rep

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“…For example, only 60% to 70% of people are documented to have antibodies potentially indicating that non‐antibody‐dependent mechanisms are responsible for platelet destruction . When considering platelet destruction in humans with ITP who lack antibodies, CD8+ T cells result in direct platelet destruction and are also involved in subsequent platelet desialylation . It is unknown if these mechanisms occur in dogs …”

Section: Discussionmentioning

confidence: 99%

“…2,18 When considering platelet destruction in humans with ITP who lack antibodies, CD8+ T cells result in direct platelet destruction and are also involved in subsequent platelet desialylation. 2,18,[29][30][31][32] It is unknown if these mechanisms occur in dogs. 18 F I G U R E 3 The percentage of antiplatelet antibodies (APA) were recorded for dogs that were divided into 4 categories: infectious, neoplastic, other, and immune thrombocytopenia (ITP).…”

Section: Discussionmentioning

confidence: 99%

Detection and dynamics of anti‐platelet antibodies in thrombocytopenic dogs with and without idiopathic immune thrombocytopenia

Shropshire

Dow

Lappin

2020

Veterinary Internal Medicne

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Background Antiplatelet antibodies are detected in multiple diseases including primary immune thrombocytopenia (ITP). Dynamics of how these antibodies change over time in ITP is unknown in dogs. Hypothesis/Objectives Antiplatelet antibodies (APA) will be detected in thrombocytopenic dogs with multiple etiologies and dynamics of APA in dogs with ITP can be used to evaluate response to treatment and relapse. Determine APA at the time of diagnosis in thrombocytopenic dogs and serially in primary ITP dogs. Animals Seventy‐nine thrombocytopenic dogs and 28 primary ITP dogs. Methods Direct flow cytometry was performed in thrombocytopenic dogs at initial evaluation and serially in suspected primary ITP dogs. In primary ITP dogs, a 2‐tailed Fisher's exact test was performed comparing survival to discharge between dogs with and without melena and to relate response to treatment and relapse to changes in APA and platelet count (repeated measures analysis, Spearman correlation). Results Twenty percent (16/79) of thrombocytopenic non‐ITP dogs with infectious, neoplastic, or other diseases and all primary ITP dogs were positive for APA. Melena at initial evaluation was associated with decreased survival to discharge (odds ratio 0.06; P = .01). Persistence of APA was not associated with response to treatment, but recurrence of antibodies was associated with relapse (odds ratio 205.0; P < .01). There was no difference in percentage of APA or platelet count at initial diagnosis between dogs that did or did not respond to treatment. Conclusions and Clinical Importance Serial monitoring of APA in dogs with primary ITP appeared beneficial for determining relapse of disease.

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“…4,5 Several pathways have been postulated in the pathogenesis of ITP, including autoantibodies against platelet membrane GP complexes, 6 B-cell clonality, 7 T regulatory cell dysfunction 8 , and T lymphocyte-mediated cytotoxicity. 9 More recently, anti-GPIbα 10 and CD8 + T-cell mediated platelet desialylation 11 has been implicated in ITP. Herein, we describe a patient with primary ITP and acquired GT.…”

Section: Introductionmentioning

confidence: 99%

Acquired Glanzmann thrombasthenia associated with platelet desialylation

Zheng

Perdomo

Leung

et al. 2020

Journal of Thrombosis and Haemostasis

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Background The notable discrepancy between platelet count and bleeding manifestations in immune thrombocytopenia (ITP) patients with acquired Glanzmann thrombasthenia (GT) has been described. Objectives We aimed to examine the mechanisms responsible for thrombocytopenia and the bleeding phenotype in a patient with acquired GT. Patient, methods, and results A patient with primary ITP underwent splenectomy due to steroid intolerance. Despite platelet count normalization, bleeding continued. Platelet aggregometry was abnormal with all agonists except for ristocetin. Flow cytometry demonstrated the presence of antiplatelet antibody, which caused dose‐dependent inhibition of fibrinogen and PAC‐1 binding, induction of neuraminidase‐1 expression as well as platelet desialylation in donor platelets. Indirect monoclonal antibody immobilization of platelet specific antigen assay (MAIPA) confirmed specificity to αIIbβ3 only, corroborated by binding on Chinese hamster ovary (CHO) cells expressing human glycoprotein αIIbβ3 but not GP Ib/IX. Both desialylation and neuraminidase expression were observed with plasma adsorbed on Ib/IX CHO cells and with the immunoglobulin G (IgG) fraction. Desialylation was inhibited in the presence of anti‐Fc‐gamma receptor IIa (FcγRIIa) antibody. A nonobese diabetic/severe combined immunodeficient ITP murine model was established, which showed rapid hepatic donor platelet clearance in the presence of patient IgG. Treatment of mice with the neuraminidase inhibitor oseltamivir significantly reduced antibody‐induced platelet destruction. Conclusions We report the first case of a patient with acquired GT due to ITP with FcγRIIa mediated platelet desialylation, independent of platelet activation. Treatment with neuraminidase inhibitor may prevent platelet clearance by anti‐αIIbβ3 antibodies.

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CD8+ T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia

Cited by 67 publications

References 52 publications

IgG-Fc glycosylation before and after rituximab treatment in immune thrombocytopenia

IgG-Fc glycosylation before and after rituximab treatment in immune thrombocytopenia

Detection and dynamics of anti‐platelet antibodies in thrombocytopenic dogs with and without idiopathic immune thrombocytopenia

Acquired Glanzmann thrombasthenia associated with platelet desialylation

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