RhIg-prophylaxis is not influenced by FCGR2/3 polymorphisms involved in red blood cell clearance

Stegmann, Tamara C.; Veldhuisen, Barbera; Nagelkerke, Sietse Q.; Winkelhorst, Dian; Schonewille, Henk; Verduin, Esther P.; Kuijpers, Taco W.; Haas, Masja de; Vidarsson, Gestur; Schoot, C. Ellen van der

doi:10.1182/blood-2016-05-716365

Cited by 14 publications

(13 citation statements)

References 26 publications

(37 reference statements)

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“…Recent elegant experiments of IgG-mediated suppression in mice immunized with allogeneic erythrocytes (murine RBC expressing transgenic human blood group antigens) arrive at the same conclusions as experiments in mice immunized with SRBC: neither requires FcγRs 10 , 13 , 15 , 32 , 33 nor clearance 11 , 12 , 48 – 50 , there is an additive suppressive effect of several monoclonal antibodies recognizing different epitopes 14 , 36 , and polyclonal IgG preparations are more efficient than monoclonal IgG antibodies 8 , 14 . In humans there is no strict correlation between clearance and prevention of anti-D alloimmunization 48 , 54 , 55 and, as mentioned above, several studies in mice arrive at the same conclusion 11 , 12 , 49 , 50 . Finally, anti-D administered after transfusion of RhD + erythrocytes 56 as well as IgG anti-SRBC administered several days after SRBC 9 , 19 , 32 , 47 effectively inhibit immunization.…”

Section: Discussionmentioning

confidence: 91%

IgG-mediated immune suppression in mice is epitope specific except during high epitope density conditions

Zhang

Heyman

2018

Sci Rep

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Specific IgG antibodies, passively administered together with erythrocytes, suppress antibody responses against the erythrocytes. Although used to prevent alloimmunization in Rhesus (Rh)D-negative women carrying RhD-positive fetuses, the mechanism behind is not understood. In mice, IgG suppresses efficiently in the absence of Fcγ-receptors and complement, suggesting an Fc-independent mechanism. In line with this, suppression is frequently restricted to the epitopes to which IgG binds. However, suppression of responses against epitopes not recognized by IgG has also been observed thus arguing against Fc-independence. Here, we explored the possibility that non-epitope specific suppression can be explained by steric hindrance when the suppressive IgG binds to an epitope present at high density. Mice were transfused with IgG anti-4-hydroxy-3-nitrophenylacetyl (NP) together with NP-conjugated sheep red blood cells (SRBC) with high, intermediate, or low NP-density. Antibody titers and the number of single antibody-forming cells were determined. As a rule, IgG suppressed NP- but not SRBC-specific responses (epitope specific suppression). However, there was one exception: suppression of both IgM anti-SRBC and IgM anti-NP responses occurred when high density SRBC-NP was administered (non-epitope specific suppression). These findings answer a longstanding question in antibody feedback regulation and are compatible with the hypothesis that epitope masking explains IgG-mediated immune suppression.

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Section: Discussionmentioning

confidence: 91%

IgG-mediated immune suppression in mice is epitope specific except during high epitope density conditions

Zhang

Heyman

2018

Sci Rep

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“…In vitro , this has been found result in stronger functional efficacy for the V158-variant ( 55 – 57 ). In vivo , conflicting reports have showed that individuals homozygous either the V158 or the F158 allotype show stronger cellular clearance ( 58 – 61 ). It should be noted that most of these studies were performed before the knowledge of FcγRIII gene being influenced by copy number variation ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Decoding the Human Immunoglobulin G-Glycan Repertoire Reveals a Spectrum of Fc-Receptor- and Complement-Mediated-Effector Activities

et al. 2017

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Glycosylation of the immunoglobulin G (IgG)-Fc tail is required for binding to Fc-gamma receptors (FcγRs) and complement-component C1q. A variety of IgG1-glycoforms is detected in human sera. Several groups have found global or antigen-specific skewing of IgG glycosylation, for example in autoimmune diseases, viral infections, and alloimmune reactions. The IgG glycoprofiles seem to correlate with disease outcome. Additionally, IgG-glycan composition contributes significantly to Ig-based therapies, as for example IVIg in autoimmune diseases and therapeutic antibodies for cancer treatment. The effect of the different glycan modifications, especially of fucosylation, has been studied before. However, the contribution of the 20 individual IgG glycoforms, in which the combined effect of all 4 modifications, to the IgG function has never been investigated. Here, we combined six glyco-engineering methods to generate all 20 major human IgG1-glycoforms and screened their functional capacity for FcγR and complement activity. Bisection had no effect on FcγR or C1q-binding, and sialylation had no- or little effect on FcγR binding. We confirmed that hypo-fucosylation of IgG1 increased binding to FcγRIIIa and FcγRIIIb by ~17-fold, but in addition we showed that this effect could be further increased to ~40-fold for FcγRIIIa upon simultaneous hypo-fucosylation and hyper-galactosylation, resulting in enhanced NK cell-mediated antibody-dependent cellular cytotoxicity. Moreover, elevated galactosylation and sialylation significantly increased (independent of fucosylation) C1q-binding, downstream complement deposition, and cytotoxicity. In conclusion, fucosylation and galactosylation are primary mediators of functional changes in IgG for FcγR- and complement-mediated effector functions, respectively, with galactose having an auxiliary role for FcγRIII-mediated functions. This knowledge could be used not only for glycan profiling of clinically important (antigen-specific) IgG but also to optimize therapeutic antibody applications.

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“…Finally, the FcγRIIc has also been associated with ITP ( 50 ). FcγRIIc is a pseudogene in most individuals, but having FcγRIIc most likely predisposes individuals to stronger immune responses ( 202 , 203 ). While the extracellular IgG-binding domain of FcγRIIc is identical to the inhibitory FcγRIIb, the intracelllular tail is identical to FcγRIIa and contains an activating motif ( 202 ).…”

Section: Pathways Involved In Platelet Clearancementioning

confidence: 99%

Emerging Concepts in Immune Thrombocytopenia

et al. 2018

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Immune thrombocytopenia (ITP) is an autoimmune disease defined by low platelet counts which presents with an increased bleeding risk. Several genetic risk factors (e.g., polymorphisms in immunity-related genes) predispose to ITP. Autoantibodies and cytotoxic CD8+ T cells (Tc) mediate the anti-platelet response leading to thrombocytopenia. Both effector arms enhance platelet clearance through phagocytosis by splenic macrophages or dendritic cells and by induction of apoptosis. Meanwhile, platelet production is inhibited by CD8+ Tc targeting megakaryocytes in the bone marrow. CD4+ T helper cells are important for B cell differentiation into autoantibody secreting plasma cells. Regulatory Tc are essential to secure immune tolerance, and reduced levels have been implicated in the development of ITP. Both Fcγ-receptor-dependent and -independent pathways are involved in the etiology of ITP. In this review, we present a simplified model for the pathogenesis of ITP, in which exposure of platelet surface antigens and a loss of tolerance are required for development of chronic anti-platelet responses. We also suggest that infections may comprise an important trigger for the development of auto-immunity against platelets in ITP. Post-translational modification of autoantigens has been firmly implicated in the development of autoimmune disorders like rheumatoid arthritis and type 1 diabetes. Based on these findings, we propose that post-translational modifications of platelet antigens may also contribute to the pathogenesis of ITP.

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RhIg-prophylaxis is not influenced by FCGR2/3 polymorphisms involved in red blood cell clearance

Cited by 14 publications

References 26 publications

IgG-mediated immune suppression in mice is epitope specific except during high epitope density conditions

IgG-mediated immune suppression in mice is epitope specific except during high epitope density conditions

Decoding the Human Immunoglobulin G-Glycan Repertoire Reveals a Spectrum of Fc-Receptor- and Complement-Mediated-Effector Activities

Emerging Concepts in Immune Thrombocytopenia

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