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- Brandsma, Arianne M., et al.
(författare)
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Potent Fc Receptor Signaling by IgA Leads to Superior Killing of Cancer Cells by Neutrophils Compared to IgG
- 2019
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Antibody therapy of cancer is increasingly used in the clinic and has improved patient's life expectancy. Except for immune checkpoint inhibition, the mode of action of many antibodies is to recognize overexpressed or specific tumor antigens and initiate either direct F(ab')(2)-mediated tumor cell killing, or Fc-mediated effects such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/P) after binding to activating Fc receptors. All antibodies used in the clinic are of the IgG isotype. The IgA isotype can, however, also elicit powerful anti-tumor responses through engagement of the activating Fc receptor for monomeric IgA (Fc alpha RI). In addition to monocytes, macrophages and eosinophils as Fc alpha RI expressing immune cells, neutrophils are especially vigorous in eliminating IgA opsonized tumor cells. However, with IgG as single agent it appears almost impossible to activate neutrophils efficiently, as we have visualized by live cell imaging of tumor cell killing. In this study, we investigated Fc receptor expression, binding and signaling to clarify why triggering of neutrophils by IgA is more efficient than by IgG. Fc alpha RI expression on neutrophils is similar to 2 times and similar to 20 times lower than that of Fc gamma receptors Fc gamma RIIa and Fc gamma RIIIb, but still, binding of neutrophils to IgA- or IgG-coated surfaces was similar. In addition, our data suggest that IgA- mediated binding of neutrophils is more stable compared to IgG. IgA engagement of neutrophils elicited stronger Fc receptor signaling than IgG as indicated by measuring the p-ERK signaling molecule. We propose that the higher stoichiometry of IgA to the Fc alpha R/FcR gamma-chain complex, activating four ITAMs (Immunoreceptor Tyrosine-based Activating Motifs) compared to a single ITAM for Fc gamma RIIa, combined with a possible decoy role of the highly expressed Fc gamma RIIIb, explains why IgA is much better than IgG at triggering tumor cell killing by neutrophils. We anticipate that harnessing the vast population of neutrophils by the use of IgA monoclonal antibodies can be a valuable addition to the growing arsenal of antibody-based therapeutics for cancer treatment.
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| 3. |
- Leusen, JHW, et al.
(författare)
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Disturbed interaction of p21-rac with mutated p67-phox causes chronic granulomatous disease
- 1996
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 184:4, s. 1243-1249
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Tidskriftsartikel (refereegranskat)abstract
- Chronic granulomatous disease (CGD) is characterized by the failure of phagocytic leukocytes to generate superoxide, needed for the intracellular killing of microorganisms. This is caused by mutations in any one of the four subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In a rare, autosomal recessive form of CGD, a 67-kD cytosolic component of this enzyme (p67-phox) is missing. We here report on a patient with a mutation in the p67-phox gene that leads to expression of a nonfunctional p67-phox protein. The purified granulocytes of this patient failed to produce superoxide and contained about half of the normal amount of p67-phox. Analysis of the cDNA and genomic DNA of this patient showed that the patient is a compound heterozygote for a triplet nucleotide deletion in the p67-phox gene, predicting an in-frame deletion of lysine 58 in the p67-phox protein and a larger deletion of 11-13 kb in the other allele. Interestingly, the 58Lys deletion in p67-phox disrupts the interaction with p21-rac1, a ras-related protein involved in the activation of the NADPH oxidase. In contrast to normal neutrophils, in which p47-phox and p67-phox translocate to the plasma membrane upon cell activation, the cells of the patient did not show this translocation, indicating that an interaction between p67-phox and p21-rac1 is essential for translocation of these cytosolic proteins and activation of the NADPH oxidase. Moreover, this CGD patient represents the first case of disease caused by a disturbed binding of a ras-related protein to its target protein.
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| 5. |
- Podgornii, Daniel, et al.
(författare)
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Heterometallic {Fe 18 M 6 } (M = Y, Gd, Dy) Pivalate Wheels Display Solvent-Induced Polymorphism
- 2022
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7505 .- 1528-7483. ; 22:9, s. 5526-55347
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Tidskriftsartikel (refereegranskat)abstract
- A new series of heterometallic wheels, isolated as [Fe18M6(piv)12(Htea)18(tea)6(N3)6]·n(solvent) (MIII = Y (1a, 1b), Gd (2a, 2b), and Dy (3a, 3b); Hpiv = pivalic acid, H3tea = triethanolamine), forms by the reaction of trinuclear μ3-oxo-linked or hexanuclear μ-OH-linked Fe(III) pivalate clusters with rare earth nitrates, H3tea, and azide ligands in MeOH/MeCN or EtOH/MeCN media under ultrasonic irradiation. Single-crystal X-ray diffraction showed that wheels 1a-3a prepared from MeOH/MeCN solutions crystallize in the triclinic space group P1¯ and have Ci symmetry, whereas wheels 1b-3b received from EtOH/MeCN solution crystallize in the trigonal space group R3¯ and have C3i symmetry. Magnetic studies reveal medium antiferromagnetic exchange interactions within the Fe3 trimeric unit (with the exchange coupling parameters of JFe3 = -13.1 cm-1 for 1a, JFe3 = -11.6 cm-1 for 1b) and weak intermolecular antiferromagnetic exchange interactions (λmf = -0.366 mol cm-3 and -0.368 mol cm-3 (zJmf = -0.19 cm-1), respectively). This leads to spin ground states of S = 5/2 for each {Fe3} unit. Substitution of diamagnetic Y(III) centers by paramagnetic Ln(III) centers (in 2a/2b by Gd(III) and in 3a/3b by Dy(III) centers) results in ferromagnetic exchange interactions between the Fe(III) and Ln(III) centers in addition to the predominant antiferromagnetic Fe···Fe interactions in 1a/1b.
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| 6. |
- Yasuma, R, et al.
(författare)
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Intravenous immune globulin suppresses angiogenesis in mice and humans
- 2016
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Ingår i: Signal transduction and targeted therapy. - : Springer Science and Business Media LLC. - 2095-9907 .- 2059-3635. ; 1
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Tidskriftsartikel (refereegranskat)abstract
- Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.
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