The high-affinity human IgG receptor FcγRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy

Abstract

Key Points• Human Fc␥RI can trigger antibody-induced inflammatory arthritis, thrombocytopenia, airway inflammation, and systemic anaphylaxis.• Human Fc␥RI can trigger antibody-mediated immunotherapy of mouse metastatic melanoma.Receptors for the Fc portion of IgG (Fc␥Rs) are mandatory for the induction of various IgG-dependent models of autoimmunity, inflammation, anaphylaxis, and cancer immunotherapy. A few Fc␥Rs have the ability to bind monomeric IgG: high-affinity mouse mFc␥RI, mFc␥RIV, and human hFc␥RI. All others bind IgG only when aggregated in complexes or bound to cells or surfaces: low-affinity mouse mFc␥RIIB and mFc␥RIII and human hFc␥RIIA/B/C and hFc␥RIIIA/B. Although it has been proposed that high-affinity Fc␥Rs are occupied by circulating IgG, multiple roles for mFc␥RI and mFc␥RIV have been reported in vivo. However, the potential roles of hFc␥RI that is expressed on monocytes, macrophages, and neutrophils have not been reported. In the present study, we therefore investigated the role of hFc␥RI in antibody-mediated models of disease and therapy by generating hFc␥RI-transgenic mice deficient for multiple endogenous FcRs. hFc␥RI was sufficient to trigger autoimmune arthritis and thrombocytopenia, immune complex-induced airway inflammation, and active and passive systemic anaphylaxis. We found monocyte/macrophages to be responsible for thrombocytopenia, neutrophils to be responsible for systemic anaphylaxis, and both cell types to be responsible for arthritis induction.

Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases

“…10 Consequently, FcgRI has been the focus of considerable interest as a therapeutic target in chronic inflammatory diseases, where inflammatory macrophages, characterized by strongly enhanced FcgRI expression, play a significant role throughout all phases of disease progression. 9,10,[13][14][15]24 Indeed, elimination of macrophages using anti-FcgRI scFv immunotoxins has been shown to effectively resolve inflammation in vitro and in animal models. 11,12,25,26 Given the finding that mFc can selectively and potently bind to FcgRI, we therefore sought to determine whether mFc-based fusion proteins could be capable of FcgRI-mediated targeting of macrophages, offering additional therapeutic benefits in treatment of chronic inflammation-related diseases.…”

“…[10][11][12][13][14] The role of FcgRI in the promotion of inflammation and anaphylaxis was also recently confirmed in mouse models. 15 It is also interesting to note that IgG4, which has been known for some time to be functionally monovalent (i.e., polyclonal IgG4 antibodies do not cross-link two antigens), can bind FcgRI but shows very low affinity to FcgRIIIa and, importantly, differs functionally from the other IgGs in its superior anti-inflammatory activity. 16,17 These findings suggest that engineering Fc with selective binding to different Fcg receptors may lead to unique properties and serve different therapeutic purposes.…”

Recombinant H22(scFv) blocks CD64 and prevents the capture of anti-TNF monoclonal antibody

“…Mouse IgG1-Fcg has been reported to have a low affinity toward human CD64, 23 which would significantly affect our experimental set-up. However, in contrast to the data found in literature, the mouse-anti-human TNF mAb used here could be strongly captured by human CD64 (and also CD16 and CD32) in our experimental cell-based in vitro system, allowing us to study the effects of CD64-blocking molecules on the capture of the anti-TNF mAb.…”

Monocytes Subpopulations and Chemiluminescent Activity in Patients With Renal Cell Carcinoma

“…Так, при ПКР в периферической кро-ви больных повышается количество моноцитов, экспрессирующих CD64, но снижается содер-жание клеток с экспрессией HLA-DR и фено-типом HLA-DR + CD64 + . CD64 (FcγRI) является высокоаффиным рецептором к Fc-фрагментам иммуноглобулинов G [20,25]. Обнаружено, что экспрессия CD64 на моноцитах индуцируется интерфероном-γ, после чего моноциты, экспрес-сирующие CD64, дифференцируются в дендрит-ные клетки с более высокой миграционной спо-собностью [20,22].…”