Fc receptor inside-out signaling and possible impact on antibody therapy.
Fc receptors (FcR) are expressed on immune cells and bind to the Fc tail of antibodies. This interaction is essential for FcR-mediated signaling and triggering of cellular effector functions. FcR activation is tightly regulated to prevent immune responses by non-antigen bound antibodies or in the absence of 'danger signals'. FcR activity may be modulated at the plasma membrane via cross-talk with integrins. In addition, cytokines at the site of infection/inflammation can increase FcR avidity, a process referred to as inside-out signaling. This regulatory mechanism has been described for FcγRI (CD64), FcγRIIa (CD32a), and FcαRI (CD89) and is also well-known for integrins. Key cellular events during inside-out signaling are (de)phosphorylation, clustering, cytoskeleton rearrangements, and conformational changes. The latter can be studied with antibodies that specifically recognize epitopes exposed by the active (high affinity) or inactive (low affinity) state of the FcR. These antibodies are important tools to investigate the role of FcR activation in disease settings. Research on FcR has gained momentum with the rise of monoclonal antibodies (mAb) entering the clinic for the treatment of cancer and other diseases. The clinical outcome of mAb therapy may be improved by increasing FcR avidity by cytokine stimulation.
Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
Arianne M
AM
Brandsma
Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
Shamir R
SR
Jacobino
Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
Saskia
S
Meyer
Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
Toine
T
ten Broeke
Immunotherapy Laboratory, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
Jeanette H W
JH
Leusen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D056747:Immunomodulation / Q000187:drug effects; D016023:Integrins / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011961:Receptors, Fc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C036832:Fc(alpha) receptor; D007136:Immunoglobulins; D016023:Integrins; D011961:Receptors, Fc; D017452:Receptors, IgG
Fc receptors; antibodies; cytokines; immunotherapy; inside-out signaling; integrins