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Soluble and surface-bound immunoglobulin triggers human monocyte activation and hydrogen peroxide release
1Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Abstract:
Human mononuclear phagocytes (MO) can mediate the destruction of a variety of foreign and tumor target cells. In most circumstances, however, peripheral blood MO are noncytotoxic and must acquire cytotoxic activity. To investigate the cell surface molecules that participate in the acquisition of MO-mediated cytotoxicity, we used a panel of monoclonal antibodies (MAbs) recognizing a variety of membrane molecules. MAbs to eight different MO surface molecules did not trigger the killing of tumor target cells. To determine if these cell surface molecules triggered an activated but incomplete lytic mechanism, the ability of these molecules to trigger hydrogen peroxide (H2O2) release was assessed. Several MAbs triggered H2O2 release from MO isolated from the peripheral blood. The pattern of MAb-triggered H2O2 release correlated not with the MO surface antigen, but with the immunoglobulin (Ig) isotype. Isotype-specific H2O2 release was abrogated with the enzymatic removal of the Fc portion of the Ig and enhanced by interferon-gamma pretreatment, indicating that the membrane signal was mediated by cell surface Fc receptors. H2O2 release was independent of the presentation of the Ig molecule. Comparable H2O2 release was observed whether the Ig was in surface-bound or soluble form. These data support an important role for Fc receptors in the acquisition of cytotoxic potential by human MO.
Insights
Human mononuclear phagocytes (MOs) gain cytotoxic potential through Fc receptors, not direct antigen recognition. Monoclonal antibodies targeting Fc receptors trigger hydrogen peroxide release, enhancing MO-mediated cell destruction.
Area of Science:
- Immunology
- Cell Biology
Background:
- Human mononuclear phagocytes (MOs) are crucial for eliminating foreign and tumor cells.
- Peripheral blood MOs typically lack cytotoxicity and require activation to become effective.
- Understanding the mechanisms of MO activation is key to harnessing their therapeutic potential.
Purpose of the Study:
- To identify cell surface molecules involved in the acquisition of MO-mediated cytotoxicity.
- To investigate the role of specific membrane molecules in triggering MO effector functions.
Main Methods:
- Utilized a panel of monoclonal antibodies (MAbs) against various MO surface molecules.
- Assessed the ability of MAbs to trigger tumor target cell killing and hydrogen peroxide (H2O2) release.
- Investigated the influence of Fc receptor engagement and immunoglobulin (Ig) isotype on H2O2 release.
Main Results:
- MAbs targeting eight different MO surface molecules did not induce direct tumor cell killing.
- Several MAbs triggered H2O2 release from peripheral blood MOs.
- H2O2 release was dependent on the immunoglobulin (Ig) isotype and mediated by Fc receptors, not direct antigen binding.
Conclusions:
- Fc receptors play a critical role in the acquisition of cytotoxic potential by human MOs.
- Activation of MOs for cytotoxicity can be triggered via Fc receptor signaling, leading to H2O2 release.
- Interferon-gamma enhances Fc receptor-mediated MO activation.