Blocking a specific immune-cell receptor called FcγRIII significantly reduced the destruction of platelets that occurs in fetal and neonatal alloimmune thrombocytopenia (FNAITFetal and neonatal alloimmune thrombocytopenia A rare condition in which a mother’s immune system attacks fetal platelets, leading to dangerously low platelet levels before and/or after birth.), according to a recent study conducted in laboratory and animal models.
In FNAIT, a mother’s immune system makes antibodies against proteins on her baby’s platelets, the cell fragments that help blood clot. These antibodies most often target a platelet marker called HPAHuman platelet antigen Proteins found on the surface of platelets. Incompatibility between maternal and fetal human platelet antigens can trigger FNAIT.-1a. The problem arises when the baby inherits this marker from the father, but the mother does not carry it herself, so her immune system treats it as foreign.
During pregnancy, the antibodies can cross the placenta, attach to the baby’s platelets, and mark them for destruction, lowering the platelet countPlatelet count A measure of how many platelets are in the blood. FNAIT is characterized by severely reduced counts in a fetus or newborn. and sometimes causing serious bleeding.
The researchers found that once anti-HPA-1a antibodies coat a baby’s platelets, immune cells called macrophages recognize and engulf those platelets in a process called phagocytosis. The macrophages do this through structures known as Fc gamma receptors, which latch onto the tail end of the antibodies. One of these receptors, FcγRIII, emerged as the main driver.
To establish this, the team tested antibodies from 10 individual FNAIT patients. In 9 of the 10 samples, the antibodies triggered FcγR-dependent platelet phagocytosis, indicating this mechanism as the major contributor to platelet destruction.
To test this in a living body, the team developed a “dual-humanized” mouse model: the mice carried platelets bearing the human HPA-1a marker and had their immune cells fitted with human Fc gamma receptors in place of the usual mouse versions, so the system would behave more like the human disease. When platelets coated with anti-HPA-1a antibodies were introduced, they cleared from the bloodstream rapidly. But when the mice were first given an antibody that blocks FcγRIII, that platelet loss slowed significantly.
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The study also looked at other ways the antibodies might damage platelets, including complement activation (a separate arm of the immune system that can tag cells for destruction), direct platelet activation, and desialylation (the stripping of sugar molecules from the platelet surface, which can shorten a platelet’s life). Each appeared in only a minority of patients, and the authors describe their overall contribution as still uncertain.
Among several study limitations, they highlighted that the study did not examine whether the antibodies trigger platelet apoptosis, a form of programmed cell death, which could add to the picture of how anti-HPA-1a antibodies clear platelets and is worth exploring in future work.
Even so, the authors noted that the findings “support FcγRIII as a promising therapeutic target” in FNAIT.
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