Functions of Phagocytes

The phagocyte system encompasses both granulocytes (neutrophils, eosinophils, basophils) and mononuclear phagocytes (monocytes and tissue macrophages), which serve as the rapid effector arm of the innate immune system.
The primary, defining properties of phagocytes are large-particle ingestion (phagocytosis) and microbial killing.
Phagocytes participate primarily in the innate immune response but also secrete chemotactic signals to attract dendritic cells and other initiators of the acquired (adaptive) immune response.
Macrophages specifically perform antigen processing and presentation, displaying degraded foreign protein fragments on their cell surface in conjunction with class II MHC proteins for interaction with CD4+ helper T cells.
Phagocytes regulate inflammation and promote tissue repair by turning off the inflammatory cascade and clearing tissue debris.

Circulating neutrophils detect low levels of chemokines from infection sites, adhere to the vascular endothelium via selectins and integrins, and transmigrate into tissues.
Phagocytes ingest microbes coated by opsonins (such as immunoglobulin and complement component C3b) into a closed vacuole known as the phagosome.
Microbial destruction within the phagosome occurs via two concomitant pathways: degranulation and the oxidative burst.
Degranulation involves the fusion of neutrophil granule membranes with the phagosome, delivering potent antimicrobial proteins and peptides.
The oxidative burst involves the assembly and activation of the nicotinamide-adenine dinucleotide phosphate (NADPH)–dependent oxidase at the phagosome membrane.
The NADPH oxidase generates large amounts of superoxide from molecular oxygen, which decomposes to produce highly microbicidal hydrogen peroxide and singlet oxygen.
Myeloperoxidase (MPO) from azurophil granules catalyzes the reaction of hydrogen peroxide with chloride ions to create hypochlorous acid, a potent agent that destroys pathogens.
Phagocytes also secrete a wide variety of cytokines and chemokines (e.g., IL-1, TNF, IL-8) that recruit additional neutrophils, monocytes, and macrophages to the site of infection.

Defects of Phagocyte Functions

Chronic Granulomatous Disease (CGD) is caused by genetic defects in the subunits of the NADPH oxidase complex (most commonly an X-linked defect in CYBB encoding gp91phox, or autosomal recessive defects in p47phox, p67phox, or p22phox).
Pathophysiologically, phagocytes in CGD possess normal chemotaxis and degranulation but fail to generate the microbicidal reactive oxygen species necessary to kill catalase-positive microorganisms.
Patients typically present with recurrent pneumonias, severe suppurative lymphadenitis, deep hepatic or subcutaneous abscesses, and osteomyelitis caused by organisms such as Staphylococcus aureus, Aspergillus, Serratia marcescens, Burkholderia cepacia, and Nocardia.
A hallmark of CGD is the formation of exuberant inflammatory granulomas that can obstruct the gastric outlet, pylorus, or urinary tract.
Diagnosis is established by evaluating the neutrophil oxidative burst using the dihydrorhodamine (DHR) reduction assay via flow cytometry.
Management includes lifelong antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX) and itraconazole, alongside subcutaneous interferon-gamma; definitive cure requires hematopoietic stem cell transplantation (HSCT).

Leukocyte Adhesion Deficiency Type 1 (LAD-1) is an autosomal recessive disorder caused by a defect in the ITGB2 gene encoding the CD18 subunit of $β_{2}$ -integrins.
Due to absent or severely reduced $β_{2}$ -integrins, neutrophils cannot firmly adhere to endothelial intercellular adhesion molecules (ICAM-1 and ICAM-2) or recognize iC3b-opsonized microbes, preventing transmigration and phagocytosis.
LAD-1 classically presents with delayed separation of the umbilical cord, severe omphalitis, and recurrent bacterial infections of the skin and mucosal surfaces characterized by a distinct lack of pus formation.
Patients exhibit extreme, persistent neutrophilic leukocytosis (often >30,000 to >100,000/µL during active infection).
LAD Type 2 results from a fucose transporter defect leading to an absence of sialyl Lewis X (required for selectin-mediated rolling), presenting with milder infections, severe intellectual disability, and the Bombay blood phenotype.
LAD Type 3 involves defective integrin activation due to pathogenic variants in FERMT3 (Kindlin-3), presenting with LAD-1-like infections and a Glanzmann thrombasthenia-like bleeding disorder.
Treatment for severe LAD-1 relies on prophylactic antibiotics and early allogeneic HSCT.

Chédiak-Higashi Syndrome is an autosomal recessive disorder caused by pathogenic variants in the LYST gene, leading to the defective coalescence of lysosomal granules and the formation of giant primary granules in all granule-bearing cells.
The abnormal granules result in reduced contents of hydrolytic enzymes, severely impairing the intracellular killing of microorganisms, particularly Staphylococcus aureus.
Clinical features include partial oculocutaneous albinism (silvery hair, photophobia), progressive sensory and motor peripheral neuropathy, and a mild bleeding diathesis due to a platelet storage pool defect.
Patients are at a uniquely high risk of developing a fatal, accelerated phase of hemophagocytic lymphohistiocytosis (HLH), characterized by pancytopenia and massive lymphohistiocytic infiltration of organs.
Treatment includes high-dose ascorbic acid to temporarily improve neutrophil function, but definitive treatment for the accelerated phase requires HSCT.

MPO deficiency is a common autosomal recessive disorder affecting the generation of hypochlorous acid in neutrophils and monocytes.
The condition is usually clinically silent due to intact redundant killing mechanisms, though rarely it can present with disseminated candidiasis in patients with concurrent diabetes mellitus.

Pure primary chemotactic defects are exceptionally rare; however, conditions like "Lazy Leukocyte Syndrome" present with impaired neutrophil locomotion and frequent bacterial infections like stomatitis and otitis despite normal bone marrow reserves.
Actin-binding protein deficiency leads to slow mobility of leukocytes resulting in recurrent infections.