Phagocytosis

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Here is a thorough breakdown of phagocytosis drawn from multiple authoritative textbooks.

Phagocytosis

Definition

Phagocytosis is the process by which certain cells - primarily neutrophils and macrophages - engulf and destroy large particulate material such as bacteria, fungi, dead cells, and foreign debris. It is a cornerstone of both innate immunity and the inflammatory response.

Robbins & Kumar Basic Pathology
Guyton and Hall Textbook of Medical Physiology

Phagocytic Cells

Feature	Neutrophils	Macrophages
Origin	HSCs in bone marrow	HSCs (inflammatory) / yolk sac/fetal liver (tissue-resident)
Life span in tissues	1-2 days	Days to weeks (inflammatory); years (tissue-resident)
Capacity	~3-20 bacteria per cell	~100 bacteria; can ingest whole RBCs, malarial parasites
ROS production	Rapid, via respiratory burst	Less prominent
Nitric oxide	Low/none	Induced via iNOS (transcriptional)
Cytokine production	Low/none	Major functional activity
Lipase content	Absent	Present - can digest lipid coats (e.g., M. tuberculosis)
Survival after phagocytosis	Typically dies after	Can survive and function for months

Robbins & Kumar Basic Pathology, Table 2.4

Steps of Phagocytosis

1. Recognition and Attachment

Phagocytes express surface receptors that recognize targets directly or indirectly:

Direct recognition: Pattern-recognition receptors such as the mannose receptor (recognizes terminal mannose residues on microbial glycoproteins) and scavenger receptors.
Indirect recognition (Opsonization): Efficiency is greatly enhanced when the target is coated with opsonins - molecules that bridge the microbe to phagocyte receptors:
- IgG antibodies (via Fc receptors, FcgRs)
- C3b - the cleavage product of complement (via complement receptors, e.g., Mac-1/CR3)
- Plasma lectins (e.g., mannose-binding lectin)

"The C3 molecules attach to receptors on the phagocyte membrane, thus initiating phagocytosis. This process whereby a pathogen is selected for phagocytosis and destruction is called opsonization." - Guyton & Hall

2. Engulfment

After receptor binding, the phagocyte undergoes dramatic cytoskeletal rearrangement:

Pseudopodia project outward in all directions around the particle.
The pseudopodia meet on the opposite side and fuse, enclosing the particle.
The enclosed membrane-bound vesicle invaginates into the cytoplasm and pinches off as a phagosome.

A neutrophil can phagocytize 3 to 20 bacteria before it becomes inactivated and dies; a macrophage can handle up to 100.

3. Phagolysosome Formation

Lysosomes (and other cytoplasmic granules) rapidly fuse with the phagosome, forming the phagolysosome. Lysosomal contents are discharged directly into the vesicle, safely away from the cell's cytoplasm.

4. Intracellular Killing and Digestion

Two main mechanisms destroy the ingested material:

a) Reactive Oxygen Species (Respiratory Burst)

Enzymes in the phagosome membrane assemble phagocyte oxidase (NADPH oxidase), generating:
- Superoxide (O2-)
- Hydrogen peroxide (H2O2)
- Hydroxyl ions (OH-)
Myeloperoxidase (MPO), a lysosomal enzyme, then catalyzes: H2O2 + Cl- → hypochlorous acid (HOCl) - an extremely potent bactericidal agent.
This is especially prominent in neutrophils.

b) Lysosomal Enzymes

Proteolytic enzymes digest bacterial proteins.
Lipases (present in macrophage lysosomes) digest thick lipid membranes of bacteria like M. tuberculosis.
Antimicrobial peptides (defensins, lysozyme) directly disrupt microbial membranes.

c) Reactive Nitrogen Species

Macrophages produce nitric oxide (NO) via inducible nitric oxide synthase (iNOS), which is toxic to pathogens.

5. Exocytosis

After digestion, the phagosome migrates to and fuses with the plasma membrane, expelling any remaining cellular debris by exocytosis. Macrophages can then reuse their components and continue functioning.

Diagram: The Phagocytosis Process

Phagocytosis diagram showing opsonized microbe being engulfed by a macrophage, forming a phagosome, fusing with lysosome to form phagolysosome, and expelling microbial debris by exocytosis

Fig. 34.3 from Guyton & Hall - showing antibody-coated bacteria being engulfed, phagosome formation, phagolysosome digestion, and exocytosis of microbial debris.

Selectivity - Why Phagocytes Don't Eat Normal Cells

Three factors govern selectivity (Guyton & Hall):

Surface texture: Normal cells have smooth surfaces that resist phagocytosis; rough surfaces (like bacterial cell walls) promote it.
Protective protein coats: Normal body cells have surface proteins that repel phagocytes; dead cells and foreign particles lack these.
Opsonization: Antibodies and complement bound to pathogens flag them specifically for destruction.

Evasion of Phagocytosis by Pathogens

Some pathogens have evolved strategies to escape:

Mechanism	Example
Resist lysosomal digestion (lipid coat)	Mycobacterium tuberculosis
Escape from phagosome into cytosol	Listeria monocytogenes, Shigella spp.
Inhibit phagosome-lysosome fusion	M. tuberculosis, Legionella
Anti-phagocytic capsules	Streptococcus pneumoniae, Klebsiella

Janeway's Immunobiology 10e

Clinical Relevance

Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase → impaired respiratory burst → recurrent infections with catalase-positive organisms.
Chediak-Higashi Syndrome: Defective lysosomal trafficking → phagocytes cannot fuse lysosomes with phagosomes effectively.
Myeloperoxidase deficiency: Mild susceptibility to Candida infections in immunosuppressed individuals.
Tuberculosis: M. tuberculosis survives inside macrophage phagosomes by inhibiting phagolysosome fusion, which is the basis of its chronic, intracellular persistence.

Sources:

Guyton and Hall Textbook of Medical Physiology, Ch. 34
Robbins & Kumar Basic Pathology, Ch. 2
Harper's Illustrated Biochemistry, Ch. 54
Janeway's Immunobiology, 10e

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