62. Granulocytes in inflammatory processes

Functions of granulocytes

Neutrophil granulocytes have 2 important immune functions: Phagocytosis and releasing contents of its granules. Neutrophils have 2 types of granules, which contain different compounds:

• Primary granules
  • Hydrolase
  • Elastase
  • Collagenase
  • Neutrophil myeloperoxidase (MPO)
  • Bactericids
• Secondary granules
  • Lactoferrin
  • NADPH oxidase elements
  • Others

Neutrophils in the body reside in the following locations:

• 90% in bone marrow
• 2-3% in the blood (The circulating amount is 4 – 8 G/L.)
• 7-8% in the tissues

There is continuous exchange between neutrophils in the circulation and neutrophils in the tissues. When granulocytes (not only neutrophils) travel between the circulation and the tissues must they first bind to selectins to the epithelium of vessels, in order to pass through the vessel wall. The process of sticking to the endothelium is called margination. A substantial number of granulocytes are in the process of margination (i.e. stuck to the endothelial wall) at any moment in time. We say that these granulocytes are part of a “marginal pool”.

The marginal pool is important because several conditions can rapidly increase the number of granulocytes in the blood by pulling granulocytes from the marginal pool (i.e., forcing them to un-bind from the endothelium and start circulating instead) if many granulocytes are suddenly needed. Adrenergic stimuli (catecholamines and sympathetic activation) drive cells from the marginal pool to the circulation, which causes granulocytosis. Viral infection drive cells to the marginal pool from the circulation, which causes granulocytopaenia.

However, when the need for granulocytes is prolonged must granulocyte production also be increased. This causes less mature granulocytes to enter the circulation as well, which causes a “left-shift” in a blood smear.

The process where granulocytes leave the circulation and enter the tissues is comprised of margination, rolling, adhesion and diapedesis, which has been described in both pathology and immunology.

After phagocytosing something will the phagosome fuse with lysosomes producing phagolysosomes, which will degrade whatever was phagocytosed.

Neutrophils can also kill bacteria and fungi by using a respiratory burst. The neutrophils use NADPH oxidase to produce free radicals and H2O2. They then use myeloperoxidase to convert H2O2 into hypochlorite (HClO–), a highly oxidizing molecule that kills bacteria.

Granulocytopaenia

The majority of circulating granulocytes are neutrophils, so we usually talk about granulocytopaenia when we mean that neutrophils are decreased. Granulocytopaenia is defined as <3 G/L circulating granulocytes. It can be caused by:

• Decreased production (problems with bone marrow)
  • Drugs
    • NSAIDs
    • Antibiotics
    • Cytotoxic agents
  • Radiation
  • Uraemia
  • Diseases of the bone marrow
  • Viral infections
  • Certain genetic disorders
• Increased cell-death (reduced lifetime)
  • Splenomegaly
  • Autoimmune diseases
    • Rheumatoid arthritis
    • SLE
  • Drugs that act as haptens
    • Methyl-DOPA
    • Penicillin

In granulocytopaenia are repeated and severe bacterial infections present in the skin, middle ear and airways. Below 1 G/L is the severity of these infections further increased. Below 0.2 G/L is there no inflammatory response.

Granulocyte dysfunction

Also called “lazy granulocytes”, it can occur in:

• Steroid treatment (pulls from marginal pool, but function is impaired)
• Chronic granulomatosis
• Uraemia
• Myeloperoxidase deficiency

Granulocytosis

The number is between 10 – 25 G/L. If the number increases beyond 30 G/L do we call it a leukemoid reaction, which only occurs during extreme stress, trauma or infection.

Granulocytosis can occur in:

• Severe infections
• Severe stress
• Severe trauma
• Corticosteroids
• Systemic inflammatory response syndrome (SIRS)

Functions of eosinophils and basophils

Basophils are associated with allergic and myeloproliferative diseases and exoparasites, such as ticks.

Eosinophils are important in parasitic infection and in allergies (especially bronchial asthma). Their granules contain eosinophil peroxidase, cationic proteins, Charcot-Leyden crystals and neurotoxin.

Eosinophilia can be caused by:

• Allergies
• Helminthiasis (parasite infection)
• Löffler syndrome
• Rheumatoid arthritis

Eosinopaenia can be caused by:

• Glucocorticoid treatment
• Acute bacterial infections
• Stress