Neutrophil

BACKGROUND

A neutrophil is a granulocyte (a type of white blood cell) that is designed to fight off infections and diseases that enter the body. Neutrophils, along with eosinophils and basophils, are members of the polymorphonuclear cells (PMNs).

These cells are filled with neutrally-staining granules, which are small pouches of enzymes that allow the cell to destroy an invading microorganism it has engulfed during phagocytosis.

Neutrophils are the most abundant type of white blood cells in the body, making up 70% of all leukocytes (white blood cells). These cells play an important role in the immune system. When a pathogen (disease-causing microorganism) enters the body, neutrophils are the first phagocytes to attack the invader.

These cells are the main component of pus, and are responsible for its yellow/white appearance.

Neutrophils are produced in the bone marrow. Mature neutrophils are normally found in the bloodstream. However, during inflammation, neutrophils move toward the affected area within an hour by a process known as chemotaxis.

STRUCTURE

Neutrophils are continually produced in the bone marrow.

A mature neutrophil has a segmented nucleus, while an immature neutrophil has a band-shaped nucleus. On average, neutrophils typically live about three days.

The neutrophil plasma membrane contains several membrane channels, adhesive proteins, receptors for various ligands (molecules that bind to specific proteins), ion pumps and ectoenzymes (enzymes located on the outer surface of the cell).

Neutrophils have a complex cytoskeleton, which is responsible for chemotaxis (movement), phagocytosis (engulfing organisms) and exocytosis (secretions released outside of the cell). Proteins that make up the cytoskeleton include, actin, actin-binding protein, alpha-actinin, myosin, tubulin gelsolin, profilin and tropomyosin. About 45% of the neutrophil cytosolic protein is made of migration inhibitory factor-related proteins (MRPs), MRP-8 and MRP-14.

Neutrophils contain a large amount of glycogen (a stored form of glucose) in the cytoplasm. The glycogen provides neutrophils with energy.

Once fully developed, neutrophils are no longer able to grow or divide. Mature neutrophils contain at least four types of granules, which are specialized lysosomes (particles that contain enzymes necessary for digestion). Granules are classified as, (1) primary or azurophil granules, (2) secondary or specific granules, (3) tertiary or gelatinase granules and (4) secretory vesicles.

TYPES OF GRANULES

Primary or azurophil granules: Azurophil granules are released into the phagocytic vesicles. They contain an enzyme called myeloperoxidase, as well as several other proteins and enzymes. Myeloperoxidase (MPO) is a catalyst in the conversion of hydrogen peroxide to hypochlorous acid. MPO is responsible for the green color of pus.

Other components of azurophilic granules include defensins, lysozyme, azurocidin, bacterial permeability-increasing protein (BPI), elastase, cathepsin G, proteinase and esterase N. Defensins are proteins that fight against bacteria, fungi and viruses. Lysozyme is an enzyme that degrades bacterial peptidoglycans, which are found in the cellular membranes of bacteria. Azurocidin demonstrates antibacterial activity and antifungal activity against Candida albicans. BPI has antibacterial activity against some gram-negative bacteria.

Secondary or specific granules: Secondary, or specific granules, are secreted outside of the neutrophil (exocytosis) Secondary granules contain apolactoferrin, vitamin B-12-binding protein, plasminogen activator, lysozyme and collagenase. Apolactoferrin binds to the iron, which deprives bacteria of iron that is needed for cell growth. The collagenase enzyme breaks down collagen, which allows neutrophils to move freely through collagen.

Tertiary or gelatinase granules: Tertiary, or gelatinase granules, contain gelatinase, acetyltransferase and lysozyme. Tertiary granules, along with specific granules, are up-regulated to the cell surface when they are stimulated. Gelatinase is used to facilitate neutrophil movement through the tissues.

Secretory vesicles: Secretory vesicles contain alkaline phosphatase, cytochrome b558 and N-formyl-1-methionyl-1-leucyl-1-phenylalanine (FMLP) receptors. Secretory vesicles can be up-regulated to the surface, even if extracellular calcium is absent. The FMLP activates neutrophils to engulf foreign invaders when it comes into contact with N-formylated peptides.

CELL DEVELOPMENT

The neutrophils replicate during the first three stages of development, and then undergo cell differentiation during the later stages.

Myeloblast stage: The first stage of neutrophil development, known as the myeloblast stage, occurs in the bone marrow. The myeloblast cell is round, and it has a large nucleus, containing 2-5 nucleoli. There is a small amount of cytoplasm, which does not contain granules. The chromatin in the nucleus is not condensed.

Promyelocyte stage: The promyelocyte cell, which is still in the bone marrow, is larger than the myeloblast. The nucleus is round or oval, and the nuclear chromatin is not condensed. As the cell develops, the nucleoli are less prominent. The azurophilic (primary granules) are present in the cytoplast. The primary granules bud off the concave surface of the Golgi complex, an organelle that modifies and creates proteins and other chemicals for use outside the cell. However, the secondary granules have not developed yet.

Myelocyte stage: In the myelocyte stage, which takes place in the bone marrow, the secondary granules develop. These granules are smaller than the primary granules, and the glycoprotein is easily seen when the cell is stained. Secondary granules arise from the convex surface of the Golgi complex, an organelle that modifies and creates proteins and other chemicals for use outside the cell. The nucleus at this stage is round or oval, and the chromatin is coarse. The nucleoli are smaller and less prominent than they are in the promyelocyte stage.

Primary granules only form during the promyelocyte stage. With each cell division, the number of primary granules decreases. In mature neutrophils, the ratio of secondary granules to primary granules in humans is about 2-3:1.

Metamyelocyte stage: The metamyelocytes are present in the blood. The metamyelocyte stage is characterized by an indented nucleus that does not contain nucleoli. The dense chromatin clumps together along the nuclear membrane. The cytoplasm is filled with primary, secondary and tertiary granules. The metamyelocyte stage is not capable of cell division. Instead, cell differentiation takes place.

Polymorphonuclear stage: In the last stage, band neutrophils undergo further condensation of the nuclear chromatin. The nucleus is sausage-shaped. The nucleus begins to develop one or more constrictions, and, as the cell develops into the polymorphonuclear stage, the nucleus has two or more lobes connected by filamentous strands. In the polymorphonuclear stage, the cytoplasm appears faintly pink due to an abundance of granules. The fully mature neutrophils are present in the blood and tissues.

KINETICS

When the invading microorganism comes into contact with antibodies, chemotactic agents are released, which activate the neutrophils. Once the neutrophils become active, they move toward blood vessel endothelium. This process is called chemotaxis. Cell surface receptors in the neutrophils allow them to detect chemical gradients of molecules, like interleukin-8 (IL-8), interferon gamma (INF-gamma) and C5a, which direct the neutrophils' migration path. The cells then undergo selectin-dependent capture and integrin-dependent adhesion. Then the neutrophils migrate into tissues, where they survive for one to two days.

FUNCTIONS

Phagocytosis: Neutrophils are phagocytes, which means they ingest harmful microorganisms that enter the body. When the microorganism is engulfed, granules containing digestive enzymes and cytotoxic proteins are released into the phagocytic vesicle, and the microorganism is destroyed.

However, each cell is only capable of one phagocytic event. The cell uses up all of its glycogen in what is called a respiratory burst.

During the respiratory burst, an NADPH (nicotinamide adenine dinucleotide phosphate) oxidase enzyme, which produces large amounts of superoxide (a reactive oxygen), is activated. Superoxide spontaneously dismutates to hydrogen peroxide, which is then converted into hypochlorous acid (HOCI). Many researchers believe that the bactericidal properties of HOCl are enough to destroy the bacteria that are engulfed by the neutrophil. However, this has not been proven conclusively in scientific studies.

Neutrophil extracellular traps (NETs): Neutrophils can also release neutrophil extracellular traps (NETs), which is a web of fibers made of chromatin and serine proteases that trap and kill microbes outside of the neutrophil. In addition to their antimicrobial properties, the NETs may act as a barrier that prevents the pathogens from spreading throughout the body.

BLOOD DISORDERS

Neutropenia :

Background: Neutropenia is defined by a low number of neutrophils. In a normal body, neutrophils make up 50-60% of circulating white blood cells, which serve as the body's primary defense mechanism against infection and disease. Neutropenic patients have an absolute neutrophil count (ANC) that is lower than 1,500 cells per microliter of blood.

Therefore, patients with neutropenia are more susceptible to disease and infection. The condition may even become life threatening. Mild neutropenia usually causes no symptoms. Severe neutropenia increases the risk of infection of the lungs, kidneys, blood and skin. Neutropenia can be acute (lasting less than three months) or chronic (lasting longer than three months).

Symptoms: Some neutropenic patients, especially those with acute neutropenia, may be asymptomatic or experience mild symptoms. The disease is usually discovered when a patient has developed severe infections or sepsis. Common symptoms of neutropenia include skin rash, mouth ulcers, abscesses, thrush, periodontal disease, lymphadenopathy (enlarged lymph nodes), mucous membrane abnormalities, fever, frequent infections, diarrhea, burning sensation when urinating, unusual redness/pain/swelling around a wound, sore throat, shortness of breath and chills.

Diagnosis: Some patients may be asymptomatic or experience mild symptoms. A complete blood count (CBC) test is usually conducted to determine how many and what types of cells are in the blood. Neutropenic patients have an absolute neutrophil count (ANC) that is lower than 1,500 cells per microliter of blood.

In serious cases, a bone marrow biopsy may be performed. During the biopsy, the patient is given a local anesthetic, and a sample of bone marrow is removed with a needle. The sample is then analyzed in the laboratory to determine whether or not the bone marrow is producing a sufficient number of neutrophils.

Treatment: Treatment for neutropenia depends on the cause. Any infection should be diagnosed and treated. According to the 1997 guidelines of the Infectious Diseases Society of America, neutropenic fever should be treated with empiric broad-spectrum antibiotics immediately. Treatment generally lasts between five to seven days.

According to the U.S Centers for Disease Control and Prevention (CDC) guidelines, vancomycin should be administered if Staphylococcus aureus infections are suspected. Delays in starting treatment are associated with higher mortality. Treatment generally lasts between five to seven days.

In rare cases, when the condition is life threatening, treatment may include blood transfusion, medicines to stimulate white blood cell production (like allopurinol, aspirin, chloroform, heparin, quinine or triamterene) and intravenous immunoglobulin (antibodies donated from blood samples).

Corticosteroids or immunosuppressive therapies may be administered in cases of autoimmune neutropenia.

In some cases, white blood cells collect in the spleen, causing it to enlarge. Possible treatment may include splenectomy (surgical removal of the spleen). In rare situations a bone marrow transplant may be necessary.

Prevention: Neutropenia is a common side effect of chemotherapy in cancer patients. According to the 2006 recommendations from the American Society of Clinical Oncology, blood cell growth factors should be used to prevent febrile neutropenia when the risk of febrile neutropenia is 20% or higher. Recombinant G-CSF (granulocyte-colony stimulating factor) or G-CSF (granulocytes colony-stimulating factor) has been used to stimulate white cell blood production. However, some patients have developed leukemia or myelodysplastic syndrome following treatment with G-CSF.

Neutrophilia :

Background: Neutrophilia occurs when there are an increased number of neutrophils in the blood. The number of neutrophils may be increased five to six times more than normal.

Neutrophilia is common during acute bacterial infections. During early infection, the neutrophil count may actually decrease briefly because early during inflammation, the white blood cells tend to occupy the periphery of the blood vessels. This is followed by a rapid increase of neutrophils from the bone marrow. During the infection, the neutrophil count remains elevated. During the recovery phase, the flow of cells from the marrow decreases, with a resultant decrease in neutrophilia.

Other causes of neutrophilia may include rapidly growing, cancerous tumors, acute or chronic administration of corticosteroids and acute hemorrhage (internal bleeding). Neutrophilia has also been associated with Cushing's disease.

Some individuals may experience shift neutrophilia, which is usually temporary (lasting about 20-30 minutes). Shift neutrophilia may occur as a result of vigorous exercise or epinephrine injection. It also occurs during seizures and paroxysmal tachycardia.

Symptoms: Symptoms vary depending on the underlying cause of neutrophilia. For instance, patients who experience neutrophilia as a result of bacterial infections may have symptoms like inflammation, enlarged lymph nodes, fever and chills. Patients who experience neutrophilia as a result of cancerous tumors may have symptoms like localized swelling, enlarged lymph nodes or unexplained weight gain or weight loss.

Diagnosis: A complete blood count (CBC) test is usually conducted to determine how many and what types of cells are in the blood. The blood test will indicate if there are an increased number of neutrophils in the bloodstream.

Treatment: Treatment options depend on the underlying cause of neutrophilia. Bacterial infections are usually treated with antibiotics. Corticosteroid treatment should be stopped if they are the suspected cause of neutrophilia.

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

• CancerSymptoms.org. Prevention of Neutropenia. www.cancersymptoms.org.
• Natural Standard: The Authority on Integrative Medicine. www.naturalstandard.com. Copyright © 2008.
• Neutropenia Support Association. www.neutropenia.ca.
• No authors listed. American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 1994 Nov;12(11):2471-508. View abstract
• Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006 Jul 1;24(19):3187-205. View abstract