Granulocytes are immune cells that fight pathogens and heal damaged cells. They play critical roles in inflammation and wound healing. High levels occur in infections, inflammation, cancer, and many other underlying health issues. Low levels can be due to infections, autoimmune disease, drugs, and many other underlying causes. Read on to find out what high and low granulocyte levels mean and what factors may decrease or increase them.
What Are Granulocytes?
Pathogen-Fighting Immune Cells
Granulocytes are white blood cells that contain small sacs called granules. The contents of these granules are released into the blood during infections, injuries, and allergic reactions. These contents include antimicrobial proteins, enzymes to digest bacteria, and reactive oxygen species [1].
There are four types of granulocytes [1]:
- Neutrophils
- Eosinophils
- Basophils
- Mast cells
Granulocytes are made in the bone marrow from stem cells and then released into the circulation. They are part of the innate immune system, which provides a quick response to pathogens. Granulocytes become activated by pathogens and damaged cells [2].
Neutrophils are by far the most abundant type of granulocytes in the blood. This means your granulocyte count is often determined by your neutrophil count [3, 4].
Granulocytes are also known as polymorphonuclear leukocytes (PML) or polymorphonuclear neutrophils (PMN).
Function
The main function of granulocytes is to engulf and destroy invading pathogens and parasites. They are responsible for starting the process of inflammation as well as resolving it. Granulocytes are also involved in wound healing and tissue remodeling [1, 5].
Immune messenger molecules (eotaxin and IL-8) recruit granulocytes from the bloodstream to injured or infected tissues. They are then activated by bacteria, viruses, and fungi or damaged cells.
When they encounter a pathogen, granulocytes engulf them and release the contents of their granules to digest and destroy them. However, they also can cause damage to your own cells in the process [1].
After a threat has been eliminated, granulocytes destroy themselves by programmed cell death (apoptosis). However, in many inflammatory diseases like rheumatoid arthritis and asthma, granulocytes last longer than they should [1].
Neutrophils
Neutrophils are the most abundant immune cells in the body. They make up 50% to 70% of all immune cells. They only survive 8-12 hours in the blood (where they normally reside) and 1-2 days in tissues (when there is an infection) [3, 6].
Neutrophils are among the first immune cells to arrive at the site of an injury or infection. They produce antimicrobial compounds called defensins, enzymes (proteases), and reactive oxygen species (superoxide and hydrogen peroxide) that break down and destroy microbes.
However, these compounds can also cause damage to surrounding healthy tissue, which can lead to delayed healing and excess scarring [7].
Neutrophils produce immune messengers called cytokines (IL-6 and TNF-a) that recruit other immune cells [7, 8].
Eosinophils
Eosinophils were thought to primarily fight parasites such as worms. However, recent research suggests that they may also allow some parasites to live while preventing them from doing too much damage [9, 10].
Together with mast cells and basophils, eosinophils play important roles in the development of allergy and asthma. They also participate in [11, 12, 13]:
- Fighting viral, bacterial, and fungal infections
- Activating acquired immunity
- Helping prepare the uterus for pregnancy
- Repairing and remodeling tissue
- Regulating blood sugar and insulin levels
Like neutrophils, they are made in the bone marrow and then released into the bloodstream. They take up residence in the gut, ovaries, and lymph nodes, where they can live for several weeks. They are usually not found in the lung, skin, or throat except in disease states [11, 14, 15].
Basophils
Basophils help fight bacteria, viruses, and parasites. They also play key roles in allergies and autoimmune diseases. They are the largest yet least common granulocyte in the body [16, 17].
Basophils become activated when they come in contact with foreign molecules, IgE (an antibody), or specific signals from other immune cells [18, 17, 19].
When basophils become active, they release the contents of their granules, which include heparin and histamine.
Histamine expands blood vessels and increases blood flow. Heparin is an anti-clotting agent that helps maintain proper blood flow. This allows immune cells easy access to the site of inflammation [20, 21, 22].
Mast Cells
Due to their similarity, mast cells were originally thought to be basophils. Whereas basophils mainly circulate in the bloodstream, mast cells live tissues. They are abundant in places that come into close contact with the environment, such as the skin, gut, and airways [17, 23, 24].
Mast cells are responsible for the early recognition of foreign invaders. Within seconds of encountering a pathogen, mast cells release histamine, enzymes, and heparin [24].
Mast cells also play key roles in asthma and allergies by overreacting to the presence of harmless substances such as pollen and pet dander. They also participate in autoimmune conditions, including rheumatoid arthritis and multiple sclerosis [25].
By releasing pro-inflammatory cytokines (TNF-α and IL-6), mast cells can recruit T cells and dendritic cells to help fight pathogens. This makes mast cells a crucial link between the innate and adaptive immune systems [25].
Immature Granulocytes
Immature granulocytes are normally located in the bone marrow and have not yet matured into granulocytes [26].
The immature granulocyte percentage (IG%) test may be used along with the WBC and CRP tests to predict the severity of infections [27].
Granulocytes Normal Range
Granulocytes are sometimes measured as part of a standard complete blood count (CBC) test.
The normal range of granulocytes is around 1.5 – 8.5 x 10^9/L or between 1,500 and 8,500 cells per microliter (µL) of blood. Levels may vary slightly between laboratories doing the testing.
Levels below this range are referred to as granulopenia, usually due to neutropenia (low neutrophil levels). Severely low levels (below 500 cells/µL) are referred to as agranulocytosis. Low levels of granulocytes reduce the body’s ability to fight infections [28].
Levels above this range are referred to as granulocytosis.
Under normal conditions, the immature granulocyte percentage (IG%) in the blood is less than 1%. Immature granulocyte levels increase rapidly during infections, inflammation, or cancer [26, 29].
High Granulocytes (Granulocytosis)
Common Causes
The causes we discuss here are commonly associated with high granulocytes. Do not attempt to self-diagnose with any medical condition based on this single symptom! Work with your doctor to find an accurate diagnosis and appropriate treatment or management plan.
1) Infections
Because neutrophils are among the main immune cells, and furthermore first responders to microbe invasions, their levels increase during infections from bacteria, fungi, viruses, and parasites [30, 31, 32].
2) Inflammation
Neutrophil levels increase in severe inflammation [33, 6, 34].
Granulocyte levels were substantially higher in patients with appendicitis (inflammation of the appendix) in a study of 456 people [34].
3) Tissue Damage In Injury/Surgery
Tissue damage due to injury or surgery can increase neutrophils [35, 36].
Granulocyte levels increased in ten patients who underwent elective spine surgery due to an increase in cortisol [36].
Neutrophils play an important role in repairing heart attack damage. Levels will greatly increase in the hours following a heart attack and are directly related to the degree of damage [37, 38].
4) Cancer
By increasing a protein called granulocyte colony stimulating factor (G-CSF), many cancers can cause granulocytosis. These include [39, 40, 41, 42, 43]:
- Lung
- Stomach
- Breast
- Skin
- Brain
- Uterine
- Lymphoma (cancer of the lymphatic system)
- Chronic myeloid leukemia (cancer of the bone marrow)
5) Bone Marrow Disorders
Bone marrow produces blood cells, including granulocytes. When the process of blood cell production is disordered, granulocytosis may arise. A variety of bone marrow disorders have been associated with granulocytosis, including [44, 45]:
- Chronic myeloid leukemia (bone marrow cancer, as mentioned above)
- Essential thrombocytosis
- Primary myelofibrosis
6) Autoimmune Disorders
Some autoimmune disorders are associated with granulocytosis, most notably rheumatoid arthritis [46].
7) Blood Disorders
A few blood disorders may produce granulocytosis as a symptom, though not always. The most common of these include platelet clumping, cryoglobulinemia, and anemia [44].
8) Pregnancy
Granulocyte counts are normally elevated during pregnancy due to a higher sympathetic nervous system activity. This increased activity helps the developing fetus get enough oxygen and nutrients [47].
9) Cushing’s Syndrome
Cushing’s syndrome is a disease in which the adrenal glands release too much cortisol. People with Cushing’s syndrome show elevated granulocyte levels due to an increase in neutrophils [48, 31].
10) Medication
Drugs associated with increased granulocyte levels include:
Associated Diseases and Conditions
1) High Blood Pressure
In a 40-year observational study of 9,400 people, high neutrophil levels increased the risk of developing high blood pressure [52].
2) Heart Disease
Neutrophils can accumulate in plaques in the artery walls and contribute to hardened arteries (atherosclerosis) [53].
High neutrophil and eosinophil levels have been linked to an increased risk of heart disease, heart attack, stroke, and death from heart disease [54, 55, 56, 57, 58, 59, 60, 61].
Low Granulocytes
Causes
The causes we discuss here are commonly associated with low granulocytes. Do not attempt to self-diagnose with any medical condition based on this single symptom! Work with your doctor to find an accurate diagnosis and appropriate treatment or management plan.
1) Infections
Certain bacterial, viral, protozoan and fungal infections can cause low granulocyte levels. The flu, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and hepatitis A, B and C are common viruses that can lead to low granulocyte levels [31, 62, 63, 64].
2) Autoimmune Diseases
In autoimmune neutropenia, antibodies attack and destroy neutrophils, which results in low granulocyte levels [65, 66].
Neutrophils die at a much quicker rate in people with lupus. Because of this, low granulocyte levels are also seen in people with lupus, with 50% having abnormally low levels [67, 68, 69, 66].
Felty’s syndrome, a complication of rheumatoid arthritis, can result in low granulocyte levels [70, 71].
Low granulocyte levels are also a common feature of Sjögren’s syndrome, an autoimmune disease that causes dry eyes and mouth [72].
3) Bone Marrow Disorders
Bone marrow disorders can decrease granulocytes by interfering with their production. Examples of bone marrow disorders include [31]:
- Leukemia (bone marrow cancer)
- Myelofibrosis
- Tumors
- Aplastic anemia
4) Cancer Treatment
Radiation therapy for cancer can destroy neutrophil precursors in the bone marrow, which causes low granulocyte levels [73, 74, 63].
5) Certain Drugs
Some medications, including antibiotics, strong anti-inflammatories (sulfasalazine), and antipsychotics (clozapine), are associated with low granulocytes. If your doctor prescribes one such medication, you may be asked to come in for regular blood tests to ensure that your white blood cells are healthy [75, 76, 77].
6) Vitamin B9, Vitamin B12, and Iron Deficiencies
Both vitamin B9 (folic acid) and vitamin B12 are needed to make granulocytes. Deficiencies in these nutrients can cause low granulocyte levels [78, 79, 69, 63].
Iron deficiency can also lead to granulopenia, but the mechanism is still unknown [64].
7) Enlarged Spleen
An enlarged spleen traps neutrophils leading to low granulocyte levels in the blood [80, 69, 81].
8) Severe Burns
Severe burns can result in very low granulocyte levels. This is due to neutrophils leaving the bloodstream and moving to the burn site [82, 83, 84].
9) Thyroid Disorders
Hypothyroidism and hyperthyroidism are found in up to 43% of people with low granulocytes. Both low and high thyroid hormones are thought to destroy granulocyte precursors. People with thyroid disorders also have high levels of antibodies to granulocytes [85, 86].
10) Dialysis
Hemodialysis is the use of a filter to clean the blood of people whose kidneys are not working properly. The process changes neutrophils so that they get stuck in the blood vessels, leading to low levels in the bloodstream [87, 88].
11) Organ Transplants
Low neutrophil levels occur in up to 28% of kidney transplants and 24% of liver transplant recipients during the first year. They are associated with more infections, organ rejection and increased mortality [85].
12) Medication
Drugs associated with decreased granulocyte levels include:
- ACE inhibitors [89, 90]
- Allopurinol [91]
- Pain-relieving drugs [31]
- Antibiotics [92]
- Anticoagulants [31]
- Antidepressants [93]
- Antidiabetics [31]
- Antiepileptics [94, 95, 96]
- Antihistamines [31]
- Antimalarial [31]
- Antipsychotics [97, 98]
- Antithyroid medication [99, 100, 101]
- Chemotherapy [102, 103]
- Cimetidine [31]
- Cocaine [104]
- Colchicine [31]
- Dapsone [105]
- Diuretics [31]
- Griseofulvin [31]
- Immunosuppressives [106]
- Levodopa [31]
- Levamisole [31]
- NSAIDs [107]
13) Rare Genetic disorders
Congenital (inborn) neutropenia is a condition of low neutrophil levels from birth due to genetic disorders [63].
Benign ethnic neutropenia (BEN) is caused by a small genetic mutation and it’s found in 25% to 50% of people of African descent. However, it is not associated with an increased risk of infections commonly seen in other forms of congenital neutropenia [108, 109].
Other forms of congenital neutropenia include Kostmann’s syndrome and cyclic neutropenia [63].
Associated Diseases and Conditions
Type 1 Diabetes
Type 1 diabetes is an autoimmune disorder that causes the destruction of the cells that produce insulin (beta cells). Low neutrophil levels were associated with an increased risk of developing type 1 diabetes in a study of 436 people [110].
Genetics of Granulocytes
Gene Mutations and Neutropenia Risk
Out of 7 children with mutations in the VPS45 gene, all had low neutrophil levels (neutropenia) and neutrophil dysfunction [111].
Mutations in the CXCR4 gene are associated with WHIM syndrome, a rare immune disorder. WHIM patients have severe neutropenia because neutrophils do not exit the bone marrow [112].
People with Kostmann’s disease have neutrophil levels lower than 0.2 ×109/l. Some of the patients have mutations in ELA2 or HAX-1. Additionally, Kostmann’s patients can also acquire CSF3R gene mutations [31].
Chediak-Higashi patients have CHS1 gene mutations, which can cause neutropenia [31].
Shwachman-Diamond is a rare disorder, where the patients have defective neutrophil movement in the blood. An SBDS gene mutation is associated with neutropenia [31].
Gene Mutations and Neutrophilia Risk
A mutation in the CSF3R gene promotes neutrophil formation. This can lead to higher susceptibility for hereditary chronic neutrophilia [31].
PSTPIP1 mutation can play a role in neutrophilic dermatoses susceptibility [113].
Other Genes
People with the GPSM3 SNP rs204989 may have decreased GPSM3 production and be protected against rheumatoid arthritis. This specific variation reduces neutrophil movement to the inflammation site, which prevents long-term inflammation that is associated with arthritis [114].
A mutation in the RAC2 gene is associated with neutrophil dysfunction and can cause a person to be predisposed to bacterial infections. It is also associated with human immunodeficiency syndrome [115].
Pelger-Huët anomaly is a genetic disorder where the nucleus of neutrophils is in odd shapes. However, patients with this disorder are mostly healthy and neutrophils still function normally. A mutation in the LBR gene causes Pelger-Huët anomaly [31].
Eosinophils and Basophils
Check the specific genes and mutations associated with abnormal eosinophil and basophil levels.
Takeaway
Granulocytes (polymorphonuclear leukocytes) are white blood cells that fight pathogens and recycle damaged cells. They include neutrophils (the main ones), eosinophils, basophils, and mast cells. They can harm healthy cells and trigger inflammatory conditions by becoming over-active.
The normal range of granulocytes is 1.5 – 8.5 x 10^9/L. Values below indicate granulopenia and values above – granulocytosis. IG (immature granulocytes) above 1% may indicate infections or chronic inflammation.
Both low and high granulocytes can be caused by many different underlying health issues.
Talk to your doctor for an accurate diagnosis and effective treatment of the underlying causes of high or low granulocytes.
