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Granulocytes: Immature, High, Low & Normal Levels

Written by Will Hunter, BA (Psychology) | Last updated:
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Will Hunter, BA (Psychology) | Last updated:

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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, autoimmune diseases, and cancer. Low levels are most often caused by infections and drugs. 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]:

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).

Granulocytes are white blood cells that fight pathogens and recycle damaged cells. Neutrophils are the most abundant type of granulocytes.

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].

Granulocytes engulf and destroy various pathogens at the site of inflammation. In some inflammatory conditions, they become overactive and harm healthy cells.

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 pathogens.

However, these compounds can also cause damage to surrounding healthy tissue, which can lead to delayed healing and excess scarring [7].

Neutrophils also produce immune messengers called cytokines (IL-6 and TNF-a) that recruit other immune cells [7, 8].

Neutrophils are the most abundant immune cells that initiate an inflammatory response and recruit other cells. In excess, they can damage healthy tissue.

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].

Eosinophils fight parasites and control blood sugar, but they can also trigger allergies and asthma. They mostly reside in the gut, ovaries, and lymph nodes.

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 activated, they release the contents of their granules, which includes 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].

Basophils help the immune system fight pathogens by releasing histamine and heparin, which increase blood flow. They can contribute to allergies and autoimmunity.

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].

Mast cells fight foreign invaders and are abundant in the skin, lungs, and gut. They release histamine and can contribute to asthma, allergies, and autoimmunity.

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 measured as part of a standard complete blood count (CBC) test.

Lab results are commonly shown as a set of values known as a reference range, which is sometimes referred to as a “normal range.” A reference range includes upper and lower limits of a lab test based on a group of otherwise healthy people.

Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.

The normal range of granulocytes is 1.5 – 8.5 x 10^9/L or between 1,500 and 8,500 cells per microliter (µL) of blood.

Levels below this range are referred to as granulopenia or 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 or neutrophilia.

Under normal conditions, the immature granulocyte percentage (IG%) in our blood is less than 1%. Immature granulocyte levels increase rapidly during infections, inflammation, or cancer [26, 29].

The normal range of granulocytes is 1.5 – 8.5 x 10^9/L. Values below indicate granulopenia (neutropenia) and values above – granulocytosis or neutrophilia. IG% should be <1.

High Granulocytes (Granulocytosis)

Common Causes

The causes we discuss here are commonly associated with granulocytosis. 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, their levels increase during infections from bacteria, fungi, viruses, and parasites [30, 31, 32].

2) Cancer

By increasing a protein called granulocyte colony stimulating factor (G-CSF), many cancers can cause granulocytosis. These include [33, 34, 35, 36, 37]:

  • Lung
  • Stomach
  • Breast
  • Skin
  • Brain
  • Uterine
  • Lymphoma (cancer of the lymphatic system)
  • Chronic myeloid leukemia (cancer of the bone marrow)

3) 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 [38, 39]:

  • Chronic myeloid leukemia (bone marrow cancer, as mentioned above)
  • Essential thrombocytosis
  • Primary myelofibrosis

4) Autoimmune Disorders

Some autoimmune disorders are associated with granulocytosis, most notably rheumatoid arthritis [40].

The most common causes of high granulocytes include infection, bone disorders, and cancer.

5) 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 [38].

6) 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 [41].

7) 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 [42, 31].

8) Surgery

Granulocyte levels increased in ten patients who underwent elective spine surgery due to an increase in cortisol [43].

8) Appendicitis

Granulocyte levels were substantially higher in patients with appendicitis in a study of 456 people [44].

9) Heart Attack

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 [45, 46].

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 [47].

2) Fatigue and Stress

Higher neutrophil levels were linked to fatigue due to stressful work in 213 people [48].

3) Heart Disease

Neutrophils can accumulate in plaques in the artery walls and contribute to hardened arteries (atherosclerosis) [49].

High neutrophil and eosinophil levels are linked to an increased risk of heart disease, heart attack, stroke, and death from heart disease [50, 51, 52, 53, 54, 55, 56, 57].

There’s a link between high granulocytes and high blood pressure, heart disease, and fatigue due to stress at work.

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) Cancer Treatment

Radiation therapy for cancer can destroy neutrophil precursors in the bone marrow, which causes low granulocyte levels [58, 59, 60].

2) 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, 61, 60, 62].

3) 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 [63, 64, 65].

4) Autoimmune Diseases

In autoimmune neutropenia, antibodies attack and destroy neutrophils, which results in low granulocyte levels [66, 67].

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 [68, 69, 70, 67].

Felty’s syndrome, a complication of rheumatoid arthritis, can result in low granulocyte levels [71, 72].

Low granulocyte levels are also a common feature of Sjögren’s syndrome, an autoimmune disease that causes dry eyes and mouth [73].

People with autoimmune diseases – including lupus and rheumatoid arthritis – often have low neutrophils.

5) 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

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 [74, 75, 70, 60].

Iron deficiency can also lead to granulopenia, but the mechanism is still unknown [62].

7) Inborn Neutropenia

Congenital (inborn) neutropenia is a condition of low neutrophil levels from birth due to genetic disorders [60].

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 [76, 77].

Other forms of congenital neutropenia include Kostmann’s syndrome and cyclic neutropenia [60].

Inborn neutropenia is a genetic disorder that can be benign or symptomatic.

8) Enlarged Spleen

Hypersplenism is a common disorder characterized by an enlarged spleen. An enlarged spleen traps neutrophils leading to low granulocyte levels in the blood [78, 70, 79].

9) 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 [80].

10) 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 [80, 81].

11) 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 [82, 83].

12) 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 [84, 85, 86].

Low granulocytes can be due to nutrient deficiency, autoimmune and bone marrow disorders, viral infections, genetic mutations, thyroid disorders, and severe burns.

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 [87].

Effects of Drugs on Granulocytes Levels

Drugs associated with increased granulocyte levels include:

Drugs associated with decreased granulocyte levels include:

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 [110].

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 [111].

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].

Mutations in certain genes – such as VPS45, CXCR4, HAX-1, ELA2, CHS1, and SBDS – are associated with rare genetic disorders with neutropenia.

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 [112].

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 [113].

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 [114].

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].

Certain genetic mutations can prevent neutrophil over-activation (GPSM3 gene) or impair their function (RAC2 gene) or shape (LBR gene).

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 (neutropenia) and values above – granulocytosis or neutrophilia. IG (immature granulocytes) above 1% may indicate infections or chronic inflammation.

Low granulocytes can occur due to nutrient deficiency, autoimmune and bone marrow disorders, viral infections, genetic mutations, thyroid disorders, and severe burns.

Talk to your doctor for an accurate diagnosis and effective treatment of the underlying causes of high or low granulocytes.

Irregular Granulocyte Levels?

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About the Author

Will Hunter

BA (Psychology)
Will received his BA in Psychology from the University of California, Los Angeles. 
Will's main passion is learning how to optimize physical and mental performance through diet, supplement, and lifestyle interventions. He focuses on systems thinking to leverage technology and information and help you get the most out of your body and brain.

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