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Lymphocytes are an essential part of the immune system.   Lymphocytes are a type of white blood cells that defend the body against external invaders such as viruses and bacteria, as well as internal threats such as cancer cells. 

They are an essential component of the adaptive immune system, which enables the body to remember and respond more effectively to pathogens it has encountered before. 

Lymphocytes are primarily found in the lymphatic system, which includes the lymph nodes, spleen, and thymus, but they also circulate in the bloodstream, surveilling for signs of infection or disease. 

There are three main types of lymphocytes, each with a specific function in the immune response: B cells, T cells, and natural killer (NK) cells. 

B cells are responsible for producing antibodies, which are proteins that specifically target and neutralize pathogens. 

T cells can be further divided into helper T cells, which assist in orchestrating the immune response, and cytotoxic T cells, which directly kill infected or malignant cells.

NK cells provide rapid responses to virally infected cells and respond to tumor formation, playing a role in the innate immune system by targeting cells that do not display "self" markers correctly.

The % lymphocytes test, also known as lymphocyte percentage or lymphocyte count, measures the proportion of lymphocytes in the total white blood cell count. 

What Are Lymphocytes?  What Do Lymphocytes Do?  [4., 6.]

Broadly, white blood cells, or immune cells, are known as leukocytes.  While an astonishing 1.6 billion leukocytes per kilogram body weight are produced daily (more than half of which are neutrophils), only 2-3% of leukocytes are in the peripheral blood.  The overwhelming majority are stored in the bone marrow.  [2.]

Lymphocytes are a type of white blood cell that circulates in the lymph and in the bloodstream.  There are two main types of lymphocytes: B cells and T cells.   

Lymphocytes are primarily produced in the bone marrow and then mature in the thymus gland (in the case of T cells) or remain in the bone marrow (in the case of B cells).  

B Cells

B cells are responsible for producing antibodies, which are proteins that target and neutralize specific pathogens such as bacteria, viruses, and toxins. When activated, B cells can differentiate into plasma cells which secrete large quantities of antibodies, providing a targeted immune response tailored to the invading pathogen. 

Each B cell is programmed to make a specific antibody. When a B cell encounters its triggering antigen, along with assistance from helper T cells, it begins to divide and mature into plasma cells that produce large quantities of its antibody. These antibodies neutralize pathogens directly or tag them for destruction by other parts of the immune system.

Additionally, B cells can also develop into memory B cells, which "remember" past infections and allow for a faster and more effective immune response upon re-exposure to the same pathogen.

T Cells

T cells, or T lymphocytes, originate from stem cells in the bone marrow but mature in the thymus.  They are further categorized into several types, each with a unique role in the immune response:

Helper T Cells (CD4+ T cells): These cells oversee and conduct the immune response. They do not directly kill infected cells; instead, they support other immune cells by secreting cytokines, substances that can stimulate or inhibit the activity of other immune cells. 

By doing so, they help organize the immune response against pathogens and are crucial in battling infections as well as in the immune system's memory.

Cytotoxic T Cells (CD8+ T cells): These are the primary means of destroying virus-infected cells and cancer cells. They recognize small fragments of the pathogen displayed by infected cells and directly kill these cells to prevent the spread of infection or the unregulated reproduction of cancer cells.

Regulatory T Cells (Tregs): These cells help maintain tolerance to self-antigens, preventing autoimmune diseases. They regulate or suppress other immune cells to ensure that the immune response does not become overactive and damage the body.

Natural Killer (NK) Cells

Natural Killer (NK) cells are effector lymphocytes of the innate immune system and play a crucial role in defending the body at the initial onset of an infection. 

They are known for their ability to recognize and kill infected cells as well as tumor cells without the need for prior activation by specific antigens, which is required for the adaptive immunity system. 

NK cells are also involved in the regulation of the immune response through the secretion of cytokines and growth factors. Unlike T and B cells, NK cells do not have antigen-specific receptors. 

Instead, they can recognize stressed cells in the absence of antibodies and MHC (major histocompatibility complex), allowing for a quicker response to infected or cancerous cells.

What Are Lymphocytes in Blood Tests?

A lymphocyte count is typically part of a complete blood count (CBC) with differential, which measures the types and numbers of cells in the blood including red blood cells, white blood cells (WBCs), and platelets. 

A complete blood count (CBC) is commonly ordered to assess overall health and detect a wide range of conditions, including infections, anemia, and various blood disorders, by providing information on the quantity and quality of different types of blood cells.

The CBC with differential provides detailed information about the total number of WBCs and breaks down the WBC count into the five major types of white blood cells including lymphocytes, monocytes, neutrophils, eosinophils, and basophils.  An elevated or decreased number of WBCs can signal a problem.

The lymphocyte count can be expressed as an absolute number or as a percentage of the total white blood cell count. 

Normal Lymphocyte Ranges

The normal range for lymphocyte counts can vary slightly depending on the laboratory and the individual's race, ethnicity and age.  However, in general, lymphocytes typically make up about 20% to 40% of the total white blood cell count. For adults, an absolute lymphocyte count in the range of 1,000 to 4,800 lymphocytes per microliter of blood is considered normal.

In children, the range can be significantly higher, reflecting the developing immune system's activity. It's important to consult with a healthcare provider or the specific reference ranges provided by the testing laboratory when interpreting lymphocyte counts.

One reference reports results as:  [2.]

Total leukocyte count: 3.0-11× 10^9/L

Absolute segmented neutrophil count: 1.5-7 × 10^9/L

Absolute lymphocyte count: 1-4.8 × 10^9/L

Absolute monocyte count: 0.1-0.8 × 10^9/L

Absolute eosinophil count: 0-0.4 × 10^9/L

Absolute basophil count: 0-0.2 × 10^9/L

Lymphocytes may also be described as a % of total white blood cells present on a CBC.  The % lymphocytes test, also known as lymphocyte percentage or lymphocyte count, measures the proportion of lymphocytes in the total white blood cell count. 

Knowing the proportion of lymphocytes relative to other types of WBCs may help to understand the relative balance of each type of WBC.  

Clinical Significance of Elevated Lymphocytes: What Do High Lymphocytes Mean?

Leukocytosis refers to an increase in total WBC count.  In adults, leukocytosis is defined as white blood cell (WBC) count > 11 × 10^9/L.  [2.] 

Hyperleukocytosis is typically defined as WBC > 100 × 10^9/L and is usually found in leukemias and myeloproliferative disorders.  [2.] 

Within leukocytosis it is important to understand which type of white blood cell is elevated.  The presence of high lymphocytes is called lymphocytosis, and is relatively common.  [3.]

Common causes of lymphocytosis include:  [3.]

• Infectious Causes:some text
  • Viral Infections:some text
    • Epstein-Barr Virus (EBV): Associated with infectious mononucleosis (IM).
    • Cytomegalovirus (CMV): Can resemble EBV IM symptoms.
    • Human Immunodeficiency Virus (HIV): Primary infection can lead to lymphocytosis.
    • Other Viruses: Influenza, hepatitis, mumps, measles, rubella, etc.
  • Bacterial Infections:some text
    • Bartonella henselae: Causes cat scratch disease with lymphadenopathy.
    • Bordetella Pertussis: Pertussis can show lymphocytosis.
    • Other: Brucellosis, syphilis, malaria.
  • Parasitic Infections:some text
    • Toxoplasma Gondii: Can cause toxoplasmosis with lymphocytosis.
    • Other: Babesiosis.
  • Mycobacterial Tuberculosis.
• Lymphoproliferative Disorders:some text
  • Chronic Lymphocytic Leukemia (CLL).
  • Non-Hodgkin Lymphoma (NHL): Different types like Mantle cell lymphoma (MCL), Marginal Zone Lymphoma (MZL), etc.
  • Hairy Cell Leukemia.
  • Large Granular Lymphocyte Leukemia (LGL).
  • Acute lymphoblastic lymphoma (ALL).
• Drugs and Drug Reactions:some text
  • Certain medications like allopurinol, carbamazepine, etc., can induce lymphocytosis.
• Monoclonal B Lymphocytosis (MBL).
• Congenital and Persistent B-cell Lymphocytosis:
• Due to genetic mutations or other congenital factors.
• Stress-Related Lymphocytosis.
• Asplenia-Related Lymphocytosis: Post-splenectomy increase in lymphocytes.

Clinical Significance of Decreased Lymphocytes: What Do Low Lymphocytes Mean?

Decreased lymphocyte levels are also called lymphopenia or lymphocytopenia.  The causes of lymphocytopenia are either inherited, or acquired (meaning that rather than being inherited, it’s acquired at some point in life).   

Common causes of lymphocytopenia include:  [4.]

• Inherited Causes of Lymphopenia:some text
  • Ataxia telangiectasia
  • Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome)
  • Common variable immunodeficiency
  • Severe combined immunodeficiency syndrome (SCID)
  • Wiskott-Aldrich syndrome
• Acquired Causes of Lymphopenia:some text
  • Infections: HIV, viral hepatitis, influenza, SARS-CoV-2 (COVID-19), tuberculosis, pneumonia, sepsis, malaria.
  • Autoimmune Disorders: Sjögren’s syndrome, lupus, rheumatoid arthritis.
  • Blood Cancer and Other Blood Diseases: Hodgkin's disease, aplastic anemia.
  • Medical Treatments: Blood and bone marrow transplant, cancer treatment, steroid therapy, major surgery.
  • Lifestyle Factors: Excessive alcohol consumption, poor nutrition (inadequate protein or other nutrients).

When to Worry About Low Lymphocytes

It's important to consider low lymphocyte counts in the context of other symptoms and test results. Isolated lymphocytopenia without any symptoms might not be an immediate cause for concern but should be monitored. 

Persistent low levels, especially if accompanied by other abnormal blood counts or symptoms like frequent infections, unexplained fatigue, or weight loss, warrant further investigation to identify and address the underlying cause.

Understanding Neutrophils and Lymphocytes

Neutrophils are the most abundant type of white blood cells and are part of the innate immune system. They are among the body's first responders to infection, particularly bacterial infections, and are known for their ability to quickly respond to and neutralize invading pathogens. 

Lymphocytes, as discussed, are pivotal mostly in the adaptive immune response, with roles in fighting viruses, bacteria, and cancer cells, and in maintaining immune memory.

Why Would Neutrophils Be High and Lymphocytes Be Low?

A high neutrophil count coupled with a low lymphocyte count can be indicative of several conditions:  [1.] 

• Acute Bacterial Infections: The body responds to bacterial invasions by increasing the production of neutrophils to fight off the infection, which can simultaneously cause a relative decrease in lymphocytes.
• Acute Stress Response: Stress, whether physical (such as surgery or trauma) or emotional, can lead to a surge in neutrophils as part of the body's immediate stress response. This can also result in a temporary decrease in lymphocyte levels, reflecting a shift in the body's priorities to address the immediate challenge.
• Steroid Use: Corticosteroids, used to treat a variety of conditions, can cause an increase in neutrophils and a decrease in lymphocytes due to their immunosuppressive effects.
• Chronic Inflammatory Conditions: Conditions like rheumatoid arthritis or severe inflammation can lead to elevated neutrophil levels and decreased lymphocytes over time, reflecting the body's ongoing battle with inflammation.

Lab Testing for Lymphocytes

The evaluation of lymphocyte levels is a critical component of routine blood work, especially in the assessment of an individual's immune system status and in diagnosing a variety of conditions. 

The primary laboratory test used for this purpose is the Complete Blood Count (CBC) with differential.

A venipuncture is required for this test.  Fasting is not required.

Complete Blood Count (CBC) with Differential

The CBC is one of the most common blood tests and provides comprehensive information about the blood, including red cells, white cells, and platelets. 

When performed with a differential count, the test goes further to quantify the different types of white blood cells including neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

Related Biomarkers to Test

When assessing an individual's immune status or diagnosing specific conditions, lymphocyte counts provide valuable information but often need to be considered in conjunction with other biomarkers for a comprehensive evaluation. 

Various additional tests and biomarkers can offer deeper insights into the immune system's functioning, the presence of autoimmune diseases, infections like HIV, and more. Below are some key biomarkers and tests that are commonly used alongside lymphocyte counts:

CD4 Count and HIV Infection

• CD4 Count: This test measures the number of CD4 T cells in the blood, a specific type of lymphocyte that HIV primarily targets and destroys. A CD4 count is crucial for assessing the immune function of individuals infected with HIV and guiding treatment decisions, including when to start antiretroviral therapy.
• HIV Viral Load: This test measures the amount of HIV RNA in the blood and is used alongside CD4 counts to monitor the effectiveness of HIV treatment. A lower viral load indicates successful suppression of the virus, while an increase can signal treatment failure or resistance.

Markers for Autoimmune Diseases

• Antinuclear Antibodies (ANA): ANA testing is often used when autoimmune diseases are suspected. These antibodies, which target the body's own tissues, are commonly found in conditions like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome.
• Rheumatoid Factor (RF) and Anti-CCP: These are specific antibodies tested for in the diagnosis of rheumatoid arthritis. RF is found in about 80% of people with RA, while anti-CCP is more specific and can indicate the likelihood of developing RA.
• ESR and CRP: The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) tests measure inflammation in the body, which can be elevated in autoimmune diseases and infections. These markers are not specific to any one disease but can indicate the presence of an inflammatory process.

Inflammatory Markers

• C-reactive Protein (CRP): Beyond its role in diagnosing autoimmune diseases, CRP is a broad biomarker for inflammation and can indicate inflammatory illnesses, infections, and chronic diseases.
• Erythrocyte Sedimentation Rate (ESR): Similar to CRP, ESR is another non-specific marker of inflammation. High levels may suggest an ongoing inflammatory process, but like CRP, ESR must be interpreted in the context of other clinical findings.

When used together, these biomarkers and tests can provide a detailed picture of an individual's immune status and help diagnose a wide range of conditions. The choice of specific tests depends on the suspected condition, symptoms, and the initial findings from basic tests like the CBC with differential and lymphocyte counts. 

Importantly, interpreting these tests requires expertise and should be done within the broader context of the patient's clinical presentation and history.

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