Lymphocytes: Definition, Ranges,Count & Functions

 Lymphocytes: Definition, Ranges,Count & Functions 

 Lymphocytes: Definition, Ranges,Count & Functions 

Definition 

Lymphocytes are one of several different types of white blood cells. Each type of white blood cell has a specific function, and they all work together to fight illness and disease.

White blood cells are an important part of your immune system. They help your body fight antigens, which are bacteria, viruses, and other toxins that make you sick. If your doctor says you have a weakened immune system, that means there aren’t enough white blood cells in your bloodstream.

 Lymphocytes: Definition, Ranges,Count & Functions 

Normal ranges and levels

Lymphocyte levels can change according to a person’s race, gender, location, and lifestyle habits.

The normal lymphocyte range in adults is between 1,000 and 4,800 lymphocytes in 1 microliter (µL) of blood. In children, the normal range is between 3,000 and 9,500 lymphocytes in 1 µL of blood.

Unusually high or low lymphocyte counts can be a sign of disease.

 Lymphocytes: Definition, Ranges,Count & Functions 

Lymphocyte Counts

Lymphocytes are a component of complete blood count (CBC) tests that include a white blood cell differential, in which the levels of the major types of white blood cells are measured. Such tests are used to assist in the detection, diagnosis, and monitoring of various medical conditions. Lymphocyte counts that are below the reference range, which varies for adults and children, may be indicative of lymphocytopenia (lymphopenia), whereas those above it are a sign of lymphocytosis. Lymphocytopenia is associated with a variety of conditions, ranging from malnutrition to rare inherited disorders such as ataxia-telangiectasia or severe combined immunodeficiency syndrome. Lymphocytosis typically is associated with infections, such as mononucleosis or whooping cough, certain cancers of the blood or lymphatic system such as multiple myeloma and chronic lymphocytic leukemia, and autoimmune disorders that cause chronic inflammation, such as inflammatory bowel disease.

What causes a low lymphocyte count?

A low lymphocyte count, called lymphocytopenia, usually occurs because:

• your body isn’t producing enough lymphocytes
• lymphocytes are being destroyed
• lymphocytes are trapped in your spleen or lymph nodes

Lymphocytopenia can point to a number of conditions and diseases. Some, like the flu or mild infections, aren’t serious for most people. But a low lymphocyte count puts you at greater risk of infection.

Other conditions that can cause lymphocytopenia include:

• undernutrition
• HIV and AIDS
• influenza
• autoimmune conditions, such as lupus
• some cancers, including lymphocytic anemia, lymphoma, and Hodgkin disease
• steroid use
• radiation therapy
• certain drugs, including chemotherapy drugs
• some inherited disorders, such as Wiskott-Aldrich syndrome and DiGeorge syndrome

What causes a high lymphocyte count

Lymphocytosis, or a high lymphocyte count, is common if you’ve had an infection. High lymphocyte levels that persist may point to a more serious illness or disease, such as:

• viral infections, including measles, mumps, and mononucleosis
• adenovirus
• hepatitis
• influenza
• tuberculosis
• toxoplasmosis
• cytomegalovirus
• brucellosis
• vasculitis
• acute lymphocytic leukemia
• chronic lymphocytic leukemia
• HIV and AIDS

 Lymphocytes: Definition, Ranges,Count & Functions 

Roles and functions

There are different types of B cells and T cells that have specific roles in the body and the immune system.

B cells

Memory B cells

Memory B cells circulate in the body to start a fast antibody response when they find a foreign substance. They remain in the body for decades and become memory cells, which remember previously found antigens and help the immune system respond faster to future attacks.

Regulatory B cells

Regulatory B cells or Bregs make up around 0.5 percent of all B cells in healthy people. Although few in number, they have a vital role to play.

Bregs have protective anti-inflammatory effects in the body and stop lymphocytes that cause inflammation. They also interact with several other immune cells and promote the production of regulatory T cells or Tregs.

T cells

Killer T cells

Killer or cytotoxic T cells scan the surface of cells in the body to see if they have become infected with germs, or if they have turned cancerous. If so, they kill these cells.

Helper T cells

Helper T cells “help” other cells in the immune system to start and control the immune response against foreign substances.

There are different types of helper T cells, and some are more effective than others against different types of germs.

For instance, a Th1 cell is more effective against germs that cause infection inside other cells, such as bacteria and viruses, while a Th2 cell is more effective against germs that cause infection outside of cells, such as certain bacteria and parasites.

Regulatory T cells or Tregs

Tregs control or suppress other cells in the immune system. They have both helpful and harmful effects.

They maintain tolerance to germs, prevent autoimmune diseases, and limit inflammatory diseases. But they can also suppress the immune system from doing its job against certain antigens and tumors.

Memory T cells

Memory T cells protect the body against previously found antigens. They live for a long time after an infection is over, helping the immune system to remember previous infections.

If the same germ enters the body a second time, memory T cells remember it and quickly multiply, helping the body to fight it more quickly.

Natural killer T cells

Natural killer T cells are a mixed group of T cells that share characteristics of both T cells and natural killer cells. They can influence other immune cells and control immune responses against substances in the body that trigger an immune response.

The Molecular Mechanism of Natural Killer Cells Function

   
The Molecular Mechanism of Natural        Killer Cells Function

Cytolytic granule mediated cell apoptosis

Cytolytic granule mediated cell apoptosis

NK cells are cytotoxic; small granules in their cytoplasm contain proteins such as perforin and proteases known as granzymes. Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through which the granzymes and associated molecules can enter, inducing either apoptosis or osmotic cell lysis. The distinction between apoptosis and cell lysis is important in immunology: lysing a virus-infected cell could potentially only release the virions, whereas apoptosis leads to destruction of the virus inside. α-defensins, antimicrobial molecules, are also secreted by NK cells, and directly kill bacteria by disrupting their cell walls in a manner analogous to that of neutrophils.^[3]

Antibody-dependent cell-mediated cytotoxicity

Antibody-dependent cell-mediated cytotoxicity

Infected cells are routinely opsonized with antibodies for detection by immune cells. Antibodies that bind to antigens can be recognised by FcϒRIII (CD16) receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis. This is a major killing mechanism of some monoclonal antibodies like rituximab (Rituxan), ofatumumab (Azzera), and others. The contribution of antibody-dependent cell-mediated cytotoxicity to tumor cell killing can be measured with a specific test that uses NK-92 that has been transfected with a high-affinity FcR. Results are compared to the "wild type" NK-92 that does not express the FcR.^[9]

Cytokine-induced NK and Cytotoxic T lymphocyte (CTL) activation

Cytokines play a crucial role in NK cell activation. As these are stress molecules released by cells upon viral infection, they serve to signal to the NK cell the presence of viral pathogens in the affected area. Cytokines involved in NK activation include IL-12, IL-15, IL-18, IL-2, and CCL5. NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response generates antigen-specific cytotoxic T cells that can clear the infection. NK cells work to control viral infections by secreting IFNγ and TNFα. IFNγ activates macrophages for phagocytosis and lysis, and TNFα acts to promote direct NK tumor cell killing. Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection.

Missing 'self' hypothesis

For NK cells to defend the body against viruses and other pathogens, they require mechanisms that enable the determination of whether a cell is infected or not. The exact mechanisms remain the subject of current investigation, but recognition of an "altered self" state is thought to be involved. To control their cytotoxic activity, NK cells possess two types of surface receptors: activating receptors and inhibitory receptors, including killer-cell immunoglobulin-like receptors. Most of these receptors are not unique to NK cells and can be present in some T cell subsets, as well.

The inhibitory receptors recognize MHC class I alleles, which could explain why NK cells preferentially kill cells that possess low levels of MHC class I molecules. This mode of NK cell target interaction is known as "missing-self recognition", a term coined by Klas Kärre and co-workers in the late 90s. MHC class I molecules are the main mechanism by which cells display viral or tumor antigens to cytotoxic T cells. A common evolutionary adaptation to this is seen in both intracellular microbes and tumors: the chronic down-regulation of MHC I molecules, which makes affected cells invisible to T cells, allowing them to evade T cell-mediated immunity. NK cells apparently evolved as an evolutionary response to this adaptation (the loss of the MHC eliminates CD4/CD8 action, so another immune cell evolved to fulfill the function).^[10]

Tumor cell surveillance

Tumor cell surveillance

Natural killer cells often lack antigen-specific cell surface receptors, so are part of innate immunity, i.e. able to react immediately with no prior exposure to the pathogen. In both mice and humans, NKs can be seen to play a role in tumor immunosurveillance by directly inducing the death of tumor cells (NKs act as cytolytic effector lymphocytes), even in the absence of surface adhesion molecules and antigenic peptides. This role of NK cells is critical to immune success particularly because T cells are unable to recognize pathogens in the absence of surface antigens.^[1] Tumor cell detection results in activation of NK cells and consequent cytokine production and release.

If tumor cells do not cause inflammation, they will also be regarded as self and will not induce a T cell response. A number of cytokines are produced by NKs, including tumor necrosis factor α (TNFα), IFNγ, and interleukin (IL-10). TNFα and IL-10 act as proinflammatory and immunosuppressors, respectively. The activation of NK cells and subsequent production of cytolytic effector cells impacts macrophages, dendritic cells, and neutrophils, which subsequently enables antigen-specific T and B cell responses. Instead of acting via antigen-specific receptors, lysis of tumor cells by NK cells is mediated by alternative receptors, including NKG2D, NKp44, NKp46, NKp30, and DNAM.NKG2D is a disulfide-linked homodimer which recognizes a number of ligands, including ULBP and MICA, which are typically expressed on tumor cells. The role of dendritic cell—NK cell interface in immunobiology have been studied and defined as critical for the comprehension of the complex immune system.^{[citation needed]}

^{NK cells, along with macrophages and several other cell types, express the Fc receptor (FcR) molecule (FC-gamma-RIII = CD16), an activating biochemical receptor that binds the Fc portion of IgG class antibodies. This allows NK cells to target cells against which a humoral response has been gone through and to lyse cells through antibody-dependant cytotoxicity (ADCC). This response depends on the affinity of the Fc receptor expressed on NK cells, which can have high, intermediate, and low affinity for the Fc portion of the antibody. This affinity is determined by the amino acid in position 158 of the protein, which can be phenylalanine (F allele) or valine (V allele). Individuals with high-affinity FcRgammRIII (158 V/V allele) respond better to antibody therapy. This has been shown for lymphoma patients who received the antibody Rituxan. Patients who express the 158 V/V allele had a better antitumor response. Only 15–25% of the population expresses the 158 V/V allele. To determine the ADCC contribution of monoclonal antibodies, NK-92 cells (a "pure" NK cell line) has been transfected with the gene for the high-affinity FcR.}

^{Adaptive features of NK cells—"memory-like", "adaptive" and memory NK cells}

^{The ability to generate memory cells following a primary infection and the consequent rapid immune activation and response to succeeding infections by the same antigen is fundamental to the role that T and B cells play in the adaptive immune response. For many years, NK cells have been considered to be a part of the innate immune system. However, recently increasing evidence suggests that NK cells can display several features that are usually attributed to adaptive immune cells (e.g. T cell responses) such as dynamic expansion and contraction of subsets, increased longevity and a form of immunological memory, characterized by a more potent response upon secondary challenge with the same antigen. In mice, the majority of research was carried out with murine cytomegalovirus (MCMV) and in models of hapten-hypersensitivity reactions. Especially, in the MCMV model, protective memory functions of MCMV-induced NK cells were discovered  and direct recognition of the MCMV-ligand m157 by the receptor Ly49 was demonstrated to be crucial for the generation of adaptive NK cell responses.In humans, most studies have focused on the expansion of an NK cell subset carrying the activating receptor NKG2C (KLRC2). Such expansions were observed primarily in response to human cytomegalovirus (HCMV),[14] but also in other infections including Hantavirus, Chikungunya virus, HIV, or viral hepatitis. However, whether these virus infections trigger the expansion of adaptive NKG2C+ NK cells or whether other infections result in re-activation of latent HCMV (as suggested for hepatitis ), remains a field of study. Notably, recent research suggests that adaptive NK cells can use the activating receptor NKG2C (KLRC2) to directly bind to human cytomegalovirus-derived peptide antigens and respond to peptide recognition with activation, expansion, and differentiation,a mechanism of responding to virus infections that was previously only known for T cells of the adaptive immune system.}

^{NK cell function in pregnancy}

^{As the majority of pregnancies involve two parents who are not tissue-matched, successful pregnancy requires the mother's immune system to be suppressed. NK cells are thought to be an important cell type in this process.These cells are known as "uterine NK cells" (uNK cells) and they differ from peripheral NK cells. They are in the CD56bright NK cell subset, potent at cytokine secretion, but with low cytotoxic ability and relatively similar to peripheral CD56bright NK cells, with a slightly different receptor profile.These uNK cells are the most abundant leukocytes present in utero in early pregnancy, representing about 70% of leukocytes here, but from where they originate remains controversial.}

^{These NK cells have the ability to elicit cell cytotoxicity in vitro, but at a lower level than peripheral NK cells, despite containing perforin. Lack of cytotoxicity in vivo may be due to the presence of ligands for their inhibitory receptors. Trophoblast cells downregulate HLA-A and HLA-B to defend against cytotoxic T cell-mediated death. This would normally trigger NK cells by missing self recognition; however, these cells survive. The selective retention of HLA-E (which is a ligand for NK cell inhibitory receptor NKG2A) and HLA-G(which is a ligand for NK cell inhibitory receptor KIR2DL4) by the trophoblast is thought to defend it against NK cell-mediated death.}

Uterine NK cells have shown no significant difference in women with recurrent miscarriage compared with controls. However, higher peripheral NK cell percentages occur in women with recurrent miscarriages than in control groups.

NK cells secrete a high level of cytokines which help mediate their function. NK cells interact with HLA-C to produce cytokines necessary for trophoblastic proliferation. Some important cytokines they secrete include TNF-α, IL-10, IFN-γ, GM-CSF and TGF-β, among others. For example, IFN-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site.

NK cell evasion by tumor cells

By shedding decoy NKG2D soluble ligands, tumor cells may avoid immune responses. These soluble NKG2D ligands bind to NK cell NKG2D receptors, activating a false NK response and consequently creating competition for the receptor site. This method of evasion occurs in prostate cancer. In addition, prostate cancer tumors can evade CD8 cell recognition due to their ability to downregulate expression of MHC class 1 molecules. This example of immune evasion actually highlights NK cells' importance in tumor surveillance and response, as CD8 cells can consequently only act on tumor cells in response to NK-initiated cytokine production (adaptive immune response).

The Molecular Mechanism of Natural Killer Cells

Natural killer cell

 The Molecular Mechanism of Natural Killer Cells

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the initial notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1.^[1] This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

 The Molecular Mechanism of Natural Killer Cells

NK cells (belonging to the group of innate lymphoid cells) are one of the three kinds of cells differentiated from the common lymphoid progenitor, the other two being B and T lymphocytes.^[2] NK cells are known to differentiate and mature in the bone marrow, lymph nodes, spleen, tonsils, and thymus, where they then enter into the circulation.^[3] NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting interferon gamma. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD57 in humans, NK1.1 or NK1.2 in C57BL/6 mice. The NKp46 cell surface marker constitutes, at the moment, another NK cell marker of preference being expressed in both humans, several strains of mice (including BALB/c mice) and in three common monkey species.^[4][5]

 The Molecular Mechanism of Natural Killer Cells

In addition to the knowledge that natural killer cells are effectors of innate immunity, recent research has uncovered information on both activating and inhibitory NK cell receptors which play important functional roles, including self tolerance and the sustaining of NK cell activity. NK cells also play a role in the adaptive immune response:^[6] numerous experiments have demonstrated their ability to readily adjust to the immediate environment and formulate antigen-specific immunological memory, fundamental for responding to secondary infections with the same antigen.^[7] The role of NK cells in both the innate and adaptive immune responses is becoming increasingly important in research using NK cell activity as a potential cancer therapy.

Monocytes under a light microscope from a peripheral blood smear surrounded by red blood cells

                      Monocyte

Fig:Monocytes under a light microscope from a peripheral blood smear surrounded by red blood cells

Monocytes are a type of leukocyte, or white blood cell. They are the largest type of leukocyte and can differentiate into macrophages and myeloid lineage dendritic cells. As a part of the vertebrate innate immune system monocytes also influence the process of adaptive immunity. There are at least three subclasses of monocytes in human blood based on their phenotypic receptors.

Structure

                  Fig:3D Rendering of a Monocyte

Monocytes are amoeboid in appearance, and have nongranulated cytoplasm.^[1], thus are classified as agranulocytes. Containing unilobar nuclei, these cells are one of the types of mononuclear leukocytes which shelter azurophil granules. The archetypal geometry of the monocyte nucleus is ellipsoidal; metaphorically bean-shaped or kidney-shaped, although the most significant distinction is that the nuclear envelope should not be hyperbolically furcated into lobes. Contrast to this classification occurs in polymorphonuclear leukocytes. Monocytes compose 2% to 10% of all leukocytes in the human body and serve multiple roles in immune function. Such roles include: replenishing resident macrophages under normal conditions; migration within approximately 8–12 hours in response to inflammation signals from sites of infection in the tissues; and differentiation into macrophages or dendritic cells to effect an immune response. In an adult human, half of the monocytes are stored in the spleen.^[2] These change into macrophages after entering into appropriate tissue spaces, and can transform into foam cells in endothelium.

Development

Monocytes are produced by the bone marrow from precursors called monoblasts, bipotent cells that differentiated from hematopoietic stem cells. Monocytes circulate in the bloodstream for about one to three days and then typically move into tissues throughout the body where they differentiate into macrophages and dendritic cells. They constitute between three and eight percent of the leukocytes in the blood. About half of the body's monocytes are stored as a reserve in the spleen in clusters in the red pulp's Cords of Billroth.^[2] Moreover, monocytes are the largest corpuscle in blood.^[13]

Fig:Monocytes involved in regulation of hematopoiesis

Monocytes which migrate from the bloodstream to other tissues will then differentiate into tissue resident macrophages or dendritic cells. Macrophages are responsible for protecting tissues from foreign substances, but are also suspected to be important in the formation of important organs like the heart and brain. They are cells that possess a large smooth nucleus, a large area of cytoplasm, and many internal vesicles for processing foreign material.

 Function

Monocytes and their macrophage and dendritic cell progeny serve three main functions in the immune system. These are phagocytosis, antigen presentation, and cytokine production. Phagocytosis is the process of uptake of microbes and particles followed by digestion and destruction of this material. Monocytes can perform phagocytosis using intermediary (opsonising) proteins such as antibodies or complement that coat the pathogen, as well as by binding to the microbe directly via pattern-recognition receptors that recognize pathogens. Monocytes are also capable of killing infected host cells via antibody-dependent cell-mediated cytotoxicity. Vacuolization may be present in a cell that has recently phagocytized foreign matter.

Many factors produced by other cells can regulate the chemotaxis and other functions of monocytes. These factors include most particularly chemokines such as monocyte chemotactic protein-1 (CCL2) and monocyte chemotactic protein-3 (CCL7); certain arachidonic acid metabolites such as Leukotriene B4 and members of the 5-Hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid family of OXE1 receptor agonists (e.g., 5-HETE and 5-oxo-ETE); and N-Formylmethionine leucyl-phenylalanine and other N-formylated oligopeptides which are made by bacteria and activate the formyl peptide receptor 1.^[15]

               Fig: Structure of Monocytes 

Microbial fragments that remain after such digestion can serve as antigens. The fragments can be incorporated into MHC molecules and then trafficked to the cell surface of monocytes (and macrophages and dendritic cells). This process is called antigen presentation and it leads to activation of T lymphocytes, which then mount a specific immune response against the antigen.

Other microbial products can directly activate monocytes and this leads to production of pro-inflammatory and, with some delay, of anti-inflammatory cytokines. Typical cytokines produced by monocytes are TNF, IL-1, and IL-12.