Cells of immune system

Cells of immune system

The immune response to an antigen can be of two types – Humoral or antibody mediated immunity (AMI) and cellular or cell mediated immunity (CMI).  Humoral immunity is mediated by antibodies produced by B cells (plasma cells) and is present in blood and other body fluids (Hence the name humoral from humor that means body fluids).  Cellular immunity is mediated directly by T lymphocytes and macrophages.

Immune system is maintained by the lymphoreticular system which is a complex organization of cells of diverse morphology and is distributed in different parts of the body. Lymphoreticular cells include lymphoid cells and reticuloendothelial cells.

Lymhoid system consists of the lymphoid cells and the lymphoid organs.

Lymphoid cells are involved in specific immune response.  They include lymphocytes.  Lymphocytes possess the attributes of diversity, specificity, memory, and self/nonself recognition, which are the hallmarks of an adaptive immune response.  Lymphoid organs are classified into two – central (primary) and peripheral (secondary) lymphoid organs.  The precursor lymphocytes proliferate, develop and acquire immunologic capability or competence in primary lymphoid organs.  From here, the lymphocytes migrate through blood and lymph and accumulate in secondary lymphoid organs where they encounter antigen and evoke immune response or immune tolerance.  Thymus, Bursa of Fabricius and Bone marrow are primary lymphoid organs.  Spleen, lymph nodes and mucosa associated lymphoid tissue (MALT) are secondary lymphoid organs.

Reticuloendothelial cells comprise of phagocytic cells.  They contribute to non-specific immunity.  They play accessory roles in adaptive immunity, by activating lymphocytes, increasing the effectiveness of antigen clearance by phagocytosis, or by secreting various immune-effector molecules (Cytokines).These cells engulf microbes, immune complex and cells and participate in inflammation.

All these cells arise from a type of cell called the hematopoietic stem cell (HSC).  Stem cells are cells that can differentiate into other cell types; they are self-renewing—they maintain their population level by cell division.  A hematopoietic stem cell is multipotent, or pluripotent, it is able to differentiate in various ways and thereby generate erythrocytes, granulocytes, monocytes, mast cells, lymphocytes and megakaryocytes. These stem cells are normally less than one HSC per 5x10⁴ cells in the bone marrow.

In hematopoiesis, a multipotent stem cell differentiates along one of two pathways, giving rise to either a common lymphoid progenitor cell or a common myeloid progenitor cell.

Common lymphoid progenitor cells give rise to B, T, and NK (natural killer or null) cells and some dendritic cells. 

Myeloid stem cells generate progenitors of red blood cells (erythrocytes), various white blood cells (neutrophils, eosinophils, basophils, monocytes, mast cells, dendritic cells) and platelets. 

Progenitor commitment or differentiation into any type of cell depends on the responsiveness to particular growth factors and cytokines such as colony-stimulating factors (CSFs), erythropoietin (EPO), etc.

In bone marrow, hematopoietic cells grow and mature on a meshwork of stromal cells, which are non-hematopoietic cells. Stromal cells include fat cells, endothelial cells, fibroblasts, and macrophages. Stromal cells influence the differentiation of hematopoietic stem cells by providing a hematopoietic-inducing microenvironment (HIM) consisting of a cellular matrix and factors that promote growth and differentiation.

       A. Lymphoid Cells

Lymphocytes are small, round cells found in blood, lymph, lymphoid organs and in many other tissues.  They constitute 20%–40% of white blood cells (leukocytes) and 99% of the cells in the lymph. There are approximately 10¹¹ lymphocytes in the human body. These lymphocytes continually circulate in the blood and lymph and are capable of migrating into the tissue spaces and lymphoid organs. 

According to their size, they are classified into three – small (5-8 µm), medium (8-12 µm) and large (12-15 µm).  Small lymphocytes are most numerous and they consist of a spherical nucleus and a thin rim of cytoplasm containing numerous ribosomes.  They are capable of slow motility. 

Depending on life span lymphocytes are of two, short lived (effector cells, about two weeks) and long lived (memory cells, three years to up to life long). 

The lymphocytes can be broadly subdivided into three populations based on the presence or absence of surface antigens or markers.  These markers are known as cluster of differentiation (CD) and are given a particular number.  There are over 150 CD markers identified so far.  The three classes are B cells, T cells, and natural killer cells or null cells.  T cells are involved in cell-mediated immunity, whereas B cells are primarily responsible for humoral immunity. 

The B lymphocyte derived its designation from its site of maturation, in the bursa of Fabricius in birds or bone marrow in mammals.  B cell has an extensive filamentous surface with numerous microvilli.  Mature B cells synthesis and display membrane-bound immunoglobulin (antibody) molecules, which serve as receptors for antigen.  Interaction between antigen and the membrane-bound antibody on a mature naive B cell (and interactions with T cells and macrophages) induces the activation and differentiation of corresponding B-cell.  B cell divides repeatedly and differentiates over a 4- to 5-day period, generating a population of plasma cells and memory cells.

Plasma cells synthesize and secrete antibody with the same antigen-binding specificity. Plasma cells are differentiated cells, and many die in 1 or 2 weeks. Though the plasma cells have a very short life span of few days they can secrete more than 2000 molecules of antibody per second. These secreted antibodies are the major effector molecule of the humoral immunity. The secreted antibodies may be one of the five classes of antibody (IgG, IgA, IgM, IgD and IgE). All clonal progeny from a given B cell secrete antibody molecules with the same antigenic specificity.

Memory B cells, as the name indicates, remains in the circulation for a long time and thus has a longer life-span. Memory cells have a life span of up to years.  It continues to express the same membrane-bound antibody as the original parent naive B cell.

Surface markers of B cells

·         Surface immunoglobulin

·         CD45 and CD40 – Signal transduction

·         CD35 (CR1) and CD21 (CR2) - Receptor for complement

·         CD32 - Receptor for Fc region of Ig G

·         CD80 (B7-1) and CD86 (B7-2) -  interact with CD28 of T cells

·         Class II MHC molecules

T lymphocytes

T lymphocytes derive their name from their site of maturation, thymus.  These cells have membrane receptors for antigen known as T-cell receptor (TCR). Unlike the membrane- bound antibody on B cells, TCR does not recognize free antigen. It recognizes antigen bound to particular classes of molecules known as major histocompatibility complex (MHC). A fundamental difference between the humoral and cell-mediated immune system is that B cell is capable of binding soluble antigen, whereas the T cell is restricted to binding antigen displayed on self-cells. To be recognized by T cells, antigen must be displayed together with MHC molecules on the surface of antigen-presenting cells (B cells, macrophages and dendritic cells) or on virus-infected cells, cancer cells, and graft cells. The T-cell system then eliminate these altered self-cells.

Surface markers of T cells

·         T-cell receptor

·         Thymus specific antigens

·         CD2 and CD3 – signal transduction

·         CD4 or CD8  - CD4 binds to class II MHC molecules and CD8 binds to class I MHC molecules

·         CD28 – bind to B7 on antigen-presenting cells

·         CD45 - signal transduction

·         CD40 ligand

T cells have two well defined subpopulations: T helper cells (T_H) cells and T cytotoxic (T_C) cells.  T_H cells and T_C cell expresses CD4+ and CD8+ glycoproteins on their surfaces respectively. Thus the ratio of T_H to T_C cells is approximately 2:1 in normal human peripheral blood.

T_H cells (CD4+) get activated when it encounters an antigen complexed with MHC class II molecules presented on an APC. Following its activation, T cell secretes various growth factors known as cytokines which play a central role in activation of B cells, T_C cells and a variety of other cells that participate in immune response. The T_H1 response produces a cytokine profile that supports inflammation and activates certain T cells and macrophages, whereas the T_H2 response activates B cells and immune responses that depend upon antibodies.T_H cell maintain memory and are the principal proliferative cells responding to foreign antigen associated with self class II MHC molecules.

T_C cells get activated when they interact with an antigen complexed with MHC class I molecules presented on an altered self-cells in the presence of appropriate cytokines. Activation results in the proliferation and differentiation of the TC cells into an effector cells called a cytotoxic T lymphocytes (CTL). CTLs recognize and eliminate altered self cells but secrete few cytokines. TC cells are generally responsible for killing virus-infected cells, transplanted tissue and cancer cells.

Another subpopulation of T lymphocytes is called T suppressor (T_S) cells and help to suppress the humoral and the cell-mediated immune system.

Natural killer cells (NK cells) or large granular lymphocytes (LGL) are large, granular lymphocytes that do not express the set of surface markers typical of B or T cells. They display cytotoxic activity against a wide range of tumor cells.  They are not antibody dependant or MHC restricted.  They lack immunologic specificity and memory as these cells lack antigen-binding receptors,.

Although NK cells do not have T-cell receptors or immunoglobulin incorporated in their plasma membranes, they can recognize potential target cells in two different ways.

·         In some cases, an NK cell employs NK cell receptors and bind to cells having unusual profile of surface antigens, for example tumor cells or viral infected cells.

·         Or NK cells will bind to antibodies bound to the surfaces of tumor cells or viral infected cells. NK cells use CD16  which attach to these antibodies and subsequently destroy the targeted cells. This process is known as antibody-dependent cell mediated cytotoxicity (ADCC).

Once bound to the glycoprotein receptors on target cells, NK cells release cytolytic factors such as perforin that causes transmembrane pores.  Through these pores cytotoxic factors such a tumour necrotic factor β enter the cell and kill the cell by apoptosis. 

Lymphokine activator killer (LAK) cells are NK cells treated with Interleukin 2 (IL-2) and are cytotoxic towards tumour cells.

       B. Mononuclear Phagocytes

The mononuclear phagocytic system consists of monocytes (circulate in blood) and macrophages (in tissues). 

During hematopoiesis in the bone marrow, granulocyte-monocyte progenitor cells differentiate into promonocytes, which leave the bone marrow and enter the blood and differentiate into mature monocytes. Monocytes circulate in the bloodstream, during which they enlarge and migrate into the tissues and differentiate into tissue macrophages.

Monocytes are the largest cells found in peripheral blood (12-15 µm).  Monocytes in circulation have a half life of 3 days.  Tissue macrophages are larger (15-20 µm). 

Differentiation of a monocyte into a tissue macrophage involves a number of changes:

·         The cell enlarges five to tenfold

·         Its intracellular organelles increase in both number and complexity

·         It acquires increased phagocytic ability

·         Produces higher levels of hydrolytic enzymes

·         Begins to secrete a variety of soluble factors.

Tissue macrophages survive for months.  Macrophages are dispersed throughout the body. Free macrophages travel by amoeboid movement throughout the tissues. Some reside in particular tissues (fixed macrophages), others remain motile (free, or wandering, macrophages).

Macrophage-like cells in different tissues are named according to their tissue location.

·         Alveolar macrophages in the lung

·         Histiocytes in connective tissues

·         Kupffer cells in the liver

·         Mesangial cells in the kidney

·         Microglial cells in the brain

·         Osteoclasts in bone

Functions of macrophages include phagocytosis, antigen presentation and secretion of cytokines. 

1        Macrophages are capable of ingesting and digesting exogenous antigens (whole microorganisms and insoluble particles) and endogenous matter (injured or dead host cells, cellular debris, and activated clotting factors).  The process is known as phagocytosis.

2        During antigen presentation, phagocytosed antigen is digested within the cell into peptides that associate with class II MHC molecules. These peptide–class II MHC complexes then move to the macrophage membrane. This processing and presentation of antigen is essential to TH-cell activation, which is essential for the development of both humoral and cell-mediated immune responses.

3        A number of important proteins are secreted by activated macrophages. These include cytokines, such as interleukin 1 (IL-1), TNF-α and interleukin 6 (IL-6), that promote inflammatory responses.

Macrophages activity can be enhanced by cytokines secreted by activated T_H cells, by mediators of the inflammatory response, and by components of bacterial cell walls. One of the most potent activators of macrophages is interferon gamma (IFN γ) secreted by activated T_H cells. Phagocytosis by macrophage can be enhanced by antibodies.  The macrophage membrane has receptors for antibody and can bind to cells or antigen bound to antibody.  Antibody functions as an opsonin, a molecule that binds to both antigen and macrophage and enhances phagocytosis. The process by which particulate antigens are rendered more susceptible to phagocytosis is called opsonization.

       C. Granulocytic Cells

The granulocytes are classified as neutrophils, eosinophils, or basophils on the basis of cellular morphology and cytoplasmic staining characteristics.

The neutrophil (50%–70% circulating WBC) has a multilobed nucleus and a granulated cytoplasm that stains with both acid and basic dyes; it is often called a polymorphonuclear leukocyte (PMN) for its multilobed nucleus.

The eosinophil (1%–3% circulating WBC) has a bilobed nucleus and a granulated cytoplasm that stains with the acid dye eosin red.

The basophil (< 1% circulating WBC) has a lobed nucleus and heavily granulated cytoplasm that stains with the basic dye methylene blue.

Both neutrophils and eosinophils are phagocytic, whereas basophils are not.

Neutrophils have a life span of only a few days.  These cells are the first to arrive at a site of inflammation.  Movement of circulating neutrophils into tissues is called extravasation.  Neutrophils are active phagocytic cells.

Phagocytosis by neutrophils is similar to that of macrophages, except that the lytic enzymes and bactericidal substances in neutrophils are contained within primary and secondary granules. The larger, denser primary granules are a type of lysosome and contain peroxidase, lysozyme, and various hydrolytic enzymes. The smaller secondary granules contain collagenase, lactoferrin, and lysozyme. Both primary and secondary granules fuse with phagosomes.

Eosinophils are motile phagocytic cells. Their phagocytic role is significantly less important than that of neutrophils, and they play a role in the defense against parasitic organisms.

Basophils are nonphagocytic granulocytes that function by releasing pharmacologically active substances (histamine, serotonin, etc) from their cytoplasmic granules. These substances play a major role in certain allergic responses.

Mast cells are found in a wide variety of tissues, including the skin, connective tissues of various organs, and mucosal epithelial tissue of the respiratory, genitourinary, and digestive tracts. Like circulating basophils, these cells have large numbers of cytoplasmic granules that contain histamine and other pharmacologically active substances. Mast cells, together with blood basophils, play an important role in the development of allergies.

      D. Dendritic cells

The dendritic cell (DC) is named so because it is covered with long membrane extensions that resemble the dendrites of nerve cells.

Four types of dendritic cells are known: Langerhans cells, interstitial dendritic cells, myeloid cells, and lymphoid dendritic cells. All dendritic cells have the same function, the presentation of antigen to T_H cells

They express high levels of both class II MHC molecules and members of the co-stimulatory B7 family. They are more potent antigen-presenting cells than macrophages and B cells, both of which need to be activated before they can function as antigen-presenting cells (APCs).

Immature or precursor dendritic cells acquire antigen by phagocytosis or endocytosis; the antigen is processed, and mature dendritic cells present it to T_H cells.