Immunity

Immunity

Disease spreads from one person to another is called as infectious disease. Infectious diseases are caused by foreign substances like fungi, bacteria, virus or parasite, when they enter in to the human body. Though the disease by such pathogen affects the body for a shorter duration, the person may survive after loosing functions of some of the organ (eg. Poliomyelitis). Some times, when the infection or disease is severe the person has to die. Yet many of the human beings are able to lead a normal life because of the immune system. The immune system provides such freedom enjoyed by an individual, in order to keep them free from diseases.

The immune system has the following functions,

·              Recognition and defense against foreign substances (antigen) irrespective of the route of entry.

·              Depending upon the nature of the pathogen, appropriate immune reaction is mounted.

·              The antigen induced Antibody combine specifically to that antigen (Specificity)

Immune system keep memory about the pathogens and when the same pathogen reenters a better immune response is produced. This forms the basis of vaccination.

·              Recognition and destruction of the mutant cells that can become cancerous and this is known as Immunosurveillance.

·              Normally, Immune system does not produce antibodies against its own body tissues (self antigens), called as Immune tolerance or Self recognization.

Depending on the nature of response towards the pathogen, Immune system is broadly classified into Natural and Acquired immunity. Immune system is classified as follows.

1. Natural Immunity

The non specific immunity present from birth is known as innate immunity or natural immunity. It protects the body against any foreign invaders and does not show any specificity. It is also functionally matured in a new born. It does not become more efficient after subsequent exposures to same organism.

Components (Cell types) involved in immunity

The cells of the immune system include leukocytes, which are also known as white blood cells (WBC). They developed from the bone marrow stem cells and give rise to two families of white blood cells namely the Myeloid cells (named after bone marrow) and the Lymphoid cells, which take their name from the lymphatic system. Myeloid cells include Basophils, Eosinophils and Neutrophils.

The monocytes give rise to macrophageswhen enter into the tissue spacefrom blood circulation. Similarly, Basophilare transformed to mast cells. Thelymphoid cells include T and B lymphocytes which get their maturation in different lymphoid organs. B-cell maturation begins in the liver (fetal) and continues within thebone marrow as maturation progresses (adult) and T cells complete their maturationin the thymus.

Mechanisms involved in Natural immunity Skin barrier

The skin covers and protects the body as a barrier to prevent invading pathogens. Intact skin prevents the penetration of most pathogens, by secreting lactic acid and fatty acids which lower the skin pH.

Mechanical barriers

Mucous membranes form the external layer where body is not covered with skin and it plays an important role in the prevention of pathogen entrance by traping them. Movement of the mucociliary process in the upper respiratory tract, the cilia in the eyelids act as escalators to remove the pathogens.

Secretions

Sweat has antibacterial substances and tears contain lysozyme. Mucous secretion in nose prevents the dust and microorganism entry into the respiratory tract. Saliva contains lysozyme, thiocyante and lactoferrin. The HCl acid secreted in the stomach kills the microbes.

Phagocytosis

The ingestion (endocytosis) and killing of microorganisms by specialized cells called as phagocytes. Phagocytes are polymorphonuclear leukocytes (eg.Neutrophils) and mononuclear cells (Monocytes and Macrophages). Opsonization -The process by which microbes are coated by a molecule called opsonin which aids attachment of microbes to the phagocytic cells which facilitates phagocytosis. Neutrophils constitutively express ligands and receptors (L-selectin) which interact with reciprocal receptors and ligands on endothelial cells (P- and E-selectin).The endothelial cells are located in the innermost layer of the blood vessels. These interactions help the neutrophils to marginate and roll along the endothelium. Neutrophil responds and move towards a group of molecules called chemo-attractants (chemical mediators) and this process is called chemotaxis (chemical attraction). The phagocytes make its way through intact capillary walls and into the surrounding tissue by a process called diapedesis (emigration of phagocytes into tissues). Chemo-attractants include complement protein C5a, bacterial products, cytokines, lipid mediators from injured tissue. The various stages of Phagocytosis given below.

Stages of Phagocytosis (Fig. 10.1)

Opsonization (process by which microbes are coated by a molecule called opsonin). Attachment to the pathogen (so that pathogen movement can be restricted).

·              Formation of Pseudopodia (hand like projections).

·              Encircling of pathogen by pseudopodia leads to the formation of Phagosome.

·              Fusion of Phagosome with lysozyme vesicle leads to the formation of phagolysosome.

Killing of Pathogen.

Killing by phagocytes

Neutrophil are able to kill the pathogen as they posses certain chemicals in the form of granules and also the lysozyme enzyme. Neutrophil invasion to an inflammed area is consider as the second line of defence. Neutrophil has three types of granules namely Primary granules( contain serine proteases, lysozyme and phospholipase A₂) Secondary granules ( include perforrin, elastase and collagenase) and Tertiarygranules ( contain gelatinase). Apart from these granules the phagocytes alsoposses a variety of oxygen dependent killing mechanisms. Phagocytes produce a respiratory burst, which produces superoxides and hydrogen peroxide. Neutrophils contain an enzyme called as myeloperoxidase, which can convert superoxide into hypochlorite ion which has a strong bactericidal activity.

Reticulo endothelial system (RES)

A diffuse system of cells that includes monocytes and macrophages, which are phagocytic in nature. The role of macrophage is consider as first order defence mechanism, as it engulf and kill more pathogens efficiently. Macrophages also takes part in antigen presentation. Apart from this, RES also involved in removing aged RBCs, denatured protein, steroids,dyes and drugs.

The macrophages derive the name according to their location.

Liver - Kupffer cells

Brain          Microglial cells

Kidney Mesangial cells

Spleen Splenic macrophages

Peritoneum Peritoneal macrophages.

Alveoli Alveolar macrophages.

Inflammation

A localized protective reaction produced in tissue response to any irritation, injury or infection is called as inflammation. This is characterized by pain, redness, swelling, and sometimes loss of function. Usually, the name of the tissue, organ and the region which develops inflammation is suffixed with ‘itis’ for example conjunctivitis, gastritis and pharyngitis respectively. The inflammatory response helps to mobilize the nonspecific defense forces to the tissue space where pathogen is present. The damaged cells release chemical mediators such as histamine from the mast cells, which dilate the near by blood vessels. The complement system gets activated and attracts phagocytes. The plasma leaking from the dilated blood vessel contains clotting system of proteins. They get activated due to the tissue damage and this process leads to “walling off” the area and this helps to prevent spreading of the infectious material. 

Natural Killer Cells

Among the immune cells, natural killer cells (NK cells) are the most aggressive. They are first line of defense against infected and cancerous cells. They are lymphocytes (Large granular lymphocytes, LGL) with no immunological memory and are part of the innate immune system. It attaches to the target and releases a lethal burst of chemicals called as perforins that penetrate the cell wall. Fluids begin to leak in and out and eventually the cell explodes.

Interferon

Interferons are proteins produced by body cells when they are invaded by viruses, is released into the bloodstream or intercellular fluid, in order to induce healthy cells to manufacture an enzyme that block viral replication.

Complement System

It is a group of proenzymes. They circulate in serum in inactive form. The complement system is the part of innate immune system plays an important defense against microorganisms, especially gram-negative bacteria. The complement system consists of a set of over twenty serum proteins which are getting activated as follows.

The complement cascade consists of two separate pathways that converge in a final common pathway (Fig.2). The pathways include the classic pathway (C1qrs, C2, C4), the alternative pathway (C3, factor B, properdin) and these two pathways converge at the component C3. The terminal complement pathway consists of all proteins activated after C3. The most notable are C5-C9 group of proteins collectively

known as the membrane attack complex (MAC). The MAC exerts powerful killing activity by creating perforations in cellular membranes. Activated C3b opsonizes bacteria and C5a function as chemotactic agent.

Antigen presenting cells (APC)

B cell,dendritic cells (lymphnodes), Langerhans cells (from skin) and macrophages are called as antigen presenting cells. All these cells, process the antigen and express the antigen over the surface of its cell membrane along with a molecule called as Major Histo Compatibility Complex (MHC) class II molecule.

Major Histocompatability complex

A set of cell surface glycoproteins are called as the Major Histocompatibility Complex or MHC molecules. Generally, they take part in differentiating self and non self antigens and the presentation of processed foreign antigen to activate the T cells. There are two classes of MHC proteins, MHC class I and MHC class II. MHC class I molecule is expressed on the cell surface of all nucleated cells of the body. MHC class I molecules with processed antigen are expressed on the surface of the infected cells, which present the processed antigen to cytotoxic T cells (CD8). MHC class II molecule are expressed on APC cell surface which present the processed antigen to Helper T cells (CD4 cells).

2. Acquired immunity

Producing specific cells and molecules which are directed against the foreign invaders. It has the special ability to keep memory of first time exposure of an antigen (primary immune response) and mounts better response when there is second time exposure of same antigen (secondary immune response). This ability of immune response forms the basis for the immunization or vaccination.

Acquired immunity is classified into humoral immunity and cell mediated immunity. Both humoral and cellular immune responses are evoked during antigen exposure.

The acquired immunity can be either active or passive.

3. Humoral immunity

The humoral immune response begins with the recognition of antigen. Though the classification separates the cell mediated and humoral immunity with different cell types they do interact to bring an effective immune response. Specific T-cells are stimulated to produce lymphokines that are responsible for the antigen-induced B-cells proliferation and differentiation.

This is for the T depended antigens. However some of the macro antigenic molecules can directly stimulate the B cells directly. Through a process of clonal selection specific B-cells are stimulated, the activated B-cell first develops into a B-lymphoblast, becoming much larger and shedding all surface immunoglobulin. This terminal differentiation stage is responsible for production of primarily IgM antibody during the primary immune response. Few newly differentiated B-cells remain as long-lived “memory cells” without secreting antibodies. Upon subsequent encounter with antigen, these cells respond very quickly to produce large amounts of IgG, IgA or IgE antibody, generating the better secondary immune response.

Pathogen or foreign protein + Macrophage / dentritic cells → processed antigen

The initial differentiation step that ultimately leads to the mature B-cell involves DNA rearrangements in heavy chain variable (V) region as well as similar rearrangements within the light chain genes to synthesis immunoglobulin. These stages are, of course, initiated upon encounter with antigen and activation by T-helper cell to secrete lymphokines. The activated B-cell first develops into a B-lymphoblast, becoming much larger. IgM antibody is formed during the ‘primaryimmune response.’ Instead, these cells undergo secondary DNA rearrangements tomodify the constant region and forms IgG, IgA or IgE antibodies during secondaryimmune response. The suppressor T-cells suppresses the immune response oncean adequate amount of antibody formed. Another way of suppression occurs by the produced antibody itself and known as, “antigen blocking”. When high doses of antibody interact with the entire antigen’s epitopes thereby inhibits interactions with B-cell receptors.

4. Cell mediated immunity

T cells are responsible for cell-mediated immunity. T cells are initially formed in the bone marrow and get its maturation and differentiation in the thymusgland. After maturation T cells migrate to secondary lymphoid organ. T cells areclassified according to their functions and cell-surface marker called CDs (clusters ofdifferentiation). They are functionally classified as T helper, T suppressor, T memoryand T killer cells. T cells are associated with certain types of allergic reactions called Delayed hypersensitivity and also in transplanted organ rejection.

The Major Histocompatibility Complex (MHC) are unique to each individual and indicate self-molecules and always these molecules are given as reference when ever an antigen is presented and this helps the immune system to differentiate the self from non-self. (fig. 3) Helper T (T_H) cells (also known as CD4 cells) activate B cells to produce antibodies against T-dependent antigens (usually protein in composition). T_H cells recognize and bind to an antigen in association with an MHC II (Fig. 3) on the surface of an antigen presenting cells (APC) and the APC cell secrete the cytokineIL-1 and induce the T_Hcell to secrete the cytokine IL-2. Only T_Hcells that have been stimulated by an antigen have receptors for IL-2 and thus these T_Hcells are specificfor only that stimulatory antigen. Production of IL-2 and other cytokines by these T_H cells stimulates the cell-mediated (e.g., T_C cells) and humoral (B cells- Plasma cell) immune responses. In Acquired Immuno Deficiency Syndrome (AIDS),the Human Immuno deficiency virus (HIV) affect the T helper cells. Suppressor (T_S) cells appear to regulate the immune response once the antibody formation reached the adequate levels. Cytotoxic T cells (CD8) identify the viral infected cells and inject the molecule called Perforin to lyse the viral infected cells. Some of the activated T cells become Tmemory cells.

Role of lymphokines

Lymphokines are the cytokines secreted by the lymphocytes and these are small molecules released due to a stimulus and help to send the signal between cells. The term interleukin (IL) is also often referring to the cytokine produced by leukocytes. There is considerable overlap between the actions of the individual lymphokines, so that many of the above effects are shared between TNFa, IL-2 to IL-12. In addition, these proinflammatory cytokines activate the immune system, mobilizing neutrophils from bone marrow, causing dendritic cells to migrate to lymph nodes, and also initiating changes in adipocyte and muscle metabolism and also responsible for inducing fever.