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This article provides a close view on immunology-the study of immunity and immune systems of vertebrates.
Immunology:
Immunology deals with the study of immunity and immune systems of vertebrates. Immunity (immunis literally means exempt/free from burden) broadly involves the resistance shown, and protection offered by the host organism against the infectious diseases.
The immune system consists of a complex network of cells and molecules, and their interactions. It is specifically designed to eliminate infectious organisms from the body. This is possible since the organism is capable of distinguishing the self from non-self, and eliminate non-self.
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Immunity is broadly divided into two types — innate (non-specific) immunity and adaptive or acquired (specific) immunity.
Innate Immunity:
Innate immunity is non-specific, and represents the inherent capability of the organism to offer resistance against diseases. It consists of defensive barriers.
First line of defense:
The skin is the largest organ in the human body, constituting about 15% of the adult body weight. The skin provides mechanical barrier to prevent the entry of microorganisms and viruses. The acidic (pH 3-5) environment on the skin surface inhibits the growth of certain microorganisms. Further, the sweat contains an enzyme lysozyme that can destroy bacterial cell wall.
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Second line of defense:
Despite the physical barriers, the microorganisms do enter the body. The body defends itself and eliminates the invading organisms by non-specific mechanisms such as sneezing and secretions of the mucus. In addition, the body also tries to kill the pathogens by phagocytosis (involving macrophages and complement system). The inflammatory response and fever response of the body also form a part of innate immunity.
The Immune System:
The immune system represents the third and most potent defense mechanism of the body. Acquired (adaptive or specific) immunity is capable of specifically recognizing and eliminating the invading microorganisms and foreign molecules (antigens).
In contrast to innate immunity, the acquired immunity displays four distinct characteristics:
i. Antigen specificity
ii. Recognition diversity
iii. Immunological memory
iv. Discrimination between self and non-self.
The body possess tremendous capability to specifically identify various antigens (antigen is a foreign substance, usually a protein or a carbohydrate that elicits immune response). Exposure to an antigen leads to the development of immunological memory.
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As a result, a second encounter of the body to the same antigen results in a heightened state of immune response. The immune system recognizes and responds to foreign antigens as it is capable of distinguishing self and non-self. Autoimmune diseases are caused due to a failure to discriminate self and non-self-antigens.
Organization of Immune System:
The immune system consists of several organs distributed throughout the body (Fig. 68.1). These lymphoid organs are categorized as primary and secondary.
Primary lymphoid organs:
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These organs provide appropriate micro- environment for the development and maturation of antigen-sensitive lymphocytes (a type of white blood cells). The thymus (situated above the heart) and bone marrow are the central or primary lymphoid organs. T-lymphocyte maturation occurs in the thymus while B-lymphocyte maturation takes place in the bone marrow.
Secondary lymphoid organs:
These are the sites for the initiation of immune response, e.g. spleen, tonsils, lymph nodes, appendix, Peyers patches in the gut. Secondary lymphoid organs provide the microenvironment for interaction between antigens and mature lymphocytes.
Cells of the Immune System:
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Two types of lymphocytes namely B-cells and T-cells are critical for the immune system. In addition, several accessory cells and effector cells also participate.
B-lymphocytes:
The site of development and maturation of B-cells occurs in bursa fabricus in birds, and bone marrow in mammals. During the course of immune response. B-cells mature into plasma cells and secrete antibodies (immunoglobulin’s). The B-cells possess the capability to specifically recognize each antigen and produce antibodies against it. B-lymphocytes are intimately associated with humoral immunity.
T-lymphocytes:
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The maturation of T-cells occurs in the thymus, hence the name. The T-cells can identify viruses and microorganisms from the antigens displayed on their surfaces.
There are at least four different types of T-cells:
i. Inducer T-cells that mediate the development of T-cells in the thymus.
ii. Cytotoxic T-cells (Tc), capable of recognizing and killing the infected or abnormal cells.
iii. Helper T-cells (TH) that initiate immune responses.
iv. Suppressor T-cells mediate the suppression of immune response.
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T-lymphocytes are responsible for the cell- mediated immunity.
Immunoglobulin’s:
The humoral immunity is mediated by a special group of proteins called immunoglobulin’s or antibodies, produced by B-lymphocytes.
Structure of Immunoglobulin’s:
All the immunoglobulin (Ig) molecules basically consist of two identical heavy (H) chains (mol. wt. 53,000 to 75,000 each) and two identical light (L) chains (mol. wt. 23,000 each) held together by disulfide linkages and non-covalent interactions (Fig. 68.2).
Thus, immunoglobulin is a Y-shaped tetramer (H2L2). Each heavy chain contains approximately 450 amino acids while each light chain has 212 amino acids. The heavy chains of Ig are linked to carbohydrates, hence immunoglobulin’s are glycoproteins.
Constant and variable regions:
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Each chain (L or H) of Ig has two regions (domains), namely the constant and the variable. The amino terminal half of the light chain is the variable region (VL) while the carboxy terminal half is the constant region (CL). As regards heavy chain, approximately one-quarter of the amino terminal region is variable (VH) while the remaining three-quarters is constant (CH1, CH2, CH3). The amino acid sequence (with its tertiary structure) of variable regions of light and heavy chains is responsible for the specific binding of immunoglobulin (antibody) with antigen.
Classes of Immunoglobulin’s:
Humans have five classes of immunoglobulin’s— namely IgG, IgA, IgM, IgD and IgE— containing the heavy chains ƴ, α, µ, δ and ɛ, respectively. The type of heavy chain ultimately determines the class and the function of a given Ig.
Two types of light chains — namely kappa (k) and lambda (λ) — are found in immunoglobulin’s. They differ in their structure in CL regions. An immunoglobulin (of any class) contains two k or two λ light chains and never a mixture. The occurrence of k chains is more common in human immunoglobulin’s than λ chains.
The characteristics of the 5 classes of human immunoglobulin’s are given in Table 68.1.
Immunoglobulin G (IgG):
IgG is the most abundant (75-80%) class of immunoglobulin’s. IgG is composed of a single Y-shaped unit (monomer). It can traverse blood vessels readily. IgG is the only immunoglobulin that can cross the placenta and transfer the mother’s immunity to the developing fetus. IgG triggers foreign cell destruction mediated by complement system.
Immunoglobulin A (IgA):
IgA occurs as a single (monomer) or double unit (dimer) held together by J chain. It is mostly found in the body secretions such as saliva, tears, sweat, milk and the walls of intestine. IgA is the most predominant antibody in the colostrum, the initial secretion from the mother’s breast after a baby is born. The IgA molecules bind with bacterial antigens present on the body (outer epithelial) surfaces and remove them. In this way, IgA prevents the foreign substances from entering the body cells.
Immunoglobulin M (IgM):
IgM is the largest immunoglobulin composed of 5 Y-shaped units (IgG type) held together by a J polypeptide chain. Thus IgM is a pentamer. Due to its large size, IgM cannot traverse blood vessels; hence it is restricted to the blood stream. IgM is the first antibody to be produced in response to an antigen and is the most effective against invading microorganisms.
Immunoglobulin D (IgD):
IgD is composed of a single Y-shaped unit and is present in a low concentration in the circulation. IgD molecules are present on the surface of B cells. Their function, however, is not known for certain. Some workers believe that IgD may function as B-cell receptor.
Immunoglobulin E (IgE):
IgE is a single Y-shaped monomer. It is normally present in minute concentration in blood. IgE levels are elevated in individuals with allergies as it is associated with the body’s allergic responses. The IgE molecules tightly bind with mast cells which release histamine and cause allergy.
Synthesis of Immunoglobulin’s:
There are millions of different antigens. It was a big puzzle for a long time how an individual can produce so many antibodies to protect against antigens. It is now recognized that a gene rearrangement involving a combination of several genes is responsible for generating an extremely large number of antibodies.
Major Histocompatibility Complex:
The major histocompatibility complex (MHC) represents a special group of proteins, present on the cell surfaces of T-lymphocytes. MHC is involved in the recognition of antigens on T-cells. It may be noted here that the B-cell receptors (antibodies) can recognize antigens and on their own, while T-cells can do so through the mediation of MHC.
In humans, the MHC proteins are encoded by a cluster of genes located on chromosome 6 (it is on chromosome 17 for mice). The major histocompatibility complex in humans is referred to as human leukocyte antigen (HLA). Three classes of MHC molecules (chemically glycoproteins) are known in human.
Class I molecules are found on almost all the nucleated cells of the body. Class II molecules are associated only with leukocytes involved in cell-mediated immune response. Class III molecules are the secreted proteins possessing immune functions e.g. complement components (C2, C4), tumor necrosis factor.
The Immune Response:
The immune response refers to the series of reactions carried out by the immune system in the body against the foreign invader. When an infection takes place or when an antigen enters the body, it is trapped by the macrophages in lymphoid organs. The phagocytic cells which are guarding the body by constant patrolling engulf and digest the foreign substance. However, the partially digested antigen (i.e. processed antigen) with antigenic epitopes attaches to lymphocytes.
T-helper cells (TH) play a key role the immune response (Fig. 68.3). This is brought out through the participation of antigen presenting cell (APC), usually a macrophage. Receptors of TH cell bind to class II MHC-antigen complex displayed on the surface of APC. APC secretes interleukin-l, which activates the TH cell. This activated TH cell actively grows and divides to produce clones of TH cells.
All the TH cells possess receptors that are specific for the MHC-antigen complex. This facilitates triggering of immune response in an exponential manner. The TH cells secrete interleukin-2 which promotes the proliferation of cytotoxic T cells (TC cells) to attack the infected cells through cell- mediated immunity. Further, interleukin-2 also activates B-cells to produce immunoglobulin’s which perform humoral immunity.
Cytokines:
Cytokines are a group of proteins that bring about communication between different cell types involved in immunity. They are low molecular weight glycoproteins and are produced by lymphoid and non-lymphoid cells during the course of immune response. Cytokines may be regarded as soluble messenger molecules of immune system.
They can act as short messengers between the cells or long range messengers by circulating in the blood and affecting cells at far off sites. The latter function is comparable to that of hormones.
The term interleukin (IL) is frequently used to represent cytokines. There are more than a dozen interleukins (IL-I…… IL12)/ produced by different cells with wide range of functions. The main function (directly or indirectly) of cytokines is to amplify immune responses and inflammatory responses.
Therapeutic uses of cytokines:
It is now possible to produce cytokines in vitro. Some of the cytokines have potential applications in the practice of medicine. For instance, IL-2 is used in cancer immunotherapy, and in the treatment of immunodeficiency diseases. IL-2 induces the proliferation and differentiation of T-and B-cells, besides increasing the cytotoxic capacity of natural killer cells. A group of cytokines namely interferon’s can combat viral infection by inhibiting their replication.
