Immunoglobulins do not actually kill or eliminate pathogenic microorganisms or antigens from the body. The role of antibodies during an infection is to bind specifically to invading pathogens so that the antigen-antibody complex so formed can be made readily available for other immune system action such as opsonization, phagocytosis, neutralization or complement fixation which ultimately spurs into action to kill and eliminate the bounded antigen from the system. And this is how the antibody-mediated effector function operates. Antibodies or immunoglobulins have various isotypes and these shall be highlighted in this section. These isotypes or classes of immunoglobulins are known as isotypes because they are variants of the main immunoglobulin molecule (i.e. immunoglobulin G). And each of these isotypes of classes or immunoglobulins is differentiated by their distinctive amino acid sequences which are known to line the heavy chain constant region of the antibody molecule.
The different immunoglobulin isotypes also have different subclasses which vary in different animal species. Differences in the heavy chains of each of the immunoglobulin isotypes are usually used to characterize the different Ig subclasses. Human beings for example have four subclasses of immunoglobulin G (IgG) viz: IgG1, IgG2, IgG3 and IgG4. Immunoglobulins also have allotypic determinants and idiotypic determinants aside the different isotypes of antibodies known. The allotypic determinants also known as allotypes are antigenic determinants mainly found in the constant regions of immunoglobulins. The idiotypic determinants or idiotypes are antigenic determinants found in the variable regions of antibodies. The five major classes or isotypes of immunoglobulins are differentiated from each other by the type of heavy (H) chain found in the antibody molecule.
- Immunoglobulin A (IgA): IgA has alpha (α) heavy chain.
- Immunoglobulin M (IgM): IgM has mu (µ) heavy chain.
- Immunoglobulin D (IgD): IgD has delta (δ) heavy chain.
- Immunoglobulin E (IgE): IgE has epsilon (ε) heavy chain.
- Immunoglobulin G (IgG): IgG has gamma (γ) heavy chain
IMMUNOGLOBULIN A (IgA)
Immunoglobulin A (IgA) is an antibody found in serum (as a monomer of about 150,000 Daltons) and in body secretions (as a dimer of about 600,000 Daltons); and it is mainly produced in the body by mucosal associated lymphoid tissue (MALT). Though it mainly exists as a monomer and dimer (Figure 4) IgA can also exist in polymeric forms. It is mainly found in external mucosal secretions of the body such as in the secretions of the GIT, lungs or bronchial secretions and the genitor-urinary tract. Saliva, tears, colostrum or breast milk, sweat and nasal fluids are other external body secretions in which IgA is found. The immunoglobulin A of external body secretions (e.g. saliva, tears and breast milk) is generally known as secretory immunoglobulin A (sIgA). sIgA is produced mainly by epithelial cells of secretory membranes; and they are usually the first line of defense against pathogenic microorganisms (inclusive of bacteria and viruses) that invade the mucosal surfaces of the body. For example, the mucous membrane surfaces especially those found in the nasal areas, GIT, genitor-urinary tract, mouth and eye region are usually the main portal of entry of some disease-causing agents such as bacterial and viral pathogens.
The main biological function of sIgA at these mucosal surfaces is to prevent the attachment of pathogens to the mucosal surfaces by specifically binding to viral and bacterial surfaces antigens. After binding, the mucous entraps the IgA-antigen complex formed; and this complex is later eliminated from the body via the ciliated epithelial cells and peristalsis mechanisms found in these mucosal surfaces. The presence of sIgA in the breast milk of infants help to protect the newborn from infectious disease and/or pathogens in their first few months of life since their immune system is not fully developed and functional. The type of immunity provided by sIgA in the breast milk of infants is known as passive immunity since this type of protection only last for a short period of time (e.g. about six months). At the mucosal surfaces, sIgA and IgA in general prevents the adherence of coated pathogenic microorganisms (e.g. bacteria and viruses) to the surfaces of mucosal cells, and thus prevent their entry into internal body tissues and into the circulatory system. IgA does not cross the placenta and it activates the complement system only via the alternative pathway.
Figure 4: Illustration of immunoglobulin A (IgA). IgA is generally a monomer (left). The illustration on the right-hand side is a schema of secretory IgA (sIgA), a dimer; and it is usually found in external body fluids or secretions such as breast milk and saliva and other internal body fluids. Immunoglobulin A protects mucosal surfaces of the body; and sIgA is the main antibody found in external secretions such as intestinal mucous, tears, saliva and respiratory and genitor-urinary tract fluids. Immunoglobulin A is also the main protective antibody in the breast milk (e.g. colostrum) of infants where it provides a passive type of immunity.
Colostrum is the first secretion of the mammary gland (breast) produced before proper lactation commences in a nursing mother. It is the first breast milk produced from the mammary gland or breast of a woman after giving birth to a baby. It is a major source of passive immunity transferred from mother to the newborn child; and colostrum confers several health benefits to the newborn inclusive of growth factors or nutrients aside its protective function in the immune system of the host. Colostrum is generally the first milk produced from a female animal inclusive of humans after 48 hours of delivery; and this milk is characteristically thick and yellowish in colouration.
The main immunoglobulin molecule found in the colostrum is immunoglobulin A (IgA) or secretary immunoglobulin A (sIgA). After birth, the newborn is exposed to plethora of microorganisms in the environment including those acquired from the vagina or birth canal of the mother; and since the immune system of the infant is not well developed and strong to fight against pathogens, it is the immunologic defense provided by the colostrum that help to protect the child from harmful activities of microbes it comes in contact with. Though this type of immunity is passive in nature and does not last long; it serves as the major basis for the development of the newborn’s own immune system at a later stage in life.
The production of colostrum in the mammary gland of humans and other animals usually continues through the early few days or weeks of delivery after its production in the last phase of pregnancy or after delivery. Nevertheless, the production of colostrum lasts for about 2 – 4 days after the lactation phase has begun in the mother. It is advisable according the World Health Organization (WHO) that mothers should ensure that their newborns have unrestricted access to this milk, and that breastfeeding should be “exclusive” since the breast milk from the mammary gland contains the major nutritive requirement for the development of the child inclusive of water for about 6 months. However, this practice of “exclusive breast feeding” is not evenly practiced in some cultures due to some religious, occupational and cultural believe of some ethnicity.
Colostrum is rich in carbohydrates, amino acids, proteins, and antibodies; and it is generally low in fats. It is also rich in vitamins and other minor and major minerals required keeping the newborn healthy. Colostrum gives a general immunity (though passive in nature) to the newborn from the mucous membrane of the mouth or throat, down to the lungs and even the gastrointestinal tract (GIT) – where it protects the infant from some GIT-related microbial infections such as diarrhea. Breast milk is still the safest and healthiest from of food for a newborn; and it is advisable that mothers exclusively breast feed their babies for six months after which they can be weaned and given other forms of food.
IMMUNOGLOBULIN M (IgM)
Immunoglobulin M (IgM) is an antibody that mainly exist as a pentamer i.e. it consists of five different monomeric units joined together by disulphide bonds and a joining (J) chain (Figure 5). The function of the J chain in the IgM structure is to help in the polymerization of the individual monomeric units that makeup the pentameric IgM antibody; and it does this via a sulphydryl residue close to the carboxyl terminal of the Fc region of the monomeric units. It is the largest antibody out of the 5 isotypes of immunoglobulins; and IgM is often known as a macroglobulin because of its relatively higher molecular weight or size which is about 900,000 Daltons (Da). Because of its large size, IgM does not cross the placenta and it does not leave the blood stream where it gives the host protection against blood-borne infections (caused by both bacteria and viruses). Though the large size of IgM confines the antibody to the bloodstream where it provides protective functions against pathogenic microorganisms, IgM has a short lifespan and it is the first antibody to disappear from the blood serum.
Immunoglobulin M is the main antibody produced in primary immune response to an invading pathogen or antigen. IgM is also the first antibody to be produced in neonates or infants; and immunoglobulin M (a pentameric antibody) is the most efficient complement fixing antibody. This is because it has ten (10) antigen-binding sites unlike other isotypes of immunoglobulins; and IgM is more efficient in binding antigens with many antigenic determinant sites or epitopes (e.g. red blood cells and viral particles). Thus IgM is a better complement fixation antibody, and it is very efficient in agglutination and in the cytolysis of microbial cells (e.g. bacteria). The complement system usually requires two adjacent Fc regions for complement activation; and this is provided by the pentameric structure of IgM; and this feature makes IgM a better complement fixation antibody than the other immunoglobulins. Increase in the production of IgM usually signifies an in utero infection in expectant mothers because it is the first immunoglobulin to be produced in neonates. IgM is usually present on the surfaces of all uncommitted or naïve B cells and it is the first immunoglobulin to be synthesized during B cell maturation in the bone marrow.
Figure 5: Schematic illustration of immunoglobulin M (IgM), a pentameric antibody. Immunoglobulin M is the first antibody to be produced during infection (i.e. in primary immune response to an antigen). The J chain helps IgM to bind to receptors on secretory mucosal cells; and this promote the entry of IgM into external body secretions (e.g. tears, saliva and breast milk). Each of the monomeric unit that make up the pentameric IgM structure are arranged with their Fc regions in the center of the pentamer while the 10 antigen-binding sites are arranged at the outside or periphery of the structure. IgA is another immunoglobulin apart from IgM that has a joining (J) chain.
IMMUNOGLOBULIN E (IgE)
Immunoglobulin E (IgE) is an antibody that is known to bind to host tissue cells (e.g. mast cells), and it is largely responsible for most hypersensitivity reactions (i.e. allergy) in the body. Some of the symptoms of the allergic reactions mediated by IgE response to the invasion of antigens include anaphylactic shock, hay fever and asthma. IgE has a structure similar to the generalized immunoglobulin structure; and it is made up of two pairs of heavy and light chains that are joined by disulfide bonds (Figure 6). The type of allergic reaction mediated by IgE is known as Type I hypersensitivity reaction. Type I hypersensitivity reaction which can also be called anaphylactic or atopic hypersensitivity is an IgE-mediated type of immediate allergic reaction that provides a systemic or local protective functions at various body sites especially on the skin. Immunoglobulin E is specifically bound to the Fc receptors found on mast cells; and it controls the activities of the mucosal associated lymphoid tissue (MALT) which provides protective functions around various mucous membrane surfaces in the body (inclusive of the nasal area, oral cavity and intestinal mucosal surfaces).
Immunoglobulin E is the main protective antibody against parasites or helminthes; and they do not cross the placental barrier. However, IgE activates the complement system by the alternative pathway. IgE exist in serum at a relatively low level, and the antibody has a MW of about 190, 000 DA. The allergic reactions mediated by IgE response to the invasion of antigens leads to the release of pharmacologically active mediators (e.g. histamines, leukotrienes and prostaglandins) by the mast cells; and it is these pharmacologically active substances released by the mast cells that are largely responsible for the hypersensitivity reactions associated with IgE function. Also, the pharmacologically active mediators facilitate the release and build up of other immune system cells and molecules that are required to defend the body against parasitic infections. The reaction that goes on between the binding of IgE to mast cells and the release of vasoactive substances by basophils is shown in Figure 7.
Figure 6: Schematic illustration of immunoglobulin E (IgE). IgE has a high affinity for mast cells (e.g. basophils); and the antibody is a cell membrane bound immunoglobulin that mediates hypersensitivity reactions in the body. IgE binds to the Fc region of basophils; and this result in the release of vasoactive substances (e.g. histamines) following the degranulation of mast cells.
Figure 7: Schematic illustration of degranulation of a mast cell by IgE-mediated binding. The bridging of two IgE molecules on mast cell membranes causes the release of granules and/or vasoactive substances as shown in the illustration. IgE is mainly responsible for the mediation of immediate Type I Hypersensitivity reactions that cause hay fever, asthma, hives, and anaphylactic shock; and the immunoglobulin assist in defending the body against parasitic or helminthic infections. IgE bind with high affinity to Fc receptors on the surfaces of mast cells and/or basophils; and this binding activates the degranulation of the mast cells to release vasoactive substances inclusive of histamines, cytokines, prostaglandins and leukotrienes amongst others. These pharmacologically active substances mediates Type I hypersensitivity reactions in the body. Source: Shakib F, Ghaemmaghami A.M and Sewell H.F (2008). The molecular basis of allergenicity. Trends in Immunology, 29(12):633-642.
IMMUNOGLOBULIN G (IgG)
Immunoglobulin G (IgG) is a monomeric antibody and the most predominant immunoglobulin in secondary (memory) immune response to an invading antigen (Figure 8). It accounts for about 80 % of the total immunoglobulin pool in blood serum or plasma and tissue fluids. IgG unlike other immunoglobulins crosses the placental barrier, and thus it provides the neonate or newborns with humoral immunity during the first six months of life. Immunoglobulin G is a moderate complement fixing antibody, and it mediates antibody dependent cell- mediated cytotoxicity (ADCC). IgG has a molecular weight of about 150,000 DA.
The ability of IgG to cross the placenta gives it an additional biological function of providing naturally acquired passive immunity to neonates in utero and even at birth. IgG appears late during an infection and it persist longer in the bloodstream unlike the other immunoglobulin isotypes. The binding of IgG to pathogenic microorganisms inclusive of bacteria and viruses facilitates the opsonization and phagocytosis of the invading antigens. Microbial cells that are opsonized are easily phagocytosed than non-opsonized antigens. IgG is mainly used in immunological research because of its relative abundance in blood serum/plasma and its high affinity and specificity for antigens.
Figure 8: Schematic illustration of immunoglobulin G (IgG). IgG is the perfect model for understanding the structure and function of other immunoglobulin isotypes. VH=variable heavy chain, CH=constant heavy chain, VL=variable light chain, CL=constant light chain.
IMMUNOGLOBULIN D (IgD)
Immunoglobulin D (IgD) is an antibody with the basic four polypeptide structure of an immunoglobulin (Figure 19.9); and IgD is mostly found attached to the membranes of B cell. IgD is a membrane bound immunoglobulin, and it has a molecular weight (MW) of about 180, 000 DA. Immunoglobulin D is present in only trace amounts in serum; and in association with IgM, IgD is the main membrane-bound antibody commonly expressed on the surfaces of mature B cells or lymphocytes where they are believed to function as antigen receptors. IgD does not fix complements, and it does not cross the placental barriers. IgD is absent from memory cells, and their full physiological function in the immune system is yet to be unraveled.
Figure 9: Illustration of immunoglobulin D (IgD), a membrane bound immunoglobulin. IgD is mainly found on the surfaces of B cells as receptors.
Abbas A.K, Lichtman A.H and Pillai S (2010). Cellular and Molecular Immunology. Sixth edition. Saunders Elsevier Inc, USA.
Actor J (2014). Introductory Immunology. First edition. Academic Press, USA.
Alberts B, Bray D, Johnson A, Lewis J, Raff M, Roberts K and Walter P (1998). Essential Cell Biology: An Introduction to the Molecular Biology of the Cell. Third edition. Garland Publishing Inc., New York.
Bach F and Sachs D (1987). Transplantation immunology. N. Engl. J. Med. 317(8):402-409.
Barrett J.T (1998). Microbiology and Immunology Concepts. Philadelphia, PA: Lippincott-Raven Publishers. USA.
Jaypal V (2007). Fundamentals of Medical Immunology. First edition. Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India.
John T.J and Samuel R (2000). Herd Immunity and Herd Effect: New Insights and Definitions. European Journal of Epidemiology, 16:601-606.
Levinson W (2010). Review of Medical Microbiology and Immunology. Twelfth edition. The McGraw-Hill Companies, USA.
Roitt I, Brostoff J and Male D (2001). Immunology. Sixth edition. Harcourt Publishers Limited, Spain.
Zon LI (1995). Developmental biology of hematopoiesis. Blood, 86(8): 2876–91.