Distribution and Function of Immunoglobulin Isotypes

1.         Entry and spread of Pathogens

a.            Extracellular pathogens may find their way to most sites in the body and antibodies must be equally distributed to combat them.

b.         Most are distributed by diffusion from their site of synthesis but specialized transport mechanisms are required to deliver them to internal epithelial surfaces, such as those of the lung and intestine.

c.         The location of antibodies is determined by their isotype, which can limit their diffusion or enable them to engage special transporters that deliver them across various epithelia.

d.         Entry of Pathogens:

i.            pathogens most commonly enter the body across epithelial barriers presented by the mucosa of the respiratory, digestive, and urogenital tracts, or through damaged skin.

ii.            pathogens entering in this way can then establish infections in the tissues.

iii.         less often, insects wounds, or hypodermic needles introduce microbes directly into the blood.

e.         The body’s mucosal surfaces, tissues and blood all need to be protected by antibodies from such infections, and antibodies of different isotypes are adapted to function in different compartments.

f.          Since a given variable region can become associated with any constant region through isotype switching, B cells can produce antibodies, all specific for the same eliciting antigen, which provide all of the protective functions for each compartment.

2.         Initial IgM production

a.         The first antibodies to be produced in a humoral immune response are always IgM.

b.         These early IgM antibodies are produced before B cells have undergone somatic hypermutation and therefore tend to be of low affinity.

c.         IgM molecules, however, form pentamers whose 10 antigen-binding sites can bind simultaneously to multivalent antigens, such as bacterial cell-wall polysaccharides.

d.         This compensates for the relatively low affinity of the monomers by multipoint binding that confers high avidity.

e.         IgM is confined to the blood and are potent in activating the complement system.

f.            Infection of the bloodstream has serious consequences unless it is controlled quickly, and the rapid production of IgM and its efficient activation of the complement system are important in controlling such infections.

3.         Roles of other Isotypes

a.            Antibodies of the other isotypes, IgG, IgA, and IgE are smaller and diffuse easily out of the blood into the tissues.

b.         IgG is the principal isotype in the blood and extracellular fluid, while IgA is the principal isotype in secretions, the most important being those of the mucous epithelium of the intestinal and respiratory tracts.

c.         While IgG efficiently opsonizes pathogens for engulfment by phagocytes and activates the complement system, IgA is a poor opsonin and a weak activator of the complement system.

d.         IgG operates mainly in the body tissues where accessory cells and molecules are available, while IgA operates mainly on body surfaces where complement and phagocytes are not normally present.

e.         IgE antibody is present at low levels in the blood or extracellular fluid, but is bound avidly by receptors on mast cells that are found just beneath the skin andm ucosa, and along blood vessels in connective tissue.

4.            Transport of IgA across epithelial barriers

a.         The role of IgA antibodies is to protect the epithelial surfaces from infectious agents and to prevent attachment of bacteria or toxins to epithelial cells.

b.         Sites of synthesis:

i.          the principal sites of IgA synthesis and secretion are the gut, the respiratory epithelium, the lactating breast, and various other exocrine glands such as the salivary and tear glands.

ii.          IgA-secreting plasma cells are found predominantly in the lamina propria, which lies immediately below the basement membrane of many surface epithelia.

iii.         from there, the IgA antibodies must be transported across the epithelium to its external surface.

c.            Transcytosis of IgA across epithelia:

i.          most IgA antibody is synthesized in plasma cells lying just beneath the epithelial basement membranes of the gut, respiratory epithelia, tears, and salivary glands.

ii.          the IgA dimer bound to a J chain diffuses across the basement membrane and is bound by the poly-Ig receptor on the basolateral surface of the epithelial cell.

iii.         the bound complex undergoes transcytosis in which it is transported in a vesicle across the cell to the apical surface, where the poly-Ig receptor is cleaved.

iv.         in this way, IgA is transported across epithelia into the lumen of several organs that are in contact with the external environment.

5.            Neutralization of Bacterial toxins

a.            Damage by bacterial toxins:

i.          many bacteria cause disease by secreting toxins that damage or disrupt the function of somatic cells.

ii.          the toxins interact with a specific molecule that serves as a receptor on the surface of the target cell.

iii.         in many toxins, the receptor-binding domain is carried on one polypeptide chain, while the toxic function is carried by a second chain.

b.            Antibodies that bind to the receptor-binding site on the toxin molecule can prevent the toxin from binding to the cell and thus protect the tell from toxic attack – neutralization.

c.         To neutralize toxins, antibodies must be able to diffuse into the tissues and bind the toxin rapidly and with high affinity.

d.            Immunization against toxins:

i.            diphtheria and tetanus toxins are among the bacterial toxins in which the toxin and the receptor-binding functions of the molecule are on two separate chains.

ii.          it is therefore possible to immunize individuals, usually infants, with modified toxin molecules in which the toxic chain has been denatured.

iii.         these modified toxin molecules, which are called toxoids, lack toxic activity, but retain the receptor-binding site, so that immunization with the toxoid induces neutralizing antibodies effective in protection against the native toxin.

e.            Diseases caused by bacterial toxins:

6.            Inhibition of Viral infectivity

a.         For a virus to infect a cell, it must insert its genes into the cytoplasm.

b.         For enveloped viruses, this requires binding of the virus to the cell surface and fusion of viral and cell membranes.

c.         Non-enveloped viruses must also bind to receptors on cell surfaces but they enter the cytoplasm by disrupting endosomes.

d.            Antibodies binding to viral surface proteins can inhibit either the initial binding of virus or its subsequent entry into the cell.

7.            Blockade of Bacterial adherence to host cells

a.         Many bacteria have specific cell-surface molecules called adhesins which allow them to bind to the surface of host cells.

b.         This adherence reaction is critical to the infectivity of these bacteria, whether they enter the cell (Salmonella spp), or remain attached to the cell surface as extracellular pathogens.

c.         IgA antibodies secreted onto the mucosal surfaces of the intestinal, respiratory, and reproductive tracts are important in preventing adhesion of bacteria and other pathogens to the epithelial cells.