THE ADAPTIVE IMMUNE SYSTEM
II. HUMORAL IMMUNITY
B. WAYS THAT ANTIBODIES HELP TO DEFEND THE BODY
The overall purpose of this Learning Object is to understand the mechanisms by which antibodies work with phagocytes to remove or neutralize antigens through a process called opsonization.
LEARNING OBJECTIVES FOR THIS SECTION
Humoral Immunity refers to the production of antibody molecules in response to an antigen (def). These antibody molecules circulate in the plasma of the blood and enter tissue and organs via the inflammatory response. Humoral immunity is most effective microbes or their toxins located in the extracellular spaces of the body.
Antibodies or immunoglobulins (def) are specific glycoprotein configurations produced by B-lymphocytes and plasma cells in response to a specific antigen and capable of reacting with that antigen.
The antibodies produced during humoral
immunity ultimately defend the body through a variety of different means. These
2. MAC Cytolysis
3. Antibody-dependent Cellular Cytotoxicity (ADCC) by NK Cells
4. Neutralization of Exotoxins
5. Neutralization of Viruses
6. Preventing Bacterial Adherence to Host Cells
7. Agglutination of Microorganisms
8. Immobilization of Bacteria and Protozoans
9. Promoting an Inflammatory Response
In this section we will look at opsonization.
2. Opsonization (def)
Opsonization, or enhanced attachment, refers to the antibody molecules IgG and IgE, the complement proteins C3b and C4b, and other opsonins (def) attaching antigens to phagocytes. This results in a much more efficient phagocytosis.
A. Opsonization with IgG, C3b, and C4b
1. The process starts with IgG or IgM being made against a surface antigen of the organism or cell to be phagocytosed. The Fab portion (def) of the antibody reacts with epitopes of the antigen. The Fc portion (def) of IgG can then bind to receptors on neutrophils and macrophages thus sticking the antigen to the phagocyte (see Fig. 1). Binding of IgG to the Fc receptor also activates the phagocyte.
2. Alternately, IgG and IgM can activate the classical complement pathway (see Fig. 2) and C3b or C4b (def) can stick the antigen to phagocytes (see Fig. 1). Like IgG, C3b, and to a lesser extent C4b, can function as opsonins (def), that is, they can attach antigens to phagocytes. One portion of the C3b binds to proteins and polysaccharides on microbial surfaces; another portion attaches to CR1 receptors on phagocytes, B-lymphocytes, and dendritic cells for enhanced phagocytosis. (see Fig. 3). (Remember that C3b and C4b are also produced during the alternative complement pathway and the lectin pathway as was discussed in Unit 4.) Activation of the complement pathway also promotes inflammation to bring phagocytes and defense chemicals from the bloodstream to the infection site as discussed later under this topic.
Actually, C3b molecule can bind to pretty much any protein or polysaccharide. Human cells, however, produce Factor H that binds to C3b and allows Factor I to inactivate the C3b. On the other hand, substances such as LPS on bacterial cells facilitate the binding of Factor B to C3b and this protects the C3b from inactivation by Factor I. In this way, C3b does not interact with our own cells but is able to interact with microbial cells.
Attachment then promotes destruction of the antigen. Microorganisms are placed in phagosomes (see Fig. 4) where they are ultimately digested by lysosomes (see Fig. 5). If the antigen is a cell too large to be ingested - such as virus-infected host cells, transplant cells, and cancer cells - the phagocyte empties the contents of its lysosomes directly on the cell for extracellular killing (see Fig. 6 and Fig. 7).
Opsonization is especially important against microorganisms with antiphagocytic structures such as capsules since opsonizing antibodies made against the capsule are able to stick capsules to phagocytes (see Fig. 8). In vaccines against pneumococccal pneumonia (inf) and Haemophilus influenzae type b (inf), it is capsular polysaccharide that is given as the antigen (def) in order to stimulate the body to make opsonizing antibodies against the encapsulated bacterium.
B. Opsonization with IgE and the promotion of inflammation
IgE is made against parasitic worms (helminths) and arthropods. The Fab portion of IgE bind to epitopes on the helminth or arthropod and the Fc portion binds to receptors on eosinophils enabling opsonization. In otherwords, IgE sticks phagocytic eosinophils to helminths and arthropods for the extracellular killing of that organism (see Fig. 9).
The Fc portion of IgE also binds to receptors on mast cells and basophils to trigger the release of inflammatory mediators (see Fig. 10) . The infammatory response then enables phagocytes and defense chemicals to leave the bloodstream and go to the infected site as will be discussed later under this topic.
C. How Bacteria Resist Attatchment to Phagocytes
As we learned in Unit 2, some bacteria by means of the activities described below are able to resist phagocytic attachment :
- Some capsules, rich in sialic acid, a common component of host cell glycoprotein, have an affinity for serum protein H, a complement regulatory protein that leads to the degradation of the opsonin C3b by factor I and the formation of C3 convertase. (Serum protein H is what normally leads to the degradation of any C3b that binds to host glycoproteins so that we don't stick our own phagocytes to our own cells with C3b.)
- An outer membrane molecule of Neisseria gonorrhoeae (inf) called Protein II and the M-protein of Streptococcus pyogenes (inf) allow these bacteria to be more resistant to phagocytic engulfment. The M-protein of S. pyogenes (inf), for example, binds factor H of the complement pathway and this leads to the degradation of the opsonin C3b by factor I and the formation of C3 convertase.
- Some capsules simply cover the C3b that does bind to the bacterial surface and prevent the C3b receptor on phagocytes from making contact with the C3b (see Fig. 11). This is seen with the capsule of Streptococcus pneumoniae (inf).
- Capsules can also resist unenhanced attachment by preventing the glycoprotein receptors on phagocytes from recognizing the bacterial cell wall components and mannose-containing carbohydrates.
- S. pneumonia activates the classical complement pathway, but resists C3b opsonization, and complement causes further inflammation in the lungs.
- Neisseria meningitidis (inf) has a capsule composed of sialic acid while Streptococcus pyogenes (group A beta streptococci) (inf) has a capsule made of hyaluronic acid. Both of these polysaccharides closely resemble carbohydrates found in human tissue polysaccharides and because they are not recognized as foreign by the lymphocytes that carry out the immune responses, antibodies are not made against these capsules.
- Some bacteria are able to coat themselves with host proteins such as fibronectin, lactferrin, or transferrin. This prevents antibody molecules from binding to epitopes on the bacterial surface.
- Staphylococcus aureus (inf) produces protein A while Streptococcus pyogenes (inf) produces protein G. Both of these proteins bind to the Fc portion of antibodies, the portion that normally binds to receptors on phagocytes (see Fig. 12). In this way the bacteria become coated with antibodies in a way that does not result in opsonization (see Fig. 13).
- Streptococcus pyogenes produces Mac proteins that are able to bind to the receptors on phagocytes to which IgG and C3b normally attach (see Fig. 14.and Fig. 15). This blocks opsonization.
- Pathogenic Yersinia, such as the one that causes plague, contact phagocytes and, by means of a type III secretion system, deliver proteins which depolymerize the actin microfilaments needed for phagocytic engulfment into the phagocytes. Another Yersinia protein degrades C3b and C5a.
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