One useful way of reviewing the various immunological mechanisms is to focus on the different possible locations in the body and analyze the mechanisms working in each situation.
Many pathogens infect the mucous membranes lining the digestive, respiratory, urinary or reproductive systems. Here they are isolated from phagocytes and some of the other potent mechanisms found in the internal environment. To deal with this, various innate mechanisms are found in secretions such as saliva, including the antibacterial enzyme, lysozyme, and antimicrobial peptides such as the defensins. For the specific immune response, the key component is IgA. This is secreted into the lumen in the following way. First, in its dimeric form, it binds to the inner surface of epithelial cells lining the intestines and other mucosal surfaces. It is then engulfed by the cell by endocytosis. Next, it moves in a vesicle across the cell and is released into the lumen by exocytosis. IgA is also found in saliva and mother's milk. By binding to microbes, IgA prevents binding and causes agglutination. Without effective binding, the microbes are sweep along the mucous membrane and out of the body.
Once a pathogen crosses a mucous membrane or the skin into the internal environment, phagocytosis by neutrophils or macrophages is its most likely fate. The various innate receptors and opsonins we have discussed play an important role. But by far the most effect opsonin is antibody in the form of IgG (or IgM). Agglutination by these antibodies helps phagocytosis as well. The complement system also can be very effective, either via innate activation or via IgG or IgM. Complement activation results in phagocytosis due in the opsonin C3b or sometimes lysis due to the membrane attack complex (MAC). Finally, in the case of worms, eosinophils become involved, especially if IgE is made.
Here we are concerned mainly with viruses after they have infected a cell, although certain bacteria and protozoa fall in this category too. One initial mechanism is to slow the spread of the infection with interferon-alpha (INF-alpha). This is released by infected cells and induces in neighboring cells an "anti-viral state", which includes the synthesis of certain proteins that slow viral replication and slow down cell growth and division. But the ultimate solution is apoptosis of the infected cell. This is caused by natural killer cells of the innnate system and cytotoxic T cells of the specific immune system. Macrophages then engulf the remains. We did not attempt to discuss the molecules used by the natural killer cells to identify a virally infected cell. But with cytotoxic T cells, of course, it is the T cell receptor identifying peptide antigens on MHC I molecules.
In some cases, pathogens are phagocytized, but are able to evade the killing mechanisms of the phagocyte. The most important case here, of course, is tuberculosis. But there are a few others, such as leprosy. If the pathogen is not being destroyed inside the phagosome, then the "activation" of macrophages by helper T cells is the next step. The helper T cell recognizes the macrophage due to antigen displayed on an MHC II molecule, which should make sense since we are dealing with a phagocyte. Once attached to the macrophage, the most important cytokine released by the helper T cell is INF-gamma. This increases the fusion of lysosomes with the phagosome and increases synthesis of oxygen radicals and other killing mechanisms. But if this turns out to be inadequate, then the remaining option is to wall off the pathogen through the formation of a granuloma. The bacteria might still be alive, but at least they are isolated.
The table below summarizes the mechanisms acting in each of the locations.
| Epithelial Surfaces |
Interstitial Spaces, Lymph, Blood |
Cytosol of Cells |
Vesicles in Cells |
|
| Organisms | Streptococus Cholera E. coli Candida albicans Worms etc |
Viruses Bacteria Protozoa Fungi Worms |
Viruses Chlamydia Protozoa |
Tuberculosis Leprosy Leishmania etc |
| Main Immune Response | Antimicrobial peptides IgA antibodies |
Antibodies Phagocytosis Complement Eosinophils |
NK cells INF alpha Cytotoxic T cells |
T cell activation of macrophages |
Let's look at hepatitis A as an example. The pertinent innate mechanism above is INF-alpha, which is released by any virally infected cells and induces the anti-viral state. The specific immune mechanisms include both B cells and T cells. B cells make IgA, which promotes mucosal immunity, and IgG and IgM, which act as opsonins for phagocytosis. The T cells are cytotoxic T cells; in other words, they are CD8+ with T cell receptors that bind viral antigen on MHC I molecules on the surface of virally infected cells and induce apoptosis.
Hepatis A is an acute infection in which the above prevent a long term problem. But hepatitis B and C can become chronic infections with long-term repercussions. It's interesting to note that are often treated with INF-alpha. A further action of this cytokine is to increase the placement of MHC I molecules on the surface of cells. This makes it much easier for cytotoxic T cells to attack the cells in which the virus is so effectively hiding. As the liver cells are attacked, the patient at first becomes ill, a necessary effect if the infected cells are to be removed. Antiviral drugs are also given at the same time.