1. A functional description of immunity
1.1 Innate immunity: The "standing army" of infection defense
When professionals in medicine and immunology discuss immunity and immune mechanisms, they usually think of lymphocytes, antibodies and the infection defenses that develop some weeks after an infection or following vaccination. But these specific or adaptive immune defenses account for only a small part of the body's defense system. In biology as a whole, they are exceptions. Specific immunity is found in only about 1.5 % of all animal species.
As its name indicates, innate immunity is inborn. It provides an all-purpose defense against all infectious organisms. In biology as a whole, innate immunity is by far the most important infection defense system. It is, of course, difficult to quantify this statement, but the fact is that most first-time infections are arrested within hours or a few days, long before antibodies or antigen specific killer cells have been induced, before the specific defense system has had time to come to the rescue.
The importance of innate immunity is most clearly manifested by the fact that invertebrates like snails, shellfish and insects are without lymphocytes (and are therefore unable to be vaccinated in the same way as more elevated animals) but have an equal or better defense against infection than humans. Throughout evolution, we have maintained, in principle, the same innate infection defense system as the invertebrates depend on entirely. But in addition to it, we have also developed specific immunity for added security---a defense system that is mobilized only when an infection overwhelms the innate defenses.
Our infection defense system falls into three distinct lines. The first one is formed by the epithelium, the second lies in the tissue structure (the so-called mesenchymal defense) and the third is the specific immune system connected with the function of lymphocytes.
There is a close functional connection between the innate immunity and the adaptive infection defenses. Innate immune cells in the tissue surfaces, including macrophages and dendritic cells, detect foreign elements and destroy invading microorganisms. Immune cells that become activated as a result of such natural challenge by infectious microbes produce signal molecules (cytokines) that recruit more immune cells to the infected region and prepare cells in the specific arm of the immune system (B- and T-cells) to produce antibodies against the intruder. In turn, when the specific immune system is provoked, cytokines are produced which have a positive feedback effect on innate immunity, making it even more effective.
1.2 Epithelial surface defense
The majority of immune cells (75 %) are found in body surfaces, particularly in gut endothelia, the largest immunological organ in the body.
The skin area of an adult human is approximately 2 m² whereas the mucosal surface area is about 400 m². Almost all microbes resulting in illness invade one of the body's mucosal surfaces and most microbes are dealt with there before they can advance further. As a logical consequence, it is a good strategy in infection control to find ways to "Man the barrier" ( Nagler-Anderson 2001) without using the injection syringe.
Epithelial defense consists first of a dense mechanical barrier. Some epithelial cells have cilia that sweep the microbes toward the body openings. Next, the epithelial cells produce mucous containing carbohydrates that prevent microbes from adhering to the surfaces. Most importantly, however, the cells produce peptide antibiotics, iron-binding substances and lysozyme.
Peptide antibiotics (defensins) have a wide-ranging effect with an efficacy per mol similar to tetracyclines (Hancock and Scott 2000; Ganz and Lehrer 2001). There is no proven acquired resistance against natural defensins, something that can be due to their crude mode of action---dissolving the cell membranes of microbes. Production of defensins and other peptide antibiotics is mostly constitutive. They are produced continuously without stimulation of the cells that produce them. However, it is known that the concentration of defensins increases under infection (Ganz and Lehrer 2001), which must mean that the production of these important anti-microbial principles in tissue surfaces can be induced to some extent.
One obvious important task for medical research in the future will be to find welldefined and safe substances which, when applied to the mucous surfaces, can stimulate increased production of defensins. The same applies to lysozyme and to iron-binding substances (e.g. lactoferrin) which compete with infectious microbes for iron because it is vital for their propagation. Since all of these anti-microbial principles in mucous are produced by innate immune cells in epithelial surfaces, immune-stimulants that target these cells are the most likely candidates.
1.3 The mesenchymal defense
The term mesenchyme is used for connective tissues, veins, and blood cells, all of which are coordinated and function together. Serious genetic innate errors in the mesenchymal system do not arise, undoubtedly because an individual with such errors is not viable even in pregnancy and would be aborted.
The mesenchymal infection defense is first and foremost connected with tissue macrophage function. Tissue macrophages are found everywhere in the body where there is connective tissue and veins including the brain where they are known as microglia.
Tissue macrophages are phagocytes. They ingest microbes and dissolve them. If a small quantity of microbes enters the connective tissue, they are quickly and completely eliminated by macrophages through phagocytosis. In addition, if several microbes have invaded, the macrophages will react by producing cytokines, especially interleukin 1 (IL1) and tumor necrosis factor (TNF). These cytokines induce changes in the endothelial tissues and start an acute inflammation. Consequently, granulocytes with an enormous capacity for phagocytosis and bacterial killing are summoned.
Local acute inflammation on a small scale should be accepted as a normal process. From time to time, all humans have a minor inflammation in some area of the body. The concentration of the acute phase C-reactive protein (CRP) in blood reflects the degree of inflammation and may therefore be a sensitive marker of infection and other disease conditions including coronary artery disease (Libby and Ridker 1999).
1.4 Innate immune cells monitor the microbial environment
The most well-known and well-described phenomenon in immunology is the production of specific antibodies and induction of antigen-specific T-cells following infection or vaccination. But the innate immune system response to infections has not been understood until recent years. As a result of a paradigm shift in immunology during the last 10 years, innate immune mechanisms have become a predominant area of immunology research. From a subordinate status in immunology, innate immunity has received "new respect" (Gura 2001) in recent years and has obtained the position as the "mastermind" of immunity.
Innate immunity not only constitutes the frontline defense, it also controls and coordinates how the specific part of the immune system reacts to various infectious challenges and to environmental factors such as allergens. Some excellent review papers can be recommended for an update on the status of innate immunity in modern immunology: Gura 2001; Levy 2001; Basset et al. 2003; Beyan et al. 2003; Lolis and Bucala 2003; Sartor 2003; Sfondrini et al. 2003; Wakimoto et al. 2003.
Innate immune cells like macrophages, dendritic cells, granulocytes and natural killer cells are equipped with surface receptors that discriminate between different microbial substances. To this date, a total of ten so-called "Toll-like receptors" (TLR) have been found, numbered TLR 1 to TLR 10. For instance, bacterial lipopolysaccharides (LPS) interact with TLR 4, bacterial DNA with TLR 9 and beta-1,3/1,6-glucans with TLR 2 and/or 6. Although all these microbial products activate innate immune mechanisms, the signals produced by the immune cells are different as are the biological responses. LPS elicits TNF production and other cytokines which induce inflammation and fever, whereas beta-1,3/1,6-glucans induce a strong Interferon-gamma production.
Innate immunity is no longer regarded as an unspecific and "blind" defense mechanism. We now know that innate immune cells are equipped with sophisticated antennas which continuously monitor the nature of the microbial environment. Our immune system has obviously evolved in a natural environment with hostile micro-organisms and has probably become dependant on their continuous challenge. This information will aid us in learning about the innate immune system's response to the microbial world and to microbial alarm molecules and can eventually help us to manipulate immunity to generate the most appropriate response. Herein lies the hope of finding the most appropriate methods to prevent inappropriate immune responses such as those causing asthma and allergy. Modern thinking leans toward stimulating immunity with substances that skew the immune response in so-called Th-1 direction rather than suppressing symptoms of such inadequate immune reactions (illustrated simplified in Figures 3 through 6).
The body's third defense line is the specific immune system. Connected with the lymphocyte system, it is characterized by extreme specificity and memory. Vaccination gives effective protection against a specific microbe but against no others. The memory, that is to say the duration of the effect, can last for years or even lifelong.
Since the activity of the specific immune system has such a significant effect and the studies of this system have produced so many valuable impulses even to fields of research other than immunology, it is easy to overlook that the non-specific infection defense connected with epithelial and mesenchymal tissue has considerably greater significance than the specific immune system, both generally within biology and also in our daily fight against infection.
The mesenchymal and lymphocyte system are cooperative with one another. Cells in the mesenchymal system often have to present antigens to lymphocytes in order to achieve an effective immunization. In the future development of vaccines, it seems a sensible strategy to try to imitate the natural infection process by activating the innate immune system in epithelial and mesenchyme tissues with the help of nature's own "danger signals" (pathogen associated molecule patterns), targeting the TLRs. By that method, it might be possible to achieve a more natural and effective adjuvant effect than with today's vaccine injections.