The Immune System--An Overview

The single most important function of the immune system is to protect the body. This protection is geared both toward assault from the outer environment in the form of microorganisms (bacteria, viruses, and fungi of all sorts and manner) and attrition indigenous to the body itself. The latter includes fending against aberrant growth, metabolic toxins and burrowed parasites.

The immune system does so by providing a framework of biological self, not unlike the way the mind allows an individual to develop the concept of an intellectual self. Thus, when the body is infected with a microbe or a cancer cell makes it appearance, the body quite literally sends out stress signals. This stress call mobilizes a vast network of cells, tissues and organs to protect the body. The totality of this collection of cells and substances made by the tissues and organs working in concert, form the immune system.

While the immune system is confusingly intricate and its machinations complex, the basic strategy is quite simple, actually: that is, to identify the assault, tag it, follow it with its entire armamentarium and neutralize it. In this brief overview, we shall see how the various immune players get into action, how they work with each other, and how the immune response is finally pacified, once the danger is brought under control. In fact, the vehement and--at least, partially--indiscriminate response by the immune system also belies its inherent "blindness" when it turns on the body it is meant to protect.

At the outset, it would be useful to consider an analogy. If the body is seen as a medieval "castle," as it were, with its appropriate deterrents, including a moat and its sheer walls; its defensive measures such as catapults, fire-tipped arrows, or boiling oil cauldrons; and successive layers of increasingly sophisticated defenses to prevent a breach, then the tug of war that is the immune system is more readily visualized. On the other side of this equation are not only the microbes external to the body but also internal threats that seek to disrupt the smooth commerce of metabolism. It is this "battleground," which makes the difference between health and disease and where the awesome firepower of the immune response is most palpable.

To get into the thick of it then, suppose that a microbial infection is imminent, say, because of a scraped knee. First, the microbe must break through the external wall, which is the skin. While skin--and, of course, the mucous membranes--provide adequate protection, they are not impermeable. When this "castle wall" is breached, the second line of defense is geared up. This happens when the trouble-making microbe begins to penetrate the tissue, and the body initiates the inflammatory response. Inflammation is the first of many distress calls intended to alert the immune system of the danger, even before the nature of the breach is fully known. This sets the stage for a flurry of molecular events whereby, in the pitched to and fro the earliest moments of the immune response, cells beget molecules and molecules beckon other cells.

Specifically, two types of cells and three molecules are linked in a blitz of urgent biochemical messages back and forth. Rather quickly after the infection, two cytokines (or messenger molecules) appear on the scene: tumor necrosis factor-alpha (TNF-?) followed by interleukin (IL)-12, and may be likened to sentries in the watchtowers. Soon after the appearance of TNF-?, increasing numbers of inflammatory cells enter the fray. The first to respond are constables on patrol, which may be seen as stalkers. This function is served by a type of cells called macrophages (M?) that prowl around in the bloodstream, and are attracted to the site of injury by distress signals from inflammatory cells there. The defense would not be complete, however, if there were no lookouts to ambush any errant microbe that may have evaded immune surveillance. In the body, dendritic cells (DCs), which typically lie immobile in the tissue, function as ambushers. When DCs snare a passing microbe (or a remnant thereof, formally known as an antigen), they too begin to migrate. Both M? and DCs amplify the stress alarm throughout the body. As a first step, these stalkers and ambushers begin to squirt IL-12 in their immediate environment, and may be akin to turning over the boiling oil cauldrons, to beckon other immune cells to the scene. In addition, macrophages and dendritic cells swallow, digest and regurgitate partially degraded microbes that is intended to elicit more specific response. This is, in part, because the molecular message must be broadcast that initial infection has not been contained and threatens to spread.

While the stage is being set for a more specific response to thwart the infection, yet another cell type kicks into action: Natural killer (NK) cells. Tugged on by IL-12 (produced by M? and DCs), once activated, NK cells carry out two important functions. One, they attack the offending microbe at the site of injury, albeit somewhat indiscriminately, as they cannot "see" what they attack. As such, they act like street brawlers or flame-throwers in the castle. Two, they multiply and chum the third molecule alluded to above, interferon-gamma (IFN-?).

This sequence of events circumscribes the initial (non-specific) immune containment strategy. Under circumstances, the combination of stalkers, ambushers and street brawlers does not quite pack the punch to fend against the microbial infection. For as effective as they are, they are not "schooled" in the art of delivering crisp, specific punches to knock out the offending microbe or an internal threat. Going back to the analogy of the castle, then, the heavy artillery should now be marshaled, as the danger seems to be spreading.

As we have seen, after their activation, M? and NK cells produce IL-12 and IFN-?. This potent combination marks the transition from the brawling, stopgap response to the more specific, efficient and decidedly lethal one.

This arm of the immune response is orchestrated by another type of white blood cells, called lymphocytes. Derived from primitive stem cells, lymphocytes are divided into two broad categories: The a and T cell types, and both have specific functions. Whereas B cell do not attack pathogen themselves, they produce antibodies that engage them. In contrast, T cells--so called, because they make a detour through the thymus before entering the circulation--search out, recognize and bind antigens glommed onto cell surfaces.

Here the cross talk at various levels of the immune system plays a critical role. Thus, when DCs (the ambushers) capture an antigen, they send a signal to a cells to start producing antibodies. The B cells cannot carry out this function by themselves, however, and must be first primed by T cells. The T cells essentially facilitate communications among the various arms of the immune system by producing cytokines, the cellular go-between, such as TNF-?, IL-12 and IFN-?, as noted above. Thus, one subset of T cells, the Th1 cells, produces anti-inflammatory cytokines, whereas another, Th2 cells, release pro-inflammatory cytokines. The balance between pro- and anti-inflammatory cytokines is central to the issue of health and diseases.

Accordingly, if Th1 cells are in relative low abundance, there is a paucity of M? and NK cells in the body, which manifests itself in compromised resistance to disease. Conversely, over-activity of Th2 cells is known to precipitate rheumatoid arthritis, a debilitating disease. Therein lies the ferment for the cellular havoc that the immune system is supposed to prevent in the first place, but an unusually robust immune response can blur the distinction between the "self" and "non-self." Hence, the balance between Th1 and Th2 cells is indispensable.

The foregoing overview demonstrates rather simplistically the nuances and layered, intertwined, calibrated nature of the immune response. Implicit in its esoteric details is not only the inkling how we contract mumps or measles only once but also why one set of cytokines must be elicited, for instance, to counter bacterial infections, viruses, and intracellular parasites on the one hand, and another set to offset helminthes (worms and nematodes), on the other.

Modulation of the immune response is one of the major challenges in biomedical research. The interaction, overlap and reciprocity of its different arms make it abundantly clear that the immune response is best affected in toto as a network rather than to balance one arm or the other by specific intervention. Specific intervention, however, may become unavoidable in severe diseases where not only the quality of life is affected but also personal autonomy of the inflicted is curtailed. Thus, for example, TNF-? therapy would be entirely called for in advanced arthritis, despite the serious side effects that may be clinically presented in at least a certain percentage of users. To an extent, this could be attributed to blockage or inhibition of one pathway at the expense of another. Which might alleviate pain, say, but may well expose an individual to other equally deleterious side effects.

While "global" modulation of the immune system is still far into the future, select nutritives could potentially tweak the immune system here and there without throwing it into a lopsided state that could eventually lead to unforeseen complications. Systemic enzymes provide one such remedy. Extensive research has shown that systemic enzymes tip the balance in favor of anti-inflammatory cytokines by modulating the function of the immune response. This happens in part by the activation of DCs by systemic enzymes, which recognize antigens--such a remnant of degraded cartilage in arthritis--and potentiate T cells to switch from pro-inflammatory to anti-inflammatory cytokines. Equally, systemic enzymes efficiently remove antibody-antigen complexes (known as circulating immune complexes) that clutter the traffic in the blood stream. These are but two of the mechanisms by which systemic enzymes support the immune system to exert its more beneficial effect on the body.

To analogize a medieval castle to the human body may seem contrived; however it serves as a useful device to visualize literally the army unleashed upon microbial infection. In fact, the jargon of immunity is replete with martial--indeed, militaristic--references. Thus, cells (killer T cells, natural killer cells) attack, lyse, eliminate, terminate, destroy and repulse invaders, interlopers, and the enemy. While useful, this type of terminology does disservice to the concerted, synchronized immune response. Recent research has introduced the concepts as subtle as contextual immunology and chrono-immunology, which are still in their infancy. Yet, the timing and context are critical to immune response. Until the molecular details emerge to more meaningfully switch the immune balance in face of external or internal antigens, systemic enzymes may provide a precursor and rudimentary biological approach to modulate the immune system.

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