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Immune System

Introduction

Innate Immunity

Acquired Immunity




WWW Immunology Sites



The Immune System is the name of a collection of Molecules, Cells and Organs whose complex interactions form an efficient system that is usually able to protect an individual from both outside invaders and its own altered internal cells.

This combination of components is the product of millions of years of evolution, which has selected those Organisms that are best able to prevent their destruction by MicroOrganisms or Tumors.

This text attempts to clarify exactly what the Immune System does, and more importantly, the mechanism of its action.

It is difficult to clearly delineate the elements of the Immune System from the rest of the body; however, a traditional, if somewhat inadequate method, divides it into two functionally distinct parts: those elements which are Innate (Non-Adaptive), and those which are Acquired (Adaptive).

It is becoming apparent, these two groups are in no way isolated, a complex dialog is constantly going on between them. As such, some attention will also be given to the "Innate/Acquired Dialogue."


The T-Cell is one of the most important elements in the human Immune System. Its role in directly destroying infected or Cancerous cells is great, and it is the control center for the rest of the Acquired and Innate Immune System.

The numerous Cytokines it produces and its array of surface molecules are critical for the control of all other Immune elements.

As AIDS demonstrates, the destruction of the Helper T-Cell lineage results in the total collapse of the Immune System. But, it is important not to suggest any kind of T-Cell independence.

Many other cell types including Macrophages, NK Cells, and B-Cells are important in the Effector phase of the Immune Response. Macrophages and Dendrite Cells are also important regulators of Immune Responses.

The elements on these (and other) cells which are central to the control of T-Cells are the Major Histocompatibility Complex (MHC) molecules. Without these, there is no presentation of internal or external Antigens to the T-Cell.

Their concentration on a cell surface is a critical determinant of the degree of T-Cell activation. And, as their name suggests, they contribute to the T-Cell's ability to discriminate between self-cells and other.


Innate Immunity

Innate Immunity (Non-Adaptive) refers to Immune elements which are Non-Specific. They are generally able to distinguish foreign tissues and Organisms, but are unable to recognize a particular invader.

Similarly, they will respond to such an Organism in the same manner, despite repeated exposures to it - they do not adapt and improve their effectiveness against previously encountered Antigens.


Barriers

Perhaps the most often forgotten fact concerning the Immune System is that it works best when it doesn't have to work at all.

That is to say, if the infectious Organism is unable to enter an individual's body, for whatever reason, no Immune response need be mounted and the person is left completely healthy.

For this reason, two anatomic features not normally associated with the Immune System also serve important Innate Immune functions: the Skin, and its close relative, the Mucosa.

While it seems elementary, the importance of Skin in resisting infection can not be overemphasized. It is the location at which most MicroOrganisms are stopped.

To appreciate its importance, it is worthwhile to consider the relative frequency of lesions forming on healthly intact skin, as compared to infections at locations where the skin has been broken.

The less effective, but close cousin of the skin is the Mucosa: the tissue which covers our Eyes, Alimentary and Genital/Urinary Tracts.

As the higher frequency of mucosal infections indicate, it is not quite as effective at resisting the myriad of challengers to which it is subjected.

Since this tissue is easier to penetrate than normal skin, it possesses a number of means to dissuade the frequent microscopic interlopers.

Tears and Saliva, as well as other Mucus Secretions act to wash away many potential invaders, and many also contain chemical elements which are effective Microbicides.


Non-Specific Chemicals

Mucosal secretions contain a number of chemical weapons to prevent infections.

There is a great variety of such elements, including several well known Enzymes, such as Lysozymes, which destroy the outer surface of many Bacteria.

Other tissues contain a complex of Plasma proteins, Complement, which coat and thereby flag the interloper for destruction.

This attracts additional Immune elements to the intruder's surface. When multiple proteins are brought together, they make destructive pores, in the MicroOrganism's membrane.

While these proteins float in their various fluids waiting to encounter a target, many other chemicals are released, when the cells producing them are stimulated.

These include the chemicals Kinins and Histamine which, when released in response to trauma or invasion, create the infamous Inflammatory Response.

An Inflammatory Response is extremely Immunologically important, because it results in the attraction of other Immune Cells, increased temperature, and blood flow to the threatened area.

Some Cytokines, including the Interferons and Chemokines, among others, are also included here; as they induce an AntiViral state, in other cells encountering them.

Other Cytokines play important roles, in regulating the interactions of the Immune System.


Non-Specific Effector Cells

The most famous Immune Cell is certainly the Macrophage; known to many by the simple moniker, "White Cell." This cell type and a number of closely related Monocyte and Granulocyte Cells act in two ways.

First
They are the major killers of invaders; which is accomplished by the Phagocytosis of MicroOrganisms and the release of high concentrations of chemicals (like Nitric Oxide), which can destroy adjacent cells.

While these activities seem rather crude, compared to the Acquired Immune System, it is probably the most important AntiMicrobial activity of any Immune Cell.

Second
These cells are vital Chemical Factories. In addition to being critical, in the destruction of dangerous Organisms and Cancerous tissues, they are key facilitators of communication, and important chemicals between Immune elements.

Not all Non-Specific Effectors are related to Macrophages. The Null Lymphocyte Cell, or Natural Killer (NK) Cell is one such cell.

As its name suggests, it is derived from a Lymphocytic lineage. However, it lacks some surface molecules necessary for specific recognition of Antigens, and is consigned to the Innate Immune System.

Like Monocyte and Granulocyte Cells, NK Cells produce Cytokines that activate and regulate other Immune elements. In addition, they independently handle the destruction of Tumor Cells.

They use a chemical arsenal composed of Complement-like molecules, which punch holes (Lysis) in undesired cells.


Acquired Immunity

Acquired (Adaptive) Immunity has only begun to be understood more recently.

Although the specificity of the Acquired Immune System makes it the focus of more research than its Innate counterpart, it must be remembered that these two arms are interrelated and mutually dependent, for a functioning Immune System.

It is able to distinguish foreign cells from self, and can distinguish one foreign Antigen from another.

While a Macrophage will engulf any foreign cell (and many self cells), Acquired Immune Cells have mechanisms for selecting, only a precisely defined target.

For this reason, the Acquired Immune System is also called the Specific Immune System (and the Innate - the Non-Specific).

The second feature of the Specific Immune System, memory, enables Immunization and resistance to reinfection, from the same MicroOrganism.

Once Acquired Immune Cells have encountered a particular Organism, they persist and convey resistance to that Organism, for an extended period of time.

For this reason, if the System has fought off an infection once, it will rapidly be able to do so again - since it will "remember" the enemy.

The cells which are responsible for these remarkable abilities are Lymphocytes, of which there are two sub-populations: B and T-Cells.

B-Cells are responsible for the rapid response to ExtraCellular and Mucosal MicroOrganisms (including Viruses and Parasites if they spend part of their life cycle in ExtraCellular fluid), against which they produce soluble factors known as AntiBodies (ImmunoGlobulin).

T-Cells serve two roles. First, as coordinator of other Acquired Immune Responses, which is accomplished by their production of a wide variety of Cytokines and surface cell signals.

The second is as the Primary Responder, to long term IntraCellular infections.


B-Cells

B-Cells are the generators of Humoral Immunity, so called because it consists of soluble proteins found in the "Humors," (Blood). Every B-Cell has an ImmunoGlobulin (Ig) molecule on its surface, due to Genetics.

Each of those ImmunoGlobulins recognizes a unique three-dimensional Epitope. In the Bone Marrow, millions of different B-Cells are created daily, and then proceed to circulate throughout the bloodstream.

Since each has a different ImmunoGlobulin, each will bind to a different substrate. It is most often the case that a B-Cell will find nothing to bind to in its short lifespan, and rapidly be replaced by a new B-Cell.

In the event that a B-Cell's ImmunoGlobulin does find a substrate, that B-Cell will Clonally Expand, resulting in many B-Cells which recognize the same target.

Over time, the clones' ImmunoGlobulin Genes will mutate to improve the affinity for the target even more.

    B-Cells also differentiate into
      • Plasma Cells
      • Memory Cells

Plasma Cells will proceed to secrete vast quantities of ImmunoGlobulins, which will be identical to their parent's original surface.

These ImmunoGlobulins (or Ig's) will pass throughout the blood and attach to the foreign object, either disabling it themselves or summoning a Non-Specific Effector Cell.

Memory Cells by contrast are much smaller than Plasma Cells and don't immediately secrete anything. Instead, they persist in the body for many years and may never be activated.

However, in the event that the same foreign Organism returns, they will develop into Plasma Cells much more rapidly than the original B-Cells and proceed to secrete their ImmunoGlobulins.


T-Cells

T-Cells are responsible for destroying infected or Cancerous Cells, and for coordinating all Acquired Immune Responses. For this reason, T-Cell Immunity is generally called Cellular Immunity.

    Two sub-types of T-Cells are responsible
      • The Cytotoxic T-Cell (CD8+)
      • The Helper T-Cell (CD4+)

Each T-Cell has a unique surface molecule much like an ImmunoGlobulin's, called a T-Cell Receptor (TCR).

Unlike Ig's that can recognize any molecule, the TCR is restricted to recognize only short Amino Acid Chains, displayed on the surface of cells, in conjunction with a molecule, called the Major Histocompatibility Complex (MHC).

Almost all the body's cells are constantly producing MHC molecules and attaching small internal proteins to them, for expression on their surface. T-Cells probe the surface of all cells for MHC complexes.

In most cases, as with B-Cells, the CD8+ Cell never finds a complex, which its unique TCR recognizes. However when it does, it grows and divides (Colonal Expansion) into mature CD8+ and Memory CD8+ Cells.

Mature CD8+ Cells move though the body, searching for cells that possess complexes, to which the TCR will bind and proceed to destroy those cells.

Memory CD8+ Cells function like Memory B-Cells, they persist and will multiply and mature if they are re-exposed to the same MHC complex.


The Helper T-Cells (CD4+) are probably the most important Immune Cells, despite the fact that by definition they do not directly destroy any diseased cells or MicroOrganisms.

Rather, they produce a plethora of chemical factors (Cytokines), and express many surface elements, thereby regulating all other aspects of the Immune System. They too act by recognizing MHC complexes with their TCRs.

However, they recognize a special type of MHC (MHC Class II) which is only found on certain other Immune Cells called, Antigen Presenting Cells (APCs).

These cells, whether they are B-Cells or Macrophages, or some other Leukocyte, consume foreign proteins (specifically or randomly), and present small portions (Peptides), in conjunction with MHC Class II.

If the complex they present is recognized by a CD4+ Cell, that cell will produce chemicals which effect the cell, which presented the MHC complex, as well as other Immune Cells.

The CD4+ Cell will go on to divide and mature, producing more Cytokines that activate other Effector Cells and Memory Cells, which function as with CD8+ and B-Cells.

No Acquired Immune Response could take place without the chemicals that a CD4+ Cell produces, and its absence, as seen in cases of HIV infection, results in a collapse of the Immune System.


Innate/Acquired Dialogue

As the CD4+ Cell illustrates, no matter how important any single part of the Immune System may be, none is effective, if it is unable to communicate with the whole.

It is the synergy of the combined Immune System, not the potency of any one element, which makes it so capable a defender.

This fact, has lead to the study of the various ways the Immune System interacts with itself and its environment. Although an enormous amount of work remains in this area, we have already learned a great deal.

First
A number of chemicals produced by damaged cells and destroyed MicroOrganisms, known as Heat Shock Proteins, are also responsible for activating the Immune System.

This fact has been crucial to understanding, how the Immune System can respond to *damage* and *foreign*. Heat Shock Proteins activate both Innate and Specific elements, increasing Immune activity around the infection. (See: alphaB-Crystallin)

Second
Cytokines produced by Non-Specific Cells clearly affect the activities of the Acquired Immune System and vice versa.

The Cytokine environment is very important in determining what kind of response is made, and its effectiveness.

Many Parasitic Diseases owe their success to their ability to induce the production of Cytokines, which lead to a response that is not harmful to the Parasite.

It also seems that the initial cells to respond to an infection, determine the future course of the response.

Natural Killer Cells may respond to an infection by producing one Cytokine, while Macrophages would produce another.

The knowledge that the initial site of infection is critical, has lead to the development of more effective vaccine adjuvants and inoculation methods.

Third
The Acquired Immune System appears to impart a degree of Specificity upon its Innate brethren, through the use of a specific Surface Receptor for ImmunoGlobulin.

This receptor enables Macrophages and CD8+ Cells to use Ig's secreted by B-Cells, to recognize specific foreign factors.

The "network" theory of Immune regulation, suggests an even larger role for Ig - that AntiBody to AntiBody communication is responsible for the activation and eventual suppression of some Immune responses.

In summary, while it is convenient for descriptive purposes to break the Immune System into Innate and Acquired branches, which themselves can be further sub-divided, this is a somewhat artificial division.

Both branches influence each other and are in turn shaped by their environment.

END


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