The role of the THYMUS in human immunity and human individuality

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A Western Perspective on Immunity

Joey Santiago winced slightly as the women poured the beans into the plastic barrel where he stood. He screwed his eyelids down tightly and cried out when the beans fell across his bare feet. But they didn't stop pouring until the beans reached to his chin. Joey could smell the dust rising from the barrel, but he couldn't tell what kind of beans these were, or that it was women who were pouring them, or even that the sun was shining outside. Joey was born blind. But, as the dry pinto beans rose round him, just like his teacher said, Joey Santiago felt for the first time what he had never seen -- where Joey ended and where things not-Joey began. And Joey smiled, then giggled, then laughed out loud. Children who have never seen their fingers and toes, who have never seen their skin, have only vague images of where they begin and end. To help blind children form a mental picture of their bodies, teachers sometimes surround them with beans or styrofoam pellets so that the children can feel all of their skin at once. And out of this burial in beans comes a first ghostly image shaped like Joey or Mike or Ellen. Those of us with sight take a lot for granted. We're so certain we know what's us and what isn't that we rarely even stop to think about it. But where did all of that come from, and just how accurate are our visions of self? Were we born with them, or did we acquire them, like poor eating habits, as we grew up? Well, science has recently shed some light on these questions. And not only are the answers a little startling, they are likely to affect the way we live and die.
Images of Self

So here are short answers to the above questions. We aren't born knowing -- even biochemically-who we are. We acquire that ability in a most unusual way. And the image we form of ourselves is the result of many different processes -- some of which we are conscious of, most of which we aren't. I find that a little unsettling. If we don't know how it is we came to know who we are, just what do we know? And how much of what we know about people we spend a lot less time with -- like our spouses, our friends, our acupuncturists -- can we take seriously? But there is a backup system we can truly rely on. Beyond the realm of sight and smell, beyond taste, beyond hearing, beyond even the realm of touch, there is another "sense" that knows exactly who we are, and is damned well prepared to see to it we stay that way. A part of us that almost never has an identity crisis or multiple personalities, never wishes to be someone else, and never goes out in costume. A part of us that quietly sees to it that the individual in each of us remains just that, an individual, even in this world full of other individuals. And a new understanding of how this part of us works could change each of our lives.
The Thymus and the Biological Individual

In August of 1973, I attended the autopsy of one Mr. Z. This wasn't just some prurient interest on my part, it was required of Pathology Department graduate students. Nearing the end of that dissection, the senior pathology resident reached into Mr. Z's chest and pointed to a small organ, shaped more or less like a tiny, white, baby-grand piano behind the man's split sternum and just above where his heart had been. "This organ," the resident said, "the thymus, is vestigial. Whatever function it once performed, it is useless in humans." The senior pathology resident was wrong, dead wrong.

The thymus is the key to immunity. Somewhere late in the third trimester of human pregnancy, a large group of white blood cells departs the bone marrow, and via the bloodstream, emigrates to the thymus. Later, when these white cells leave the thymus, they have acquired all, or almost all, of the skills necessary for the maintenance and defense of the individual. No one knows how this happens. The process remains the shiniest of the Grails of immunology. But we do know a couple of things for sure. Most, possibly 95%, of the cells that check into the thymus, don't check out. The cells that do check out (the T lymphocytes) have been permanently marked by their experience. And finally, if the thymus fails to develop, your self image goes all to hell. Nude mice are a breed of mice in which the thymus never develops. You can graft chicken skin onto nude mice, and the mice will grow feathers. Now, while many people imagine that it is deep thought and all of those things we talked about in Psych 101 that allow us to come to know ourselves as individuals, I've become suspect. If a mouse that doesn't have a thymus can't tell itself from a chicken, then there's more to this than what they told us in school. Maybe the thymus and those lymphocytes that once rented space in the thymus are a lot more important than we've been led to believe.

If you aren't convinced, let me offer one more grim piece of evidence incriminating the thymus. The human immunodeficiency virus (HIV), the cause of AIDS, interferes mostly with the function of just one type of cell, a T lymphocyte. And often, HIV infection culminates in the complete loss of biological individuality, often ends with the fusion of a human being with the rest of the biosphere. And simply because some T lymphocytes were destroyed, a person we knew and loved gradually becomes a thing much more than a person, and we can only sit and watch as an individual human being becomes a community of living things. It is the thymus and the immune system that ultimately form the finest pictures of ourselves as selves. And it is the thymus and the immune system that ultimately define and defend us as individuals. There's little doubt that a host of factors -- psychological and philosophical -- are involved in the development of a self-image, but for the rest of the biological world, everything other than T-cells and the thymus is just window dressing.
Immunity and Sense of Self

We have a sixth sense that few of us ever suspected. This sense tells us about dangers that can't be seen, heard, tasted, smelled, or touched. And every one of the neurotransmitters that are produced by or that affect brain neurons are also produced by and affect T lymphocytes. So this sixth sense, the immune system, affects all the other senses and interacts directly with the brain, where images of self are born. This may explain why there exists a surprisingly good correlation between immunological development and the development of personality and ego. And if none of that moves you, there's good evidence that your immune system can kill you, that immunity is important to such seemingly unrelated events as childbirth and senility, heart disease and infertility, a broken heart and whom we choose to take as lovers. And finally, manipulation of the immune system is about to change the way we treat a whole variety of diseases, including diabetes, arthritis, and cancer, as well as all of the diseases of kidney, heart, liver, and lung that rely on transplantation therapy, and all of the infectious diseases, including AIDS.

So how does all this happen? How does the immune system develop and do that ego-centric voodoo that it does so well. Ultimately, to answer these questions, we must know the character of the thymus itself. But many of the functions of the thymus are still shrouded in mystery. So to gain some insight into these questions, we'll begin in another place, a much much older place. And we'll begin by asking, what was the driving-force behind the creation and the defense of the individual in the first place? Or in other words, what's the biological usefulness of individuality? It seems logical enough to propose that each of has an immune system to protect us from infection. But infections are a rather recent development, and I think even a casual consideration of the history of the immune system suggests an older, grander purpose.
The Biological Need for Self-Awareness

Sometime in the Precambrian, there was a dramatic change in the way living things did business. Among the hordes of single-celled organisms, there appeared collections of cells held together by a thin glue and a dedication to a single purpose -- survival of the whole. These were the first colonial or multicellular organisms, and this was a very big day in the history of life; multicellular organisms were the future. To this point in evolution, every cell had to do every job -- gather food, perceive light, respond to changes in salt concentration, eat, excrete, contract, locomote, reproduce, and so on. This left very little time in a cell's life for any of the higher pursuits, like color vision, taste, thought, or opposable thumbs. Because these new organisms were multicellular, designation of tasks, separation of management and labor -- that is, cellular specialization with all its wondrous potential was now possible. Just one thing stood in the road, but it was kind of a big thing. All of the advantages that accrue from cellular specialization -- eyeballs, bones, blood vessels, power tools, symphony orchestras, etc. -- are only advantageous if cellular communication is kept in-house. Put another way, a colonial organism gains no reproductive advantage -- which is the name of the game in evolution -- by designating certain cells as food-gathering cells if the food these cells gather is randomly shared with organisms who happen to be nearby. No, I gain an advantage only if I pass the primordial soup to just my cells. Only then are some of my cells free to give up food gathering and become kidneys or muscles or lungs.

But how do you learn to distinguish among billions of amoebas or bacteria? How do you learn to identify an individual and distinguish him or her or it from all the others in the shallow end of the pool? How did we learn to separate me from not-me. Well, it's no longer clear just how our ancestors accomplished this formidable task. But it is dear that they did. It is clear that from this primitive need to distinguish self from not-self came the primordial individual, the first concepts of self, and the beginnings of the modern immune system.
The Best Offense is a Good Defense

Fast forward a few million years. Multicellular organisms are everywhere now, at least everywhere in the water. They've got blobs and patches that will one day be ears or elbows or noses or fingernails. But among all the free-floating colonials, sessile organisms -- primitive sponges perhaps anchored firmly to the ocean floor -- have begun to appear. And there are a lot of advantages to being fixed in place -- proximity to food sources, more efficient sexual reproduction, near to family, a sense of place, etc. But as always, one thing stands in the road. And again, it's kind of a big thing. Crowded multicellular organisms have the potential to grow right into one another. That is, as organism A's fingers grow longer and longer, they may grow right into organism B's eyes, or ears, or nose -- and then what? And as if that weren't enough, a free-floating life form could just drop in at any time. It's no longer enough just to know who I am and who I am not. The continued existence of me as an individual is critically dependent not only on my ability to identify non-self, but also on my ability to destroy it -- self defense. As we watch, a sponge-like creature fixed to the ragged floor of some silent sea begins to darken in all the places where it has grown up against or into another fixed but slightly more modern-looking sponge-like creature. As this first recorded incidence of self-defense proceeds, the dark spots become larger, and then the first sponge-like creature topples, and driven by an unseen current, slowly rolls end-over-end into the darkness of the primitive sea. The concept of self has acquired teeth, and the true individual is born. Fast forward again, to a closeup of the human thymus and the slow rotation of a T-cell entering the thymic cortex. From a simple need for diversification and defense has come the most complex of human functions, save thought, perhaps. But then, maybe immunity is nothing more than a form of thought.
The Tabernacle of Narcissism

How does the thymus help each of us to learn who we truly are? In the first trimester of pregnancy, or thereabouts, just as the primitive cell layers appear in the fetus, there is a gradual protrusion of the third pharyngeal pouch, a portion of the fetal endoderm. At the same time a corresponding infolding occurs in the third branchial cleft, a component of fetal ectoderm. The protrusion is eventually surrounded by the infolding and pinched off to form the rudimentary thymus. At this point, the thymus is composed mostly of thymic stroma, the scaffolding that will support the thymic epithelium and the white blood cells that will work the egotistical magic thymuses are known for. The rest of thymic development depends on the bone marrow.Bone marrow, the source of all the cells of the blood, and of all self-awareness in the thymus, develops to a functional state late in the third trimester of pregnancy. At this point, the thymic rudiment with its stromal elements has also completed its development and sends a graduation announcement to the bone marrow.

A variety of cell types are just waiting for this signal and they move in large numbers out of the bone marrow, into the blood, and head for the thymus. The cells include macrophages and dendritic cells (white blood cells that will fill out the thymic epithelium) and many many millions of lymphocytes (also white blood cells, but very different from macrophages and dendritic cells). When these lymphocytes have completed their development, they will become T-lymphocytes or T-cells (T for thymus) and capable of things no other cell in the body can even approach.

Late in pregnancy all of these bone marrow cells arrive in the thymus and set up housekeeping, and by the day of birth, the thymus is fully functional, fully prepared to help the newborn boy or girl along the path of self discovery and fully prepared to begin its lifelong commitment to protection of a unique human being. The process of self-definition has begun.

But, because the immune system is a little slow to respond at the outset, we begin life with a little help from our mothers in the form of immunoglobulins (antibodies) passed via the placental circulation and the colostrum, or first milk. These antibodies protect us from the bacteria and viruses we are likely to encounter immediately after birth. I think it's interesting that during this time, children are also generally unable to distinguish themselves as individuals apart from their mothers. Thus at birth, self definition appears incomplete psychologically as well as immunologically.

But more to the point, the antibodies our mothers gave us protect us while our own immune system gradually comes up to full speed through exposure to the various specific microorganisms in our immediate environment.
The Biological Basis of Discrimination

Now back to the basic questions raised above. What happens inside of our thymuses during the last trimester of pregnancy to prepare us for the onslaught of infections we face as newly born human beings?

It begins with a mostly magical thing that occurs inside of the lymphocytes on their way to becoming T-cells. It is estimated that during their lifetime, the average person may encounter a billion to ten billion different foreign molecules -- molecules, that is, that came from some other living thing. As a group such molecules are called antigens. Antigens are most often proteins, and most frequently we encounter antigenic proteins on viruses or bacteria or parasites which invade our bodies. So the immune system cannot afford to ignore antigens. Each one must be examined and, if possible, an appropriate response must be initiated. Well, as luck (or evolution) would have it, we have a specific T-cell for just about every one of those antigens. That's nearly one T-cell for each antigen, and that's about ten billion unique populations of T-cells. Convenient certainly, but difficult to accommodate intellectually. T-cells, "see" antigens via a particular cell surface protein called the T-cell receptor. The receptor molecule allows T-cells to detect antigens and, with a little help from their friends, respond to those antigens. Seems okay so far, right? Well the problem is that there are only a few hundred genetic elements involved in producing these T-cell receptors. We all learned in high school (though some of us may have forgotten) that one gene encodes one protein. So how can a few hundred bits of DNA produce a few billion T-cell receptor proteins?

T-cells generate receptors specific for all of these different antigens by taking those few hundred bits of DNA and shuffling them repeatedly, like a cards, and each unique combination of genetic elements (cards) generates a different protein that can be used as a T-cell receptor. And as soon as one good T-cell receptor is generated, that T-cell stops its shuffling and wanders off looking for one, and only one (more or less), antigen. So when a T-cell is born, the genetic elements that will eventually come together to encode a T-cell receptor protein are not all together on the chromosome, as are the genes for all other proteins (with one other immunological exception). Instead T-cell receptors are encoded by a series of physically isolated bits of DNA called gene segments. These gene segments can be arranged in thousands, maybe hundreds of thousands, of combinations. The remainder of the required T-cell receptor diversity is generated by specialized mechanisms that cause occasional insertion and deletion of nucleotides (the basic stuff of DNA) as the T-cell receptor gene is formed. Together, these events generate billions of different T-cell receptors.

Here's how it works. Each T-cell receptor is composed of two proteins, an alpha-chain and a beta-chain (protein chemists are fond of Greek).And among the chromosomes of each T-cell there are two corresponding "families" of gene segments that are used to assemble these two chains of the T-cell receptor -- the alpha-chain gene family and the beta-chain gene family. The alpha-chain family contains variable gene segments, joining gene segments, and constant region gene segments. The beta-chain gene family also contains variable, joining, and constant gene segments, as well as one more group of genetic elements, called diversity gene segments.

When potential T-cells enter the thymus, each T-cell is induced to begin a process called genetic rearrangement -- shuffling the gene segment deck. In an apparently random fashion, beginning with the beta-chain gene family, one diversity (D) gene segment is selected, and one joining (J) gene segment is selected. Then, all of the intervening DNA is trimmed out, and those particular D and J gene segments are cemented directly to one another. Then, again apparently randomly, a variable (V) gene segment is selected, and all of the DNA between that V gene segment and the preformed DJ segment pair is also trimmed out. This VDJ "gene" is then transcribed along with a constant (C) gene segment to produce a particular type of RNA, called nuclear RNA or nRNA. Unnecessary pieces of this nRNA are then trimmed away and messenger RNA or mRNA is produced. From this "message" the T-cell then produces a beta-chain protein.

By a means that remains relatively obscure, the thymus and the T-cell have a way of knowing whether this beta-chain looks like it ought to -- that is, whether this beta chain has been made so it has the potential to join with an alpha-chain and form a functional T-cell receptor. No one knows exactly how this is done, but it is done well, and T-cells with beta-chains that look like pretzels or cheese doodles are quickly disposed of.

Each T-cell may actually have several shots at producing a good beta chain, since each cell can use gene segments on both homologous chromosomes (remember all chromosomes come in functionally similar pairs) as well as the potential to continue rearranging any gene segments that weren't clipped out when the first rearrangement occurred.

Once a "functional" beta-chain gene appears on the T-cell, the cell stops rearranging (shuffling) beta-chain gene segments and begins rearranging alpha-chain gene segments. Rearrangement of the alpha-chain gene segments occurs in similar fashion. But, because the alpha chain gene family contains no D gene segments, rearrangement is complete once a V gene segment has been joined to a J gene segment. Again, the T-cell has some means of identifying functional alpha-chain/beta-chain combinations (that is, a functional T-cell receptor). And once this event has occurred all rearrangement of gene segments ceases.

These genes are transcribed into nRNA, then trimmed to mRNA, translated into proteins, and inserted into the membrane of the T-cells. The T-cell has then acquired a unique T-cell receptor. Because the nature of the antigen that can be bound by a T-cell receptor is determined by the specific gene segments in each alpha- and beta-chain, the acquisition of a T-cell receptor makes each T-cell a specific for one antigen, one piece of one microorganism that may someday pose a threat to our continued survival. The T-cell will spend the rest of its life looking for just that antigen.

Well from all of this, it's pretty easy to see how, through the magic of genetic rearrangement, T-cells could generate a lot of different T-cell receptors. But, since there are only a few D segments, no more than a dozen or so J segments, and at most a hundred or so V segments, genetic rearrangement alone, as powerful as it is, cannot be responsible for the billions of different T-cell receptors needed to deal with all of the antigens we might encounter in an average lifetime.

Well, to solve this problem, the immune system has evolved another level of immunological legerdemain. As each of the D segments is joined to a J segment, and as each V segment is joined to a J or DJ segment, nucleotides (the ground stuff of genes) are randomly added or deleted where the splice is formed between the gene segments. The net effect is to change, add, or delete one or more amino acids in the protein produced from these genes. As it turns out, the areas of the alpha-chain and beta-chain genes where the splices form correspond directly to the part of the T-cell receptor that is in closest contact with an antigen. As a result, the number of possible T-cell receptors goes up dramatically and in a completely unpredictable way.

When all of this is taken together, it becomes possible for T-cells as a group to generate over 1016 different T-cell receptors. That's 10 with 16 zeros after it, which is a very large number. And usually more than enough to deal with all the creatures we encounter between birth and death.

Nowhere else but in lymphocytes does the DNA ever change, except by mutation. Every other cell in our bodies is limited to just the DNA that parents provided. But lymphocytes can re-sort this DNA, add to it, trim it, and put it all back together in novel ways. That's a pretty remarkable adaptation -- T-lymphocytes, the cells that define us as immunological individuals, are not limited by the DNA that was our mother's or our father's. T-cells can, and do, reassemble their DNA into configurations that are absolutely unique to each individual. The result is that lymphocytes, the cells responsible for defining and defending our individuality, are the only cells in the body with DNA that is absolutely-unique to each of us, DNA that is demonstrably different from the DNA we received from our mothers and fathers. I find this at least intriguing.
Eliminating Self-Destructive Tendencies

I mentioned that this process appears to occur in a completely random fashion. That means, the development of T-cells isn't driven by any foreknowledge of the antigens they are likely to encounter as they roam the battle ground of the body. Or in other words, T-cell receptors generated by genetic rearrangement in the thymus are in no way preselected to react with non-self (i.e. antigens, bacteria, viruses, etc.). That means that following random selection of V, D, and J gene segments for the assembly of a T-cell receptor in the thymus, the T-cell receptor produced from those gene segments may react with: a) nothing, b) a protein on the cells of our own kidneys, or c) the most recent strain of flu virus. So the newly formed T-cell is a little like a child with a hand gun in a room full of people that may be family or may be foe -- power enough to kill, but not yet sense enough to know who to kill.

Two things need to be done quickly -- determine if the gun is loaded and teach the child how to recognize his own flesh and blood. Those two things are in essence what the thymus does and are the means by which we come to know and defend ourselves as individuals. The way the thymus does this is, I think, rather remarkable. Beyond inducing the rearrangement of gene segments, it also the job of the thymus to determine if the assembled T-cell receptor is capable of binding anything (loaded), and if it can bind something, whether that something is a part of our own bodies (aimed at our own flesh and blood). Both of these are clearly important jobs. We can't allow our immune system to get cluttered up with T-cells that are incapable of helping us in our time of need (infection). And even more importantly, we can't allow T-cells to leave the thymus if those T-cells are bent on destroying some essential part of us, like our pancreas. The means by which all of this is accomplished by the thymus aren't completely clear. But since this is such an important part of how we come to know ourselves and how we avoid at least some forms of self-destructive behavior, let's consider what is known.

First of all, you might imagine that the thymus has some means of identifying T-cells as they arise and then destroying useless or dangerous ones -- as the immune system does with bacteria. Well, that doesn't seem to be the case. It actually appears that the thymus is more into the salvation game. Either shortly before or soon after potential T-cells enter the thymus, a fail-safe program is turned on. Basically, a self-destruct button is activated, and if something isn't done to turn it off, each T-cell will eventually implode. This programmed cell death is called apoptosis, and it is a means by which human bodies get rid of lots of cells as they become unnecessary. But in the thymus, what this means is that each cell is suicidal, and only if it is saved from self-destruction by the thymus will any T-cell live to see battle in the trenches beyond.

So as the T-cells move from the thymic cortex (the outer portion) to the medulla, they must meet two criteria, or they will die. Each T-cell must produce a functional T-cell receptor -- that is, a T-cell receptor that can "see" antigen (we'll talk about what that means shortly). And, that T-cell receptor must not see self, at least self as it appears in the thymus. Only then is the self-destruct button in the T-cell turned off, only then is the T-cell rescued from its pre-commitment to an early death. Most T-cells (more than 95 percent) don't make it.

How the first of these tasks is performed by the thymus -- that is, how the thymus can tell if the T-cell has assembled a functional T-cell receptor -- is poorly understood. Apparently, T-cells must exchange some sort of handshake with the cells of the thymic epithelium, and in return, the cells of the thymic epithelium provide the code that shuts off the self-destruct sequence. And that all important handshake can only occur after a normal T-cell receptor has formed. Beyond that, not much is clear. But the end result is that once the T-cell receptor is formed on the T-cell, the thymus quickly determines if the T-cell's gun (T-cell receptor) is loaded. If it's empty that T-cell's self destruct program continues uninterrupted and the cell soon dies. If the gun is loaded, the cell is given a brief reprieve while the thymus figures out who the gun is aimed at.

Much more is understood about this second part of the process -- how the thymus comes to know if the T-cell receptor is aimed at self or than non-self. This interrogation of the T-cell, this evaluation of the T-cell's ultimate motive, involves at least two types of cells found in the thymic epithelium, cells that also come to the thymus from the bone marrow -- thymic macrophages and dendritic cells.

Macrophages and dendritic cells are also white blood cells, but they are very different from lymphocytes. The job of macrophages and dendritic cells is essentially that of the police librarian -- they catalogue and display descriptions of every character (biological macromolecule/pathogenic microorganism) good or bad (self or non-self) that's recently been in the vicinity. In the thymus, developing T-cells are forced to read through this library and the thymus sorts out those cells with a predilection for self from those with a predilection for non-self. Only T-cells with exclusive interest in non-self are rescued from their self-destructive tendencies and allowed to complete their development. Just how this happens forms the basis of not only thymic "education" but also of nearly every immune response. It involves a remarkable group of macrophage and dendritic cell proteins encoded by genes within a specialized region of human chromosome 6, a region called the major histocompatibility complex (MHC).

It's called the major histocompatibility complex because this complex of genes was discovered during research on grafting of mammalian tissue including organs and skin (histo = tissue). And, it was shown that the products of these genes had a major effect on the survival of the graft or the compatibility between the graft recipient and the graft. But, the products of MHC genes do much more than just affect graft survival.

Genes of the MHC encode molecules that grab up bits of any protein (and probably other biological macromolecules like carbohydrates and lipids) produced inside of or recently eaten by any cell -- this includes proteins from infectious agents as well as proteins produced by our own cells, and most especially, MHC-encoded molecules grab up bits of proteins produced and eaten by macrophages and dendritic cells. Once they have hold of these bits of protein -- self or non-self -- MHC molecules race off to the surface of the macrophage or dendritic cell and display their proteins to anyone who is interested -- and T-cells are interested, very interested.

This process is called antigen presentation, and there are actually two types of antigen presentation performed by two types of MHC molecules -- cleverly named MHC class I and MHC class II molecules. MHC class I molecules specialize in presentation of proteins produced inside of cells, and MHC class II molecules specialize in proteins eaten by cells. MHC class I molecules appear on nearly all cells of the body. MHC class II molecules are found only on specialized antigen-presenting cells -- like macrophages and dendritic cells. And between them, MHC class I and II molecules allow macrophages and dendritic cells to present all of the self or non-self proteins found inside or nearby. This is a nearly ideal system for keeping track of who's in the neighborhood, and whether they're friends or not.
The End of Indifference

As I mentioned, an MHC molecule is equally capable of binding up bits of self and non-self proteins, and this is important later on for the development of the immune response. But in the thymus, the situation is a little different. The thymus is, in a sense, isolated from the blood and lymph circulation. So, under normal circumstances, infectious agents, such as bacteria and viruses, are excluded from the thymus. As a result, all of the proteins available for presentation by thymic dendritic cells and macrophages are, by definition, self proteins. As T-cells develop in the thymus, each cell is forced to examine the bits of self protein displayed by thymic macrophages and dendritic cells. If a T-cell recognizes one of these bits of self protein -- that is, if this cell's T-cell receptor binds to a piece of self protein on the surface of a macrophage or dendritic cell -- that T-cell is declared self-reactive and is allowed to complete its self-destruct program and die. If, on the other hand, a T-cell demonstrates a true ignorance of self (fails to bind to any of the self proteins displayed on the thymic macrophages and dendritic cells), that T-cell is given its graduation and its commission. Its allegiance established, this fully armed T-cell is then sent off to the biological wars.

If a newly graduated T-cell has acquired a T-cell receptor that reacts with a bit of foreign (non-self) protein presented by an MHC class II molecule, the cell is called a T-helper cell. If, on the other hand, a T-cell has acquired the ability to react with a bit of foreign protein presented by an MHC class I molecule, the cell is called a T-cytolytic cell. Each of these types of T-cells performs a unique set of functions in an immune response. More on that later.

But the end result is that the thymus, using a couple of relatively simple tests, has eliminated all T-cells with useless receptors and most T-cells with self-reactive receptors. The remaining T-helper cells and T-cytolytic cells are then released into the tissues and fluids of the body where they monitor all cells for infection or ingestion of infectious microorganisms.

A pretty nifty system, huh? But clearly not a fool-proof system. All self molecules aren't present in the thymus. For example all of the proteins found in kidney or liver cells are probably not available for presentation by thymic macrophages and dendritic cells. So T-cells reactive with some of the molecules found in our kidney or liver cells may (and actually do) escape the thymus. Other mechanisms are in place to deal with these cells and we will talk about them later. But, because most of the metabolic activities of a liver cell (respiration, replication, elimination, etc.) are identical to those of a thymic macrophage, more, much more, than ninety-percent of the proteins in these two cell types (and most other cell types) are the same. Because of this, elimination of T-cells reactive with thymic macrophages and dendritic cells coincidentally eliminates T-cells reactive with most of the proteins found in all other cells of the body.

Shortly before birth, the cells which will form the adult immune system begin to appear in our bone marrow. They wait there for a signal from the thymus. These bone marrow cells, destined to become lymphocytes, have nearly unimaginable potential for recognition and destruction of microorganisms. But if this potential is released outside the educational confines of the human thymus, biological chaos would follow. Instead, in a normal fetus, these lymphocytes migrate to the thymus when called, and there they are educated in the ways of individuality.

As each lymphocyte enters the thymus, two switches are thrown. The first switch initiates a program of events that will ultimately result in the death of the cell, unless something else happens to turn the program off. The second switch causes the lymphocyte to begin assembling bits of diverse genetic material into a gene that will produce a protein called a T-cell receptor. If the T-cell receptor is assembled properly, it arrives at the surface of the lymphocyte and this cell is no longer blind to antigen (self or non-self). The thymus then moves quickly to do two things. First, the thymus temporarily discontinues the lymphocyte's self-destruct program; and second, the macrophages and dendritic cells of the thymus immediately determine whether the newly formed T-cell receptor is reactive with self. If the T-cell receptor is a threat to self, the lymphocyte's destruct program is allowed to run its course, and the cell dies. If the T-cell receptor is not self-reactive, the destruct program is switched off and that lymphocyte is allowed to emigrate from the thymus as either a T-helper or T cytolytic cell.
So What Does it All Mean?

The consequence? Inside each of our thymuses an image has formed -- a negative image -- created by the destruction of self-reactive T-cells. And within the collective consciousness of the remaining T-cells is a shape, an image of self surrounded by an pointillist portrait of the rest of the world. A thymic hologram, in a sense, with a precise picture of exactly which proteins are ours and which belong to measles, mumps, and flu viruses; a color-reversal of which cerebrosides and gangliosides make up our brains and spinal columns and which are parts of other minds; a bit-map describing every facet of the biological world, and at the very center, the image of a human being, unique in every way.

No one knows for certain all the ways we use this thymic image. But we do know for certain that the thymus and all the other elements of the immune system regularly speak with the brain and all the other elements of the nervous system. Of course, no one ones exactly what lymphocytes and neurons say to one another. But I imagine, these cells, like the rest of us, are prone to focus on themselves at times, are given to certain egocentricities and idiosyncrasies that ultimately have a great deal to do with just who we think we are.
Elements & Function in Immune Response B-cell

• Lymphocytes - reside in lymph nodes, spleen, or other lymphoid tissues, where it is induced to replicate by antigen binding and helper T-cell interactions; its progeny (clone members) form memory cells plasma cells.

• Plasma cell - Antibody-producing "factory;" produces huge numbers of antibodies (immunoglobulins) with the same antigen specificity; represents further specialization of B-cell clone descendants.

• Helper T-cell - A regulatory T-cell that binds with a specific antigen presented by a macrophage; upon circulating into spleen and lymph nodes, it stimulates production of other cells (killer T-cells and B-cells) to help fight invader; acts both directly and indirectly by releasing lymphokines.

• Cytotxic T-cell - Also called cytolytic or killer T-cells; activated by antigen presented by any body cell recruited and activity enhanced by helper T-cells; its specialty is killing virus-invaded body cells and cancer cells; it is involved in rejection of foreign tissue grafts.

• Suppressor cell - A T-cell that most likely activated by antigen presented by a macrophage; slows or stops activity of B and T-cells once infection (or onslaught by foreign cells) has been conquered.

• Memory cell Descendant of activated B-cell or any class of T-cell; generated during initial immune response (primary response); may exist in body for years after, enabling it to respond quickly and efficiently to subsequent infections or meetings with same antigen Macrophage Engulfs and digests antigens that it encounters and presents parts of them on its plasma membrane or recognition by T-cells bearing receptors for same antigen; this function, antigen presentation, is essential for normal cell-mediated responses; also releases chemicals that activate T-cells and prevent viral multiplication.

• Antibody Protein produced by B-cell or by plasma cell; antibodies produced by plasma cells are released into body fluids (blood, lymph, saliva, mucus, etc.), where they attach to antigens, causing complement fixation, neutralization, precipitation, or agglutination, which "mark" the antigens for destruction by complement or phagocytes

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By Gerald N. Callahan

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