1. Cellular Immunity:

     In the last chapter, it was noted that skin and mucus membranes are a fairly effective mechanical barrier to invasion. Nevertheless, foreign objects and foreign organisms pass this barrier continuously. Yet, even after the barrier is passed, there are two lines of cellular defense. Which of these two lines is first crossed is related to the way in which the invasion is introduced and the nature of the invasion.

     When, as usual, the primary route of entry of the invading organisms or particles leads them to the interstitium but not into the blood, the first defense is ordinarily a reaction of certain large tissue cells, histocytes, which are sometimes able to engulf them. These cells, because they are large, macro-, and appear to eat, -phage, the offending materials are also called tissue macrophages. Such invaders as gain access to the lymphatic system are carried to the lymph nodes. These nodes are structurally a network, a reticulum, containing lymphocytes through which lymph is sieved. The walls are heavily lined by cells which show the same ability to carry out phagocytosis as the histiocytes. Other cells, to be discussed below, are also present. The lymph nodes are part of the reticulo-endothelial system, which is widely dispersed throughout the body. The spleen, bone marrow, and liver are three important centers for this system, but the monocytes of the circulating blood and the histiocytes themselves are part of it.

     The reticulo-endothelial system removes foreign particulate matter from the body fluids. In the case of non-living materials, this reaction is usually useful, though it may become harmful in circumstances to be discussed below. Most living invaders may be destroyed by the cells of the reticulo-endothelial system, but some flourish within these cells, for example, the tuberculous organism. In either case, invasion usually stimulates the growth of the reticuloendothelial system, which is often noticed as enlargement of the lymph nodes. Swollen lymph nodes, "glands", are often observed in infectious and invasive processes, and the spleen and liver may become enlarged.

     The neutrophiles of the blood are also phagocytic. Unlike the macrophages, they move very actively, for being blood-borne, they can get quickly to the vicinity of any invasive process. Through an extraordinary but ill-understood process, they insinuate themselves through the capillary wall. In the interstitial space, they act as if they "heard a call" from the area of invasion and proceed toward it. The chemical agent which summons the leukocytes is called leukotoxin. Another agent causes increased production of leukocytes. Increased production of leukocytes and their attraction to the site of invasion are the characteristic responses to certain infections, the pus producing (pyogenic) ones.

     At the invasion site, the neutrophiles, like the histiocytes, phagocytize the invaders. By their own motility, they are more able to find the invaders where they are. They also appear to phagocytize more rapidly than the histiocytes. Thus, the neutrophiles may act as a second line of defense, giving support to faltering histiocytes. As noted above, the neutrophiles, described as a second line of defense, may act as a first line of defense if, for example, the initial invasion is directly into the blood stream.

     If the combined activities of histiocytes, lymph nodes, and neutrophiles fail to confine the invasion, it may reach the blood stream, by which it can be widely disseminated. Neutrophilic activity in the blood stream may serve to diminish the numbers of the invaders or even to destroy them altogether, but usually by the time invading microorganisms have found their way to the blood stream, bacteremia, very widespread infections result, septicemia. Only a few years ago, septicemia or blood poisoning, which essentially represented a failure of the mechanisms of cellular immunity, almost always had a fatal outcome. This picture has been considerably changed by the development of the sulfa drugs and the antibiotics, but even today, the development of septicemia must be taken as a very serious sign.

2. Chemical Immunity:

     The knowledge that persons who had had certain diseases did not contract them a second time is very old. The Greeks seem to have been aware of it, as were the Chinese, who even made practical use of it by inhaling dried and powdered crusts of the lesions of persons with smallpox. This produced a mild smallpox (the disease is about 50% fatal normally), and after recovery, a lifetime immunity.

     Edward Jenner, an English practioner of medicine who was born and died before the epic work of Pasteur, appears to have arrived at the idea of immunization independently. In his practice, he had become aware of a popular belief that one could not develop smallpox if he had had cowpox, a mild disease quite common among milk maids. It is to Jenner's credit that he did not treat this information as a folk legend, but pursued it. Just before the beginning of the 19th century, Jenner's investigations led him to propose that cowpox be deliberately induced to ward off the more serious disease.

     The procedure worked, but there was a temporary setback when one of Jenner's followers tried to induce cowpox in his London patients. Some of them got smallpox instead. It was shown later by Jenner that the vaccine responsible for this disaster contained the smallpox agent as well. Within 15 years, the vaccination procedure had been accepted in most civilized countries, and it is now required of most persons that they and their children be vaccinated.

     The extent of Jenner's accomplishment can perhaps be better appreciated if it is realized that the bacterial and viral theories of disease were yet to come, that the chemistry of the time had no word for the nature of the infecting agent (or for that matter the protecting one), and that the medical folk lore of the time was, on the whole, no more correct than it is today.

     Louis Pasteur, the founder of bacteriology, made the next great contribution. The bacteria of chicken cholera survive in a culture broth, and inoculation of the broth produces the disease in other chickens which is quite fatal. By chance, such a culture was left in Pasteur's laboratory for a few months. This "old" culture produced a very mild disease in other chickens. A new culture was then given to the same chickens. They were immune to the disease. Pasteur recognized the similarity to Jenner's work and named the procedure of giving an old, weak (attenuated) strain of bacteria to produce immunity without disease vaccination.

     In one of the most famous medical experiments of all time, Pasteur immunized a number of farm animals against anthrax. In this case, attenuation was produced by culturing the anthrax organisms at unnaturally high temperatures. The injured organisms conferred immunity without causing disease. Following the same line of thought, Pasteur attempted to immunize people bitten by dogs with rabies. This disease, also called hydrophobia, invades the central nervous system. The dried spinal cords of rabbits infected with rabies presumably contain the virus in attenuated form. Extracts of such cords, given just after a dog bite, have been thought to protect against rabies in man. Oddly enough, more than three quarters of a century later, it is not known whether this vaccine is really effective, it is not always known whether the animal inflecting the bite was rabid, nor is it at all certain that all people bitten by rabid animals will develop the disease. The best guess is that only 15% will. Thus, the rabies immunization procedure is often used in people who would not have needed it. The procedure was not in itself harmless, and new methods of attenuating the virus have reduced the risk of the immunization.

     After Pasteur, the field of immunology experienced explosive growth. The idea that infectious organisms produced antigens which provoked the body to produce neutralizing antibodies was followed by the recognition that the antibodies produced in response to the injection of one antigen might react with other antigens as well. Detrimental effects of the antigen-antibody reaction began to be noted. For example, the reaction may result in the formation of undesirable products, the most familiar is allergy, in which a relatively harmless antigen provokes the formation of an antibody. When the antigen and antibody react, substances may be produced which actually damage cells more than the antigen, an effect which may be seen in hay fever and food allergies. A more serious abnormality occurs in persons who, as a result of bacterial alteration of some of their own organs, produce antibodies against these very organs which in time destroy the organs. The bane of transplantation is an unwanted immunity, which results in the rejection phenomenon (See Chapter 31).

     The extraordinary progress made in immunology is sometimes used to explain the disappearance of the common infectious diseases. In fact, most of these diseases, which were once the dominant causes of illness and death, began their decline in the United States between 1900 and 1910. Effective immunizations against them were developed later, sometimes much later. It is not clear why these diseases have been declining, but the student should avoid the easy temptation to attribute the decline to the development of immunization or treatments based on immunological principles. However, it seems quite likely that the immunology of the future may result in important changes in our concepts of some diseases, perhaps also in our methods of treatment.

     As noted, infecting organisms may produce an antigen or a group of antigens. However, antigens need not be a part of an organism at all. Thus, some fairly simple compounds, including a number of drugs, may be antigenic, and the toxins of some bacteria, quite free of the bacteria, may be very effective antigens. The diphtheria toxin, for example, is a very potent antigen. This toxin can be modified so that it is no longer toxic (toxoid), yet it is still antigenic.

     When an antigen is introduced into an organism, it appears to be "read". It is not clear what cells do the "reading", but in general, the result of the reading is clear. If the antigen is recognized as being foreign, antibodies against it will be produced. If the antigen is accepted, no antibodies will be made. It may be noted here that the newborn animal is virtually devoid of the mechanisms of chemical immunity. It appears that in its first days of life it familiarizes itself with its own antigens, which are thereafter found acceptable, while other antigens are rejected.

     The source of antibodies is somewhat controversial. They were long believed to be directly derived from small lymphocytes, but it now appears more probable that these lymphocytes respond to a new antigen by giving rise to two lines of cells, one of which becomes the plasma cells, the actual producers of the antibodies, and the other of which looks like the original small lymphocytes, but has been altered by the antigen in such a way that it "stores" the memory of the antigen. This modified small lymphocyte can presumably change quickly into a plasma cell, properly constructed to produce exactly the right antibody for the antigen with virtually no delay.

     Plasma cells, which are very rich in ribosomes and endoplasmic reticulum, appear unusually well suited for protein synthesis. They are found, although in small numbers, in the walls of the vessels of the reticulo-endothelial system. It seems probable that plasma cells produce the antibodies which react with the original antigen throughout their lives. A new confrontation with antigen acts to metamorphose the lymphocytes altered by the original antigen to plasma cells, which may appear in large numbers upon this second confrontation.

     Thus the small lymphocyte, faced with a new antigen for which the correct antibody must be made, may in effect be considered as if it were "studying" it. After completing its "study", it gives rise to the plasma cells which have been "instructed" to produce the correct antibodies, also to small lymphocytes which have "memorized" the antigen and the appropriate antibody response and can, on very short notice, convert into plasma cells which make the right antibody for the now "known" antigen.

     Antibodies are very large proteins, molecular weight 160,000 to 1,000,000, that travel with the globulins of the blood. They are specific for their responsible antigen, but the specificity is an imperfect one. One may imagine the antigen molecule as a sword containing a harmless handle attached to a harmful blade, for which the antibody acts as a sheath. The antibody will react with the antigen which provoked its production, but it will also react with similar antigens, whose "blades" are sheathed by it provided that these "blades" fit the "sheath".

     Of course, not all antigens have the same configuration. Thus, the antibody to one antigen may not work at all on another antigen

      The analogy may be pursued further. The antigen "blade" provokes the formation of the antibody "sheath", which conceals it exactly. Antigen and its made-to-order antibody may present an external molecular facade which the organism recognizes as familiar. Yet internally, the strangeness of the antigen is precisely matched by the strangeness of the antibody, just as the strangeness of the blade is matched by the strangeness at the sheath fashioned to fit it.

     The combination of antigen and antibody is usually associated with the disappearance of a group of plasma proteins called complement. This disappearance, called complement fixation, is not necessary for some antigen-antibody reactions. When it does occur, a very complicated and incompletely understood series of reactions between the components of complement and cells which bind antibody at their surface may result in cellular injury. Nevertheless, there is no evidence that the presence of complement enhances the defense reaction against invasion. In fact, the major harm done by complement fixation appears to be to the host itself, and complement fixation may be responsible for some allergies.

     The overall effect of the antigen-antibody reaction is one of neutralization of the antigenic pact of the foreign invader. In the case of chemical antigens, no effect may be seen beyond loss of biological potency. When the antigen is part of a cell surface, the surface may be so altered that the cells may stick to each other, or agglutination; sometimes the surface alterations result in the formation of weak spots so that the cells rupture, lysis. In many cases of bacterial infection, the antigen-antibody reactions neutralize the products of the invader (eg. toxins) without doing particular harm to the invaders themselves. The cellular immunity mechanisms, in such cases, defend from the invading cells, while the antigen-antibody mechanism defend from the toxins produced by these cells.

a. Interspecies and Intraspecies Immunity:

     The same mechanisms which recognize "non-self" antigens in other organisms and foreign substances recognize the "non-self" character of tissues and organs from other animals of the same species. The greater the antigenic dissimilarities between the accepted "self" and the rejected "non-self", the more rapid and diverse will be the formation of antibodies. Thus, most of the proteins of the heart of a pig named Snowball probably have sequences which read "pig" as well as other sequences which read "pig-Snowball". An extract of this heart injected into a pig named Napoleon who has sequences reading "pig-Napoleon" will result in the formation of anti "pig-Snowball" antibodies, but Napoleon will not form "antipig" antibodies. The "pig-Snowball" sequences will be considered strange, and antibodies will neutralize them, but perhaps not for a little while. On the other hand, extracts of the proteins of the heart of a horse named Boxer, containing horse-Boxer sequences, are doubly strange to pig Napoleon, who will respond to them by fashioning "anti-horse" and "anti-horse-Boxer" antibodies, which will neutralize the doubly strange antigen much more quickly than the singly strange antigen of pig-Snowball.

     This fact, which will be considered again in the next chapter, puts a much more formidable obstacle in the way of animal organ transplants to man than is the case with man-to-man transplants. As yet, no solution to the problem of heterotransplant rejection is known, but it is by no means inconceivable that it will be found.

     The transfusion of human blood illustrates many of the principles of chemical immunity. Though such transfusions are a kind of transplantation, they will be taken up here to illustrate these principles.

3. Blood Transfusion:

     Though blood transfusion may be considered a kind of transplantation, the problems are much simpler and may serve as a useful introduction to transplantation problems.

     A number of rather unfortunate attempts to transfuse animal blood to human recipients had disastrous results, which was probably because the blood transfused was, in essence, totally strange to the recipient. Antibodies would be fashioned against the blood antigens very quickly, the cells of the transfused blood would be agglutinated or lysed, its proteins would be precipitated, and complement fixation would injure the body cells of the recipient. It was soon realized that only human donors could be used for human transfusions.

     Even here, serious problems were encountered. Different humans appear to have different antigen-antibody systems in their blood streams. Fortunately, the specificity is not so great as is the specificity of other body cells, though it has some rather peculiar characteristics.

     A number of antigens have been identified in human red blood cells. The oddest thing about some of these antigens is that other humans already have antibodies to them. This is rather different from the usual antigen-antibody response, where antibody is formed after antigen is introduced. In man, the antibody is already present.

     The principle antigens in red cells which follow this rule are the antigens long ago named A and B. Some persons' red cells contain antigen A, some contain B, some contain both, and some contain neither. So far as these antigens are concerned, there are already antibodies in the plasma to the other antigens, not self. Thus, a person with B cells contains the anti-A antibody, symbolized "a", while a person with A cells contains "b" antibody. If both A and B antigens are present, there will be no antibodies, but if the cells contain neither, there will be antibodies to both.

     This arrangement, symbolized in the Table that follows, is indeed strange. One may wonder what useful purpose can be served by being immune to another person's red cells. Yet it is always true that this type of immunity between blood types exists.

     Examination of this Table will show that any blood type is incompatible with any other. Thus when 0 blood is given to an AB recipient, the a and b antibodies of the donor will react with the A and B antigens of the recipient. The 0 cells of the donor will not be attacked, but the AB cells of the recipient will be. Note, however, that the a and b antigens of the 0 donor will be quite dilute in the AB recipient, so the reaction may be quite slow. This has given rise to the idea that the person with 0 type blood can act as a universal donor. This is a very unsafe assumption, and its mirror image is that the AB person, who has neither a nor b antibodies, can safely receive any type of human blood, an equally unsafe assumption. In extreme emergency, 0 type blood may be used, if nothing else is available for a person of another blood type, and likewise, in extreme emergency, AB persons may receive any type of blood, but the emergency in either case should be genuine.

     The blood types listed above are those in which antigen on red cells have antibody counterparts in the plasma of other persons already present. There are, however, at least 60 other antigens on the red cell whose presences are capable of eliciting antibody formation. Most of these are of minor importance; however, at least one of them has excited an enormous amount of popular and medical interest.

     This is the Rh antigen, so named because antisera to Rhesus monkey red cells react with human red cells containing this antigen. Persons whose cells carry the Rh antigens are called Rh positive, who make up about 85% of the population in the United States.

     In normal circumstances, there is no Rh antibody in either Rh positive or Rh negative persons. However, the formation of anti Rh antibody can be induced in any Rh negative person by giving him Rh positive cells. This has, in the past, led to very serious consequences. Thus, a person of type 0 who is Rh negative, may have received Rh positive type 0 blood from a donor before the Rh factor was identified (Rh factor was first recognized in 1938). The recipient in such a case would develop Rh antibodies, which would do no particular harm, for the donor cells would be destroyed quite slowly as the antibody developed. The recipient would, however, be modified to have Rh antibodies already present in circulation. If, at some later time, another transfusion was required, and the donor was again Rh positive, the donor cells would encounter the Rh antibody already formed in the recipient. Though both donor and recipient were of type 0, their bloods would be quite incompatible.

     This incompatibility is sometimes seen in pregnancy. It may occur in one of two ways. An Rh negative woman who has developed Rh antibodies through a previous transfusion may become pregnant with an Rh positive child. Usually, maternal and fetal circulations are quite separate; however, if there is any crossing over of blood between them--and this does happen--the anti Rh plasma of the mother can attack the Rh antigens of her child, damaging or destroying its red cells. Such a child may be born with severe hemolytic disease, and some die during pregnancy. The condition, called erythroblastosis fetalis, is not confined to the children of women who have had obvious transfusions. An Rh positive fetus in an Rh negative mother may through breakdown of the placental barrier cause its mother to develop anti Rh antibodies. These will not usually injure the fetus, which provoked their formation, but the next pregnancy may result in the formation of an Rh positive fetus and also show transmission of the maternal Rh antibody across a damaged placenta. The fetus will be damaged just as if the mother had had a transfusion of Rh positive blood earlier. Fortunately, this condition is quite rare and there are fairly effective treatments for it.

     The most heroic treatment now in routine use is complete replacement of the fetal blood with Rh negative blood of the correct type. Note that transfusion is not usually enoug, for the blood of the infant must actually be removed and replaced with the blood of the donor.

     It is impossible to leave this subject without stressing that the conditions required for the production of erythroblastosis fetalis occur very rarely. Only one woman in seven is Rh negative, and of these, one-seventh will marry Rh negative men and have no problems. The six in seven who marry Rh positive men will have Rh negative children about one-seventh of the time, so these pregnancies will also be uneventful so far as the Rh factor goes. The Rh negative woman married to an Rh positive man producing an Rh positive baby, which will occur in 10% of all pregnancies, will develop Rh antibodies as the result of placental transfer one-twentieth of the time, or in 0.5% of pregnancies. First pregnancies are almost never affected, even though the mother develops Rh antibodies. It is the second and later pregnancies which have some hazard, but, again, there must be placental transfer of the antibody, which occurs only one time in twenty. Furthermore, most cases of the disease are quite mild, and recovery is usually spontaneous. There have been serious suggestions made that marriages between Rh negative women and Rh positive men be forbidden, but these suggestions show a splendid isolation from the facts of human biology as well as human behavior, though they cannot be dismissed entirely in a country which once outlawed alcoholic beverages.

     There are many other antigens attached to red cells, but few of them cause trouble. They are chiefly interesting because their hereditary transmission follows known rules, so they are therefore used occasionally in deciding paternity of a child, though in a surprising number of cases, such evidence is not admissible in court.

4. Diseases of the Immunity Mechanisms:

     In general, cellular immunity mechanisms tend to become less effective in older persons. The slow healing of wounds in such people is well known. There have been interesting attempts to reverse this tendency; one of them, designed to prolong life and youth indefinitely, was designed by the Soviet biologist, Bogomolets. He was able to produce a substance called antireticular cytoxin serum, which by attacking the reticuloendothelial system, induced its increased responsiveness and reversed the changes of aging. Unfortunately, Bogomolets was unable to follow through on his work, dying of old age in his early sixties. Little has been heard of antireticular cytoxic serum since.

     The granulocytes, particularly the neutrophiles, which are an important line of defense against invasion, are produced in bone marrow. Some drugs cause complete suppression of granulocyte formation, agranulocytosis. These persons, deprived of granulocytic defenses, are easily invaded by a variety of organisms. Before the development of antibiotics, they would almost invariably die, but even now, their chances are not good.

     The troublesome thing about agranulotosis is that it seems to be so unpredictable. A drug which has proved perfectly safe in a thousand people may produce a total agranulocytosis in the next. Some drugs are more likely to produce agranulocytosis than others, but no general rule has been found for the prediction of safety as yet. Two of the most dangerous drugs from this standpoint are aminopyrine, once used as a pain reliever, but since taken off the market, and chlocomycetin, an extremely potent antiobiotic. The latter is still available, since it is life saving in certain bacterial infections, but should only be used when the benefits to be obtained from it outweigh its rather considerable dangers.

     Antibodies circulate in the blood stream as gamma globulins. These large protein molecules are ultimately derived from the plasma cells. In certain congenital diseases, the development of plasma cells is impaired. In some diseases, the lymphocytes, from which the plasma cells are derived, are destroyed. In either case, there is striking inability to produce antibodies after antigenic challenge, leading to susceptibility to a great number of infections, particularly bacterial ones. For some reason, virus infections are not serious problems in these people except for infectious hepatitis. The condition, called hypogamniaglobulinemia, may also be induced by the use of immunosuppressive drugs (see Chapter 31).

     Anaphylaxis and Allergy: An antigen may be given to an animal which has not had that antigen before without serious consequences for the animal. If, however, the animal has been exposed to the antigen earlier, the second exposure may lead to an explosively destructive reaction, which may have fatal consequences. This response, the anaphylactic response, appears to depend on the formation of the antigen-antibody complex more rapidly than the animal can dispose of its end products. Of course, the most important end product of the antigen-antibody reaction is the inert complex of the two. In addition, however, two compounds are released immediately, histamine and serotonin, two are released later, bradykinin and a substance called slowly reacting substance-anaphylaxis. All these compounds, presumably arising in the reacting cells that contain the antigen or the antibody, are exceedingly active on smooth muscle, and they are particularly active on vascular smooth muscle.

     Cutaneous anaphylaxis is seen when an antigen to which an antibody is present in the blood is injected into the skin. The sensitive animal responds with reddening and swelling at the injection site. This test, which spares the individual the constitutional symptoms of anaphylaxis, is very often used to determine whether an individual is hypersensitive to a drug or other substance which is to be administered to him. For example, in certain tests of kidney function, large quantities of a substance concentrated by the kidney and visible in x-ray may be given. In some subjects, some of these substances produce anaphylactic reactions. Persons who will show these anaphylactic reactions can usually be detected by skin testing with a small amount a little before the large dose is given. Skin testing with local anesthetics is often done in people who are to have dental work with the particular anesthetic, for example, novocaine.

     Many people show cutaneous hypersensitivity to antigens for which they have rather low blood antibody levels. These people, whose chemical immune mechanisms are concentrated in their skin and mucus membranes, are said to show atopy. About 10% of the population of the United States suffers from this condition. These people may become sensitive to pollens, house dust, animal fur, certain other people, some foods, etc., and life can be extremely unpleasant for them. Fortunately, treatment is possible.

     The nature of the treatments illustrates some of the phenomena of the anaphylactic reaction. A number of antihistamines have been synthesized which are of considerable value in controlling anaphylaxis in atopic persons. Some of these antihistamines have undesirable side effects, though one very useful one tends to induce sleep in certain people almost in seizures. The variability in individual response to antihistamines makes it imperative that the allergic person try the drug in safe surroundings before attempting its routine use in daily life, when he may be seized with an uncontrollable sleepiness while driving a car. Many antihistamines can be bought without prescriptions, making this precaution even more urgent.

     An extremely interesting pharmacological relationship has to do with the production of serotonin in the anaphylactic individual. Serotonin has many of the effects of histamine, but its effects are easily blocked by LSD. So far no enterprising students have made an issue of their need for LSD to control their allergies, but this oversight will undoubtedly be remedied as soon as this effect of LSD becomes more popularly known.

     Another method of controlling cutaneous hypersensitivity appears to work, though its theoretical basis is uncertain. Persons sensitive to an antigen may be desensitized by giving repeated doses of the antigen, at first in very small quantities, then the dose is gradually increased. It is possible that this procedure results in the formation of a different kind of antibody which reacts with the antigen, perhaps with less or slower formation of the undesirable reaction by-products. The protection is, unfortunately, a temporary one.

     Intermediate Immune Responses: Anaphylaxis, as described above, is an immediate response depending on antigen-antibody reactions. A rather similar response is delayed a little in time but is easily explained in the same terms.

     If one is given a serum from another species, say a horse, to which he has no antibodies, the foreign serum proteins act as antigens. Antibodies are produced, but not very quickly. The horse proteins disappear from the circulation slowly, and at the same time antibodies against them build up slowly. If the horse proteins and the antibodies are present in substantial quantities at the same time, a condition called serum sickness develops. The patient develops an itch, a rash, fever, and various aches and pains. Recovery is usually complete as the antibody disappears from the circulation. However, a person who has had serum sickness should never be retreated with the serum which caused it, for on the next occasion, he will already have the antibodies to that serum and will show an anaphylactic reaction which may be fatal.

     Delayed Immune Responses: Anaphylaxis and serum sickness are clearly related to antigen-antibody reactions. Some adverse immune reactions appear to be based primarily on over-responsiveness of the cellular resistance mechanisms. This type of delayed response is seen exceptionally well in the response to tuberculosis organisms.

     After an original tuberculous infection, the organism is, as it were, primed to combat that infection by cellular mechanism. Little if any antibody is produced. A second infection with the tuberculosis organism leads to an overwhelming, and indeed an excessive, cellular response, involving macrophages from the tissues and blood, lymphocytes, and neutrophiles. This response is so great that the area of reinfection, having become "choked" with the protective cells, becomes short of blood and may die. The inflammed tissue is sacrificed uselessly, for the bacteria survive better than the tissue cells so vigorously overdefended. In fact, the defense against the disease is far more disabling than the disease itself.

     Unlike anaphylaxis and serum sickness, which may be treated with antihistamines, delayed immune responses are unaffected by these drugs. However, they are quite responsive to the anti-inflammatory effects of the glucocorticoids of the adrenal and to synthetic glucocosteroids.

     Delayed hypersensitivity is seen throughout the organism; the skin is quite sensitive. This skin hypersensitivity is the basis of the tuberculin test. A small amount of tuberculosis bacterial extract injected into the skin or placed in contact with the skin with an adhesive bandage gives rise to an intense inflammatory reaction in persons who have had tuberculous infections. The test does not distinguish between active tuberculosis and arrested tuberculosis. It only indicates that the individual has once been infected with the organism. Persons who have never had tuberculous infections show no response, a negative tuberculin test.

     Auto Immune Diseases: As shown in the last few paragraphs, the immunity mechanisms often get out of hand, producing harm rather than defending the organism. No where is this more apparent than in the "auto immune" diseases. In these, the body seems to turn on one or more of its own organs, which are no longer recognized as "self" and are rejected as if they were foreign. The mechanisms of auto-immunity are very variable. In some cases, the "self" cell is altered by an infectious agent, perhaps a virus, which makes it strange to the body, so that it and all others like it will, in time, be destroyed by either anaphylactic or delayed immune mechanisms. In others, the antibody-producing mechanism begins to produce antibodies against cells once recognized as "self". In still others, tissues which were never exposed to the "self recognizing" system are suddenly brought into contact with it. The brain and the lens and cornea of the eye are examples. The brain, because of the blood-brain barrier, and the eye structures are never in real contact with the immunological systems of the body. If the blood-brain barrier breaks down, or if the eye structures come into contact with blood, auto immune responses may occur. In some cases, the auto-immunity is spurious; it appears that antibodies developed against certain bacterial toxins cross-react with some tissue cells. The cells are not truly antigenic in the animal in which they are living, but the structure of the antibody produced to the bacterial toxin is, by chance, suited to react with certain groups on their surfaces.

     A partial list of diseases which are believed to be auto immune includes the following: self destruction of the thyroid, Hashimoto's disease; multiple sclerosis, a disease of the brain in which myelin is destroyed in a patchy and unpredictable manner; and sympathetic ophthalmia, in which destruction of the contents of one eye brings its proteins into contact with the blood, and antibodies develop which destroy the other eye.

     An ill understood group of probably spurious auto-immune diseases follows infections with hemolytic streptococci. These organisms cause scarlet fever and septic sore throat. Recovery from the initial infection is the rule. Subsequently, however, the victim may develop glomerulonephritis, rheumatic fever, or rheumatoid arthritis. It seems likely that these diseases are auto immune only in the sense that the affected organs cross-react with the streptococeal antigen as noted above.

Continue to Chapter 31.