9.4Mechanisms of Immune Response
The Mechanism by which the Immune System Recognizes and Responds to an Attack at the Source of Infection
Let us discuss how the immune response is commenced in effect. Microorganisms invade the body from the skin when it is scraped after injury, e.g., when you fall down, from the mucous membranes of the respiratory tract when you passed by someone who coughed, and from the alimentary canal when the food you ate was rotten. If these microorganisms destroy the epithelium or its surface is damaged due to other reasons, macrophages and dendritic cells habitually residing between epithelial cells or in connective tissues directly underneath perceive their invasion and emit danger signals (Fig. 9-6). These cells possess a group of recognition molecules called Toll-Like Receptor (TLR) and sugar chain-recognizing molecules called lectins, which transmit danger signals in accordance with the characteristics of invader molecules. In concrete terms, transmitting danger signals means secreting proteins referred to as cytokines and chemokines that are physiologically active even with a minute amount. By secreting inflammatory cytokines and chemokines, macrophages mobilize neutrophils, the cells with a strong ability to directly obliterate microorganisms, from the blood to the tissues. This stimulates the thermoregulatory center to elevate the body temperature, thereby inducing swelling of the infected sites.
In general, the response up to this point is a part of natural immunity and is important in the activation itself of biological defense and acquired immunity until the subsequent processes of acquired immunity are activated in earnest. Dendritic cells present the constituent proteins of microorganisms to lymphocytes (antigen presentation: see Column below) to induce their proliferation and activation. At this point, the lymphocytes are expressing on their surfaces molecules (such as antibodies) that can recognize the antigens presented by the dendritic cells. Although these responses occur within one day after the invasion of microorganisms, it requires at least 2 to 3 days before antigen-specific lymphocytes proliferate to reach a sufficient number. Some of the activated lymphocytes eventually start producing antibodies that can bind to microorganism-derived antigens in several days. As a result of the series of immune response, infection sources are wiped away in an effective manner.
Human Leukocyte Antigens (HLA) and Rejection Response
Human leukocyte antigens are antigens responsible for rejection response to transplanted allogeneic organs (human to human transplantation) with each individual expressing several types of HLA in a specific combination. If the HLA combination of the transplanted organ does not correspond to that of the recipient, the organ is attacked and rejected as nonself by the immune system of the recipient*7. In the case of bone marrow transplantation, however, as a suite of immune system is transplanted from outside the body, it will be the tissues of the recipient that are subject to be attacked by the immune system of the donor when the HLA does not correspond.
There exist an enormous number of HLA types: in theory, the number of possible combinations of HLA far exceeds the entire human population on the earth. It is therefore very rare for two individuals to have the same HLA, thus contributing to the difficulty in finding organ transplant donors. All the HLA genes are situated on the same chromosomes. Each of the several HLA owned by an individual is inherited from either of his/her biological parents. In the actual practice of organ transplantation, it is not necessary for each and every HLA to correspond. Although depending on the organ to be transplanted, one criterion is the correspondence of 6 important HLA in case of bone marrow transplantation. Provided these 6 genes are inherited from parents, the probability of all 6 of them corresponding completely is a quarter between siblings*8. For monozygotic twins, they match perfectly.
The original function of HLA is not to interfere with organ transplantation but rather to play a vital role called "antigen presentation" in the immune system. If nonself components that invaded the body are ingested by cells in one way or another, they are fragmented in the cells and then appear on the cell surface, binding to HLA. The subsequent reactions differ depending on what cells recognize these antigens binding to HLA, or primarily what cells are presenting the antigens with what sorts of HLA. Nevertheless, the ensuing reaction will basically be the activation of the fundamental function of the immune system to eliminate nonself. The attack target is the presented antigens along with microorganisms, cells, and transplants containing a part of the antigens. Since these mechanisms were unraveled using mice, HLA is referred to as major histocompatibility complex (MHC) more often than not; in other words, human MHC is HLA.
*7 In the actual practice of organ transplantation, it is sometimes necessary that the ABO blood group is compatible; therefore, HLA alone does not determine transplantation.
*8 Strictly speaking, recombination between homologous chromosomes and the probability of the parents having partially identical HLA to begin with should be taken into consideration.
Humoral Immunity and Cellular Immunity
The final mechanisms to eliminate pathogens (bacteria, viruses, parasites, etc.) as a consequence of the immune response are classified into two broad categories: humoral immunity (in which antibodies produced by B cells play pivotal roles) and cellular immunity (T cells play pivotal roles) (Fig. 9-6). Antibodies are soluble proteins secreted into the blood, and are produced by the same genes that produce receptors that recognize the antigens on the surfaces of lymphocytes. Humoral immunity and cellular immunity often work cooperatively with each other, with the former being more crucial to dealing with extracellular parasites such as parasitic worms, and the latter to intracellular parasites such as viruses and tubercle bacilli. Antibodies bind to the surfaces of bacteria to facilitate attack by other immune systems and bind to viruses to inactivate them. In cellular immunity, there exist cells specialized in certain roles such as attacking other cells infected with viruses to induce their cell death.
Some of the lymphocytes that participate in the immune response stay alive even after the end of response. Upon encountering the same antigens again, these cells are activated instantaneously to exhibit faster and stronger immune responses than the first time. This is how the mechanism of "memory" in acquired immunity functions. This is why the same infectious diseases once contracted before will never infect that same individual again, or even if they did, the symptoms are abated. Vaccines are pathogenic microorganism-derived substances and similar attenuated pathogens, which are used to induce the first immune response without actually developing infectious diseases. It is an attempt to elicit strong immune response during the genuine first infection in order to thwart the development or exacerbation of the diseases.
Allergies exemplify the cases in which normally unnecessary immune responses give rise to diseases and are also classified into those stemming from humoral immunity (e.g., pollinosis) and those from cellular immunity (e.g., contact dermatitis). With respect to the former, allergic symptoms are manifested in response to the extracellular release of chemical compounds conducive to allergic reactions, which is triggered by the binding of antibodies to cells containing a copious amount of such compounds (e.g., histamine; see Column below).
Allergy is also known as hypersensitivity and indicates conditions in which immune responses result in inconvenient consequences for individuals. Pollinosis is a type of allergic reaction, and in the medical sense of the term, is a concept combining (seasonal) allergic rhinitis (snivel and sniffles) with allergic conjunctivitis (itchy eyes). The causative antigen is pollen with cedar pollen in the spring being typical. The cases of these conditions have increased in recent years presumably because of the increased amount of airborne pollen scattered from the cedar trees planted in the postwar period that have reached the age where they release a plenty of it. On the other hand, there have been empirical data suggesting the influence of air pollution.
Column Figure 9-3 shows the mechanism of developing the symptoms of pollinosis. In seasons when pollen is scattered, airborne pollen comes into contact with the nasal mucosa and ocular conjunctiva, prompting the immune system to produce antibodies corresponding to the pollen antigens. Pollinosis patents produce a plenty of antigens of different types from those that function in biological defense against infectious diseases etc. These antibodies bind the surfaces of mast cells in the mucosa and tissues, which store various chemical compounds in their granules. Of these chemical compounds, histamine is an epitome of allergic substances, involved not only in nasal symptoms but also in skin itchiness. Now that the preparation for developing the symptoms of pollinosis is complete, the subsequent contact of pollen with the mucosa will make it bind to the antibodies on the surfaces of the mast cells, thereby triggering a torrential release of the chemical compounds in the granules. The stimulation of the nasal nerves with these chemical compounds provokes reflexive sneezing and runny nose, whereas the stimulation of the blood vessels causes swelling of the mucosa, leading to congestion in the nose (the sniffles).
A basic way to cure allergies including, but not limited to, pollinosis is to avoid contacting causative antigens. However, it is difficult to completely get rid of pollen from the environment. It is not easy either to relocate from the pollen-rich Kanto region to Okinawa or Hokkaido, where the scattering of pollen is few and far between. Wearing a mask or goggles may be one way, and pharmacotherapy is another option. The latter consists mainly of using drugs that inhibit released chemical compounds from reaching other targets. Besides, there are drugs that act on the nerves, blood vessels, and the entire immune system, but they have both their pros and cons.
Column Fig. 9-3. Mechanism of Developing Allergic Symptoms
When the pollen is inhaled into the nose, the mast cells in the tissues of nasal mucosa are stimulated by the pollen components, thereby releasing chemical compounds in the secretory granules. These chemical compounds are represented by histamine, which is a causative substance of the symptoms of allergy. Antibody molecules bind to the surfaces of the mast cells, and the overproduction of antibodies reacting to the pollen facilitates the development of pollinosis.
Control of Immune Response and Autoimmunity
In addition to activation mechanisms, the immune system is equipped with mechanisms to suppress as well as to terminate immune responses. The termination of the responses can be simply attributed to the inactivation of lymphocytes due to the exclusion of all antigens, leading to apoptosis. However, as has been described above, some lymphocytes are known to remain alive as "memory cells," which exhibit responsiveness to specific antigens. The fact that immune memory is retained for almost lifetime implies an extremely long life span of memory cells.
Defects in the system to control and terminate the immune response are considered to be the causes of autoimmune disorders and allergies. There are almost innumerable control points such as this in every step of the immune response; any one of them can be the cause of disorders or the target of treatment. For instance, as mentioned above, cytokines are danger signal molecules emitted from cells that recognize antigens in the first stage of the immune response, of which TNF-α is one of the strongest cytokines released from macrophages at the very beginning. Antibodies that bind to TNF-α for its neutralization exert a strong influence as medicines for rheumatoid arthritis (see Column in Section 2 of Chapter 9).
Meanwhile, as has been described in Section 3 of this chapter, among receptors and antibodies that can recognize antigens on the surfaces of lymphocytes, there can be those with a capacity to recognize autoantigens. The mechanism to eradicate or inactivate such autoantigenic lymphocytes is intrinsic to the bone marrow and the thymus, where lymphocytes differentiation occurs along with gene recombination (they are also referred to as the primary immune organs). Broadly speaking, they sift out autoantigenic cells one by one from all cells and make them undergo apoptosis. On the other hand, these organs need to prepare every self-produced protein in the body. Thymic epithelial cells in the thymus at least appear to possess special machinery expressing proteins that are normally produced only in specific tissues in the body, e.g., insulin produced only in the pancreas and keratins found only in the skin. Abnormalities in the genes of proteins responsible for such transcriptional control are known to contribute to the occurrence of autoimmune reactions toward multiple organs.
Unlike such an autoimmune disorder with a comparatively rare genetic background, there are a multitude of direct pathogenic triggers even though genetic backgrounds influence the susceptibility to many autoimmune disorders. In this context, Guillain-Barré syndrome, which causes paralysis of the extremities on account of autoimmune responses to peripheral motor nerves, is interesting. Some of the patients of Guillain-Barré syndrome are known to be infected with a bacterium known as Campylobacter that causes intense diarrhea before developing the symptoms. The surface of this bacterium abounds with substances with an extremely similar chemical structure to those expressed on the surface of motor nerve cells. It is postulated that antibodies produced in response to Campylobacter damage the motor nerve cells, thereby causing paralysis of the muscles. This illustrates how difficult it is for the immune system, as a duty, to exclude infectious parasites by distinguishing self from nonself based on subtle differences.