9.3What Is immunity?
Origin of the Immune System
As has been described thus far, microorganisms such as bacteria, fungi, and viruses can either coexist symbiotically with or cause infectious diseases in higher organisms including humans. Infectious diseases are diversified and their severity varies with some having an extremely high mortality rate. Multicellular organisms are equipped with mechanisms to preclude the invasion of these parasites (Fig. 9-4), i.e., biological defense mechanisms. The biological defense mechanism of vertebrates, including humans, are characterized by the feature that it either negates or alleviates the symptoms of the diseases they have contracted previously and recovered from already. This both effective and specific defense system of eradicating infectious sources is known as the immune system.
The understanding and utilization of the immune system have enabled humankind to escape the danger of a number of infectious diseases and live with security. At the same time, many refractory diseases with no known cause or cure have been gradually revealed to be autoimmune disorders deriving from deficiencies in the system. Recently, there has been a marked increase in the number of people suffering from allergies caused by excessive immune responses, such as a seasonal allergy caused by pollens ("pollinosis") (see Column Sections 4 of Chapter 9). These facts suggest that the immune system has problems that need to be solved, and thus, indicates the need to proceed with efforts to understand the system while developing methods to control it hereafter. The immune system makes a major contribution to not only infectious diseases, autoimmune disorders, and rejection responses toward transplanted organs, but also to cancer, metabolic disorders, neurological disorders, etc. In particular, the possibility of applying the immune system to the treatment of cancer is raising expectations considerably.
The immune system responds to pathogens and allergens*5 upon recognizing them. This process is referred to as the immune response. In the early stage of infection, innate immunity (to be described later) plays an important role, followed by the activation of acquired immunity. The significant features of the immune system include the ability to distinguish between self and nonself, as well as the ability to respond specifically and expeditiously. It is also important that things to be responded are remembered in acquired immunity. As a result of storing memories, the immune system is able to respond to the same exogenous antigen in a more efficient manner for the second time. This mechanism is called "acquired immunity" because it is something that is acquired after birth through encounters with antigen. As invertebrates such as insects do not possess acquired immunity and rely solely on natural immunity, they can contract the same disease twice. Nevertheless, they have been surviving as organisms, while resisting succumbing to infectious microorganisms. The mechanism of natural immunity is also inherent in vertebrates, working in collaboration with the system of acquired immunity.
*5 Abnormal immune response that occurs after encountering causative substances for the second or subsequent time is called allergy; the causative substances are referred to as allergens.
Cells and Tissues Responsible for Immunity
In vertebrates, a majority of immune cells continue being produced from the stem cells in the bone marrow through their entire life and are distributed within the body as they differentiate (Fig. 9-5). Leukocyte is one of the immune cells present in the blood. Leukocytes include neutrophils, whose main function is to engulf bacteria, as well as eosinophils and basophils, which are associated with parasite elimination and allergy. When infectious parasites invade the body, macrophages differentiated from monocytes that entered the tissues, along with cells called dendritic cells, transmit danger signals to activate neutrophils and lymphocytes.
Lymphocytes comprise B cells and T cells. They are directly in control of the acquired immune response and recognize nonself via receptors on their plasma membranes. Molecules and molecule fragments with nonself characteristics that can be recognized by these receptors are referred to as antigens. Some lymphocytes secrete proteins with the same properties as the transmembrane molecules recognizing nonself. These proteins are called antibodies, which play crucial roles in the immune system after secretion (see Column at the bottom). Lymphocytes determine the antigens they recognize by means of the receptors they express. These receptors are not predetermined for the antigens they are going to recognize; rather, in a myriad of receptors, those that happen to recognize certain antigens are believed to be reserved for the future immune responses against those types of antigens*6. Naturally, there can exist receptors recognizing self, but they are excluded in the early stages of differentiation, and thus, do not participate in the normal immune system.
Upon receiving danger signals from macrophages and dendritic cells, lymphocytes start proliferating in order to combat pathogens. At this point, only those lymphocytes that produce molecules that react specifically to the invading pathogens can proliferate. These reactions occur in the tissues called secondary immune organs that exist locally in the lymph nodes and mucous membranes, where interactions among lymphocytes or ones between lymphocytes and antigens take place. Viral infection in the tonsils makes the lymph nodes in the cervical region swell because that is where lymphocytes congregate and proliferate.
Antibodies are glycoproteins called immunoglobulins (Column Fig. 9-2). Each of them consists of a total of 4 polypeptides (chains formed from the linking of many amino acids): 2 heavy chains and 2 light chains. An antigen-binding site is situated at the amino terminus, and its amino acid sequence varies depending on the antigen to which each antibody is supposed to bind; therefore, this site is called a variable region. The variable regions of light and heavy chains each have 3 loop-shaped structures forming antigen-binding sites. These sites are complementary to antigens, and the amino acid sequences are different from antibody to antibody; thus, they are called "hypervariable regions." The third hypervariable region is where diversity arises through gene recombination (see footnote *6).
Immunoglobulins also function as receptors expressed on the plasma membranes of lymphocytes that recognize antigens. Besides, soluble immunoglobulins are classified into 5 classes, each of which possesses a different structure at the carboxy terminus. They are engaged in the elimination of exogenous antigens through intrinsic functions such as multimerization, transportation to the lumen side of epithelium, and activation of other immune system-related proteins.
*6 If receptor molecules and antibodies expressed by lymphocytes were constructed based on genetic information, an infinite number of genes comparable with the types of antigens to be recognized would be necessary. It has been elucidated that a sufficient diversity to correspond to innumerable types of antigens is achieved with a finite amount of genetic information as below: (1) a sufficient number of genes exist; (2) mutations occur in somatic cells to give rise to more new types; and (3) gene recombination occurs in somatic cells.