INTRODUCTION
The term, immunology, denotes a biomedical science that deals with the study of all aspects of the immune system, i.e. defense mechanism, in humans, nay all organisms. For instance it deals with the:
- Physiological functioning of the immune system in health and disease.
- Malfunctions of the immune system in immunological disorders (autoimmune diseases, hypersensitivities, immune deficiency, transplant rejection).
- Physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ and in vivo.1
An immunologist is a research scientist who works in laboratories addressing immunological aspects or a physician who treats patients suffering from disorders of the immunological system. An immunologist may well be both laboratory researcher as also physician.
Over and above the normal workings of the immune system, an immunologist studies unwanted immune responses such as allergies, essentially immunological responses of the body to substances or organisms that, as a rule, do not affect most people and autoimmune diseases (e.g. rheumatoid arthritis and disseminated lupus erythematosus), which occur when the body reacts immunologically to some of its own constituents.
A large number of procedures have been developed to detect and measure quantities of immunologically active substances such as circulating antibodies and immune globulins. Immune globulins that can be given intravenously have been found to be more effective against antibody deficiencies and certain autoimmune diseases than their older intramuscular counterparts; their use in a wide spectrum of bacterial and viral infections is under study. Current research in immunology is also aimed at understanding the role of T lymphocytes that play a major part in the body's defenses against infections and neoplasms.
All affluent countries and some resource-limited countries have their own centers of immunology. In India, we have the National Institute of Immunology (NII), which is an autonomous advance center supported by 4the Union Government's Department of Biotechnology. The Institute is committed to advanced research addressing the basic mechanisms involved in body's defense, host-pathogen interactions and related areas. The objective is to contribute to the creation of an internationally competitive intellectual knowledge base, as a sustainable source of innovative futuristic modalities of potential use in health care.
This Chapter proposes to provide a comprehensive review of the fundamentals of the field of immunology, as also the integrated clinical and applied immunologic knowledge and research as applicable to the field of clinical pediatrics.
HISTORICAL ASPECTS
The concept “immunology”, a science that examines the structure and function of the immune system, has its origin from medicine and early studies on the causes of immunity to disease.1 The first known mention of “immunity” appears to date back to 430 BC when the plague of Athens caused a disaster. A striking observation made was that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. In the 18th century, experiments were made with scorpion venom. It was observed that certain dogs and mice were immune to this venom.
Later, Louis Pasteur could exploit this and other observations of acquired immunity in the form of development of vaccination. Additionally, this also firmed the basis of his proposed germ theory of disease. Notably, Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory.
Much later, precisely in 1891, Robert Koch demostrate that microorganisms were indeed the cause of infectious diseases. In 1905, he received Nobel Prize for this discovery. Subsequently, Walter Reed, in 1901, confirmed that viruses were could be human pathogens, with the discovery of the yellow fever virus.
The end of the 19th century stands out majestically for great advances in immunology, through rapid developments, in the study of humoral immunity and cellular immunity. The work of Paul Ehrlich (Fig. 1.1), who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction and his contributions to the understanding of humoral immunity were recognized in the form of the award of a Nobel Prize in 1908. In fact, the award was jointly presented to Ehrlich and the founder of cellular immunology, Elie Metchnikoff.
TYPES OF IMMUNOLOGY
Immunology has applications in several disciplines of science and as such is further divided into:
- Immunogenetics
- Classical immunology
-
Fig. 1.1: Nobel Laureate Paul Ehrlich: He is credited with the side-chain hypothesis as an explanation specificity of antigen-antibody reaction. For his extraordinary contribution to understand the humoral immunity, he was bestowed the honor of Nobel Prize in 1908 (along with Sir Elie Metchnikoff, the founder of the concept “cellular immunology”
- Diagnostic immunology
- Therapeutic immunology (immunotherapy)
- Developmental immunology
- Evolutionary immunology
- Reproductive immunology.
Immunogenetics
The subdiscipline, immunogenetics, is the study of the genetics (inheritance) of the immune response. The study of the blood groups, Rh and ABO. Equally important is the human leukocyte antigen (HLA) system in relation to the kidneys and other transplants. Immunogenetics also examines the genetic control of the individual's ability to respond to an antigen.
Classical Immunology
The term, classical immunology, pertains to the relationship between the body systems, pathogens and immunity in the fields of epidemiology and medicine. Central to immunology is the study of the molecular and cellular components comprising the immune system, including their function and interaction. The immune system has been divided into:
- A more primitive innate immune system
Acquired immunity is further divided into:
- Humoral
- Cellular components.
The humoral (antibody) response is the interaction between antibodies and antigens. Antigens are elements (usually proteins) that elicit generation of antibodies. In other words, they are the antibody generators. On the other hand, antibodies are specific proteins released from a certain class of immune cells (B lymphocytes). The understanding of immunology is based on an understanding of the properties of these two biological entities. No less important is the cellular response, which can not only kill infected cells in its own right, but is also critical in controlling the antibody response. In simple terms, both systems are highly interdependent.
With the onset of the 21st century, immunology has broadened its horizons with much research being performed in the more specialized niches of immunology, including:
- Immunological function of cells, organs and systems not normally associated with the immune system.
- Function of the immune system outside classical models of immunity.
Clinical Immunology
Clinical immunology is the study of diseases caused by disorders of the immune system such as failure, aberrant action and malignant growth of the cellular elements of the system. The field also involves diseases of other systems in which immune reactions play a part in the pathology and clinical features.
The diseases caused by disorders of the immune system fall into two broad categories:
- Immunodeficiency, in which parts of the immune system fail to provide an adequate response (examples include chronic granulomatous disease).
- Autoimmunity, in which the immune system attacks its own host's body. Systemic lupus erythematosus (SLE), rheumatoid arthritis, Hashimoto disease and myasthenia gravis are some such diseases. Among additional immune system disorders figure different hypersensitivities, in which the system responds inappropriately to harmless compounds (asthma and other allergies) or responds too intensely.
The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology.
Human immunodeficiency virus (HIV)/Acquired immunodeficiency syndrome (AIDS) is the glaring example of diseases that affects the immune system. It is an immunodeficiency characterized by the remarkable deficiency of CD4+ (“helper”) T-cells and macrophages.
The area of operation of clinical immunologists includes study of means to prevent transplant rejection, in which the immune system attempts to destroy allografts.7
Diagnostic Immunology
Thanks to the specificity of the bond between antibody and antigen, today we have an excellent tool in the detection of substances through a variety of diagnostic techniques. Antibodies specific for a desired antigen can be conjugated with a radiolabel, fluorescent label, or color-forming enzyme and are used as a “probe” to detect it. However, the similarity between some antigens can lead to false positives and other errors in such tests by antibodies cross-reacting with antigens that are not exact matche.
Therapeutic Immunology (Immunotherapy)
The term, immunotherapy, denotes the use of immune system components to treat a disease or disorder. Immunotherapy is, as a rule, employed in the treatment of:
- Malignancies in conjunction with cancer chemotherapy and radiotherapy.
- Immunosuppression (say, HIV) and other immunodeficiencies or autoimmune diseases.
Developmental Immunology
An individual's age, antigen type, maternal factors and the area, where the antigen is presented have a considerable bearing on the body's capability to react to antigen.
For instance, the neonates are said to be in a state of physiological immunodeficiency, because both their innate and adaptive immunological responses are greatly suppressed. Once born, a child's immune system responds favorably to protein antigens, while not as well to glycoproteins and polysaccharides. In fact, many of the infections acquired by neonates are caused by low-virulence organisms like Staphylococcus and Pseudomonas. Why? In neonates, opsonic activity and the ability to activate the complement cascade is very limited, the mean level of C3 in a newborn being only 60 to 70% of that found in the adult. Moreover, phagocytic activity is also greatly impaired in newborns due to lower opsonic activity and up-regulation of integrin and selectin receptors, which limit the ability of neutrophils to interact with adhesion molecules in the endothelium. The monocytes are slow and have a reduced adenosine triphosphate (ATP) production, further limiting the newborns phagocytic activity.
Despite considerably higher number of total lymphocytes compared to adults, the cellular and humoral immunity is impaired. Antigen-presenting cells have a reduced capability to activate T-cells, which proliferate poorly and produce very small amounts of cytokines like IL-2, IL-4, IL-5, IL-12 and IFN-γ. This limits their capacity to activate the humoral response as also the phagocitic activity of macrophage. B-cells develop early in gestation, but are not fully active.8
The individual's immune response is influenced by the maternal factors too. IgG is the only immunoglobulin that can cross the placenta; IgM, IgD, IgE and IgA are more or less incapable of doing so and are, therefore, almost undetectable at birth. Undoubtedly, some IgA is provided in breast milk.
These passively acquired antibodies can protect the newborn up to 18 months, but their response is usually short-live and of low affinity. These antibodies can also produce a negative response. If a child is exposed to the antibody for a particular antigen before being exposed to the antigen itself then the child will produce a dampened response. Passively acquired maternal antibodies can suppress the antibody response to active immunization. Similarly, the response of T-cells to vaccination differs in children compared to adults and vaccines that induce Th-1 responses in adults do not readily elicit these same responses in neonates. By 6 to 9 months after birth, a child's immune system begins to respond more strongly to glycoproteins. Not until 12 to 24 months of age is there a marked improvement in the body's response to polysaccharides. This can be the reason for the specific time frames found in vaccination schedules.
Various hormones begin and mediate several physical, physiological and immunological changes during adolescence. Depending on the sex either testosterone or 17-β-estradiol, act on male and female bodies accordingly, start acting at ages of 12 and 10 years. There is evidence that these steroids act directly not only on the primary and secondary sexual characteristics, but also have an effect on the development and regulation of the immune system.7 There is an increased risk in developing autoimmunity for pubescent and postpubescent females and males.8 There is also some evidence that cell surface receptors on B-cells and macrophages may detect sex hormones in the system. The female sex hormone 17-β-estradiol has been shown to regulate the level of immunological response.
Likewise, some male androgens, like testosterone, seem to suppress the stress response to infection. However, other androgens like DHEA have the opposite effect, i.e. they increase the immune response instead of down playing it. http://en.wikipedia.org/wiki/Immunology-cite_note-10. As in females, the male sex hormones seem to have more control of the immune system during puberty and the time right after than in fully developed adults. Other than hormonal changes, physical changes like the involution of the thymus during puberty also affect the immunological response of the individual.
Evolutionary Immunology
Evolutionary immunology is the study of the immune system in extant species. It provides us a key understanding of the evolution of species and the immune system.
A development of complexity of the immune system can be seen from simple phagocytotic protection of single-celled organisms, to circulating antimicrobial peptides in insects to lymphoid organs in vertebrates. 9Nevertheless, it is important to recognize that every organism living today has an immune system that has evolved to be absolutely capable of protecting it from most forms of harm. The organisms that failed to adapt their immune systems to external threats have disappeared.
Interestingly, insects and other arthropods do not possess true adaptive immunity. However, they show highly evolved systems of innate immunity. Additionally, they are protected from external injury (and exposure to pathogens) by their chitinous shells.
Reproductive Immunology
Reproductive immunology comprises the study of immunological aspects of the reproductive process, including:
- Fetus acceptance
- Fertility problems
- Recurrent miscarriages
- Premature deliveries
- Dangerous complications, especially toxemias of pregnancy.
IMMUNITY
Conventionally speaking, immunity refers to the defense mechanism that protects an individual against invasion by an infection.1 Today, it is believed to have an extended defense function in the form of immunologic surveillance limiting the development of tumor cells, malignant cell clones, moulds and grafts.
Precisely, the immune system is a network of cells, tissues and organs that work together to defend the body against attacks by the foreign invaders—primarily microbes such as bacteria, parasites, fungi and viruses that can cause infections. The human body provides an ideal environment for invasion by the microbes. The immune system tends to keep them out or, failing that, to destroy them.1,2
The researchers continue to study how the body launches attacks that destroy invading microbes, infected cells and tumors, while ignoring healthy tissues. New technologies for identifying individual immune cells are now allowing scientists to determine quickly, which targets are triggering an immune response. Improvements in microscopy are permitting the first-ever observations of living B-cells, T-cells and other cells as they interact within lymph nodes and other body tissues. Moreover, the researchers are rapidly unraveling the genetic blueprints that direct the human immune response, as well as those that dictate the biology of bacteria, viruses, fungi and parasites.
Embryologically, in humans, the immune system begins to develop in the embryo. The system starts with hematopoietic (Greek term, meaning “blood-making”) stem cells. The stem cells differentiate into the major players in the immune system, i.e. granulocytes, monocytes and lymphocytes.10
Fig. 1.2: Hematopoietic stem cells: It is the stem cells that produce cells in blood and lymph that are the major players of the immunologic system3
These cells also differentiate into cells in the blood that are not involved in immune function, say erythrocytes and megakaryocytes. Stem cells continue to be produced and differentiated throughout life (Fig. 1.2).3
Immunologic system operates with involvement of:
- Lymphocytes: T and B-cells, natural killer (NK) cells
- Plasma cells
- Phagocytic cells: Macrophages
- Complement proteins.Immunity may be innate or adaptive (acquired).
Innate immunity may be genetically passed on from one generation to another without depending on previous contact with a microbe. When it indicates a degree of resistance to all infections, it is termed nonspecific. When there is a resistance to a particular pathogen, it is called specific. Innate immunity is also expressed in relation to species, race or individual. Such factors as age, hormonal influences and nutrition considerably affect immune response.
Innate immunity comes into play when the first defense line, i.e. skin or mucus membrane or some other physical barrier breaks down. As the invading pathogen breaches such a barrier, innate immunity tends to provide an immediate, though nonspecific, response in the form of defense.
Leukocytes act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the phagocytes (macrophages, neutrophils and dendritic cells), mast cells, 11eosinophils, basophils and NK cells. These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. Additionally, innate cells are the important mediators in the activation of the adaptive immune system.
Phagocytosis is an important feature of cellular innate immunity performed by cells called ‘phagocytes’ that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle, phagosome, which subsequently fuses with another vesicle, lysosome, to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome.
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. http://en.wikipedia.org/wiki/Immune_system-cite_note-41. http://en.wikipedia.org/wiki/Immune_ system-cite_note-I and F-42. During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation by chemotaxis.
Fig. 1.3: Classification of immunity: Note that innate immunity can further be specific and nonspecific
Fig. 1.4: Phagocytosis: Note the stages starting with attachment by nonspecific receptors followed by pseudopodia forming a phagosome and lysosome fusion and killing and ending up with release of the microbial products. (Courtesy: Prof Brown)
They are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins and regulatory factors such as interleukin.1 Macrophages also act as scavengers, ridding the body of worn-out cells and other debris and as antigen-presenting cells that activate the adaptive immune system.
Dendritic cells are phagocytes in tissues that are in contact with the external environment. Understandably, they are located mainly in the skin, nose, lungs, stomach and intestines. http://en.wikipedia.org/wiki/Immune_system - cite_note-Guermonprez-44. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigen to T-cells, one of the key cell types of the adaptive immune system.
Mast cells reside in connective tissues and mucous membranes and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma. Natural killer cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses.
ADAPTIVE OR ACQUIRED IMMUNITY
Once the invading organism has failed to be handled by the innate immunity, adaptive (acquired) immunity comes into play. The activate response is adapted following an infection. The aim is to improve its identification of the invading pathogen. This recognition of the pathogen is then retained following the elimination of the pathogen. This is what is termed “immunologic memory”. By virtue of this immunologic memory, as and when this patrticular pathogen attacks in the future, adaptive immunity attempts to repel it through a powerful counter attack.
The adaptive immune response is antigen-specific and requires the recognition of specific “nonself” antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by “memory cells”. Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.
Two components of adoptive (acquired) immunity are: humoral and cellular.
Humoral immunity, the dominant defense system against bacteria, is mediated by circulating immunoglobulin (antibodies) produced by B- lymphocytes in blood. By activating the complement system, immunoglobulins attack and neutralize antigens.
Cellular immunity, mediated by T lymphocytes, comes into play for delayed-hypersensitivity reactions and rejection of foreign tissue 13transplants. It is this immunity that provides dominant protection against invading viruses, fungi and Mycobacterium tuberculosis as also tumors.
The origin of the cells of the immune system is explicitly shown in Figure 1.5.
Lymphocytes
Lymphocytes are the cells involved in immunologic system. B-cells and T-cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B-cells are involved in the humoral immune response. T-cells are involved in cell-mediated immune response.
Both B-cells and T-cells carry receptor molecules that recognize specific targets. T-cells recognize a “nonself” target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a “self” receptor called a major histocompatibility complex (MHC) molecule.
Two major subtypes of T-cells are: the killer T-cell and the helper T-cell. Killer T-cells only recognize antigens coupled to class I MHC molecules, while helper T-cells only recognize antigens coupled to class II MHC molecules.
These two mechanisms of antigen presentation reflect the different roles of the two types of T-cell.
B-cell antigen-specific receptor is an antibody molecule on the B-cell surface and recognizes whole pathogens without any need for antigen processing. Each lineage of B-cell expresses a different antibody, so the complete set of B-cell antigen receptors represent all the antibodies that the body can manufacture.
Killer T-Cells
Killer T-cells are a sub-group of T-cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. As with B-cells, each type of T-cell recognises a different antigen. Killer T-cells are activated when their T-cell receptor (TCR) binds to this specific antigen in a complex with the MHC class I receptor of another cell. Recognition of this MHC-antigen complex is aided by a coreceptor on the T-cell, called CD8. The T-cell then travels throughout the body in search of cells, where the MHC I receptors bear this antigen. When an activated T-cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis. http://en.wikipedia.org/wiki/Immune_system-cite_note-Radoja-52. T-cell killing of host cells is particularly important in preventing the replication of viruses. T-cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by “helper” T-cells.
Helper T-Cells
Antigen-presenting cells (APCs) present antigen on their class II MHC molecules (MHC2). Helper T-cells recognize these, with the help of their expression of CD4 coreceptor (CD4+).
The activation of a resting helper T-cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T-cells and B-cells, the latter producing antibodies. The stimulation of B-cells and macrophages succeeds a proliferation of T-helper cells.
Helper T-cells regulate both the innate and adaptive immune responses and help determine which types of immune responses the body will make to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.
Helper T-cells express TCR that recognize antigen bound to Class II MHC molecules. The MHC-antigen complex is also recognized by the helper cell's CD4 coreceptor, which recruits molecules inside the T-cell that are responsible for the T-cell's activation. Helper T-cells have a weaker association with the MHC-antigen complex than observed for killer T-cells, meaning many receptors (around 200–300) on the helper T-cell must be bound by an MHC-antigen in order to activate the helper cell, while killer T-cells can be activated by engagement of a single MHC-antigen molecule. Helper T-cell activation also requires longer duration of engagement with an antigen-presenting cell. The activation of a resting helper T-cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T-cells enhance the microbicidal function of macrophages and the activity of killer T-cells. In addition, helper T-cell activation causes an upregulation of molecules expressed on the T-cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B-cells.
Fig. 1.7: Killer T-cells directly attack other cells carrying foreign or abnormal antigens on their surfaces1
Gamma delta (γδ) T-cells possess an alternative TCR as opposed to CD4+ and CD8+ (αβ) T-cells and share the characteristics of helper T-cells, cytotoxic T-cells and NK cells. The conditions that produce responses from γδ T-cells are not fully understood. Like other ‘unconventional’ T-cell subsets bearing invariant TCRs, such as CD1d-restricted natural killer T-cells, γδ T-cells straddle the border between innate and adaptive immunity. On one hand, γδ T-cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T-cells respond within hours to common molecules produced by microbes and highly restricted Vδ1+ T-cells in epithelia will respond to stressed epithelial cells.
In nutshell, cell-mediated immunity (CMI) is affected by its functional cell, T lymphocyte, which is thymus-dependent and initially stems from the precursors in the bone marrow as is the case with B lymphocytes. These cells form about 75% of the lymphocytes and mostly circulate in blood, interstitial space and lymph in the marrow. A recently described thymus hormone, thymosin, is claimed to maintain their activity. Functions of T lymphocytes include:
- T-helper function.
- T suppressor function.
- T killer function.
- Containment of acid-fast bacilli.
- Containment of certain viral infections (EBV, slow virus).
- Containment of fungal infections (Candida).
- Containment of protozoal infections (Pneumocystis carinii).
- Rejection of allograft (tumors).
- Graft vs host disease (GVHD).
- Contact dermatitis.
Lymphokines are soluble mediator substances, which are liberated when an antigen-sensitive T lymphocyte comes into contact with the specific antigen at the periphery. The major soluble factors include:
- Mitogenic factor, which enhances lymphocyte multiplication
- Permeability increasing factor
- Lymphocytotoxin
- Migration inhibiting factor, which favors phagocytosis
- Transfer factor, which transfers to the uncommitted cells the characteristics of the antigen-sensitized cells.
Cellular immune response ends up in destruction of the antigen. This may either be directly through the action of the sensitized lymphocytes or by activity of lymphocytotoxin.17
ANTIGEN PRESENTING CELLS /DENDRITIC CELLS
The term, antigen presenting cells (APC), refers to specialized.
- Dendritic cells in lymph nodes and spleen
- Langerhans dendritic cells in the skin.
At times, macrophages and B-cells may take up the function of APCs.
A notable feature of APCs is that the polypeptide products of antigen digestion are coupled to protein products of the MHC genes—termed human leukocyte antigens (HLA)—on cell surface. CD4 antigen is able to recognize antigen in relation to class H antigen. CD8 cells are capable of recognizing cell-bound antigens only in association with class 1 MHC proteins.
CYTOKINES
Cytokines are agents, which recognize the host responses—all the three, namely immunologic, inflammatory and reparative. Box 1.1 lists their classification and the cytokines falling under each category.
Fig. 1.8: Innate immunity and inflammation: Note the two pathways: On left with positive outcome and on right with negative outcome
MACROPHAGES
As apart of phagocyte system, macrophsges perform certain function in relation to immune response (Box 1.2).
Macrophage deficiency is a feature of both congenital (chronic granulomatous disease) and acquired immunodeficiency (Gram-negative bacilli, Staphylococcus, fungus infections). In acquired deficiency, usually seen in diabetes, malnutrition and malignancies, vulnerability to infections, especially involving skin, periorifacial and deep organ, is high.
COMPLEMENT SYSTEM
The term, complement system, denotes a series of factors in the normal serum that are activated by antigen-antibody interaction and subsequently, mediate a number of biologically significant consequences. Complement forms about 10% of human serum globulin. There are 9 distinct components of complement system, one of them having 3 subunits (C'1g'C'1r'C'1s') thereby making a total of 11 proteins.
There are two pathways (also termed “enzyme cascades”) activate the complement system:
- Classical pathway: Chain of event in which complement components react in specific sequence following activation of antigen-antibody complexes and culminating in immune cytolysis is known as classical C' pathway.
- Alternate pathway: Activation of C'3' without prior participation of C'1' C'4' and C'2' is called alternate pathway. Triggering factor is contact with a bacteria, virus, fungus or tumor cell.Activities of the complement immunity against infection may be outlined as per Box 1.3.
In short, complement system contributes to killing of invading antigen by opsonization, chemotaxis and lysis of the cell and also, partially serve as a bridge between innate and adaptive immunity. The latter function is attained by activation of the B-cells.
Lymphocytic response is affected by either humoral or cellular mechanism, or both.
Humoral immunity is concerned with synthesis and release of antibodies (immunoglobulins) secreted by plasma cells, as also complement, interferon and lysozyme. Its functional cell is B lymphocyte, the bursa-dependent cell, which stems from the precursor in the bone marrow.
About 25% lymphocytes are B-cells. They are mostly restricted to lymphoid tissue. T-helper cells are essential for their transformation into antigen-recognition cells and production of immunoglobulins. T-suppressor cells suppress the activity and lessen formation of antibodies. Thus, the immune response is maintained within a tolerable level.
On entry of an offending agent (antigen), B-cells develop into plasma cells, which secrete specific antibodies to antagonize the antigen. Once the illness is over, level of circulating antibodies falls slowly over a period of several weeks. In case the same illness returns, level of antibodies against the antigen rises rapidly, thereby halting the invasion by the same antigen and acquisition of specific immunity.
Fig. 1.9: Immunity cascade: The modus operandi of production of immunity and destruction of the invading antigen. (Courtesy: Nature Reviews/Immunology)
Fig. 1.10: Complement system: Following activation of complement by various pathways, a cleavage of the C3 develops. The breadown products of the C3 and other complement proteins plus the membrane attack complex (MAC) mediate the function of the complement system.
This happens since the body remembers the mechanisms by which the antibody was produced earlier. This is called immunologic memory.
Immunoglobulins, produced by B-cells, are the globulin molecules associated with antibody activity, extending in electrophoretic activity from 21alpha2 to gamma regions. Basically, their structure consists of two polypeptide chains. First, i.e. light chain, may be kappa (κ) or lambda (λ). Second, i.e. heavy chain, imparts class specificity. Structurally, 5 major types are recognized—IgG, IgA, IgM, IgD and IgE.
IgG is the major immunoglobulin, constituting around 75% of the immunoglobulin content of the serum. In the fetus, it is by far the only immunoglobulin present. The newborn receives it, by transport across the placenta, in sufficient amount depending on the gestational age, weight and efficiency of placental function. IgG so received from the mother gradually begins to fall after birth, so that at 2 to 6 months the infant suffers from what is known as physiological hypogammaglobulinemia G, which is discussed later. There are further subclasses of IgG, say IgG1, IgG2, IgG3 and IgG4, based on differences in heavy polypeptide chain (Fc).
IgA and IgM are very low at birth, the adult levels reaching by the age of 2 years. The exact role of IgM in immune response is not yet clearly understood. IgA is, however, well known to play an important part in human defence against infection, particularly pertaining to respiratory tract and gastrointestinal tract. Agammaglobulinemia is always accompanied by deficiency of secretory component of IgA (Table 1.1).
Fig. 1.11: Immunoglobulin: Note the structure as represented diagrammatically8
Today, immunoglobulins are extensively used for amelioration of several immunologic disorders like immune/idiopathic thrombocytopenic purpura (ITP), Guillain-Barré syndrome, Kawasaki disease, hemolytic-uremic syndrome, etc.4
Let us take up the sequence of events following invasion by a pathogenic antigen. Once the first-line barrier is broken, by virtue innate immunity, the body recognizes the antigen. Million of T and B-cells then demonstrate a response to the said antigen.
As regards T-cell, an APC takes up the antigen. After processing, it is presented to the T lymphocytes by MHC molecules present on the APC. Thereafter high affinity binding occurs. Of course, specific molecules are required to be present on the T-cells and APCs. Antigenic binding prompts the T-cells to produce cytokines, thereby causing activation and proliferation of T-cells which secrete lymphokines that aggregate and activate macrophages. These macrophages phagocytose and destroy the invading antigen. Concurrently, the macrophages attract polymorphonuclear cells and monocytes to the focus of infection. As a consequence of T-helper cells stimulating B-cells, humoral immune response is induced.
Just a word about the primary immune rresponse. Here, native antigen is carried to a lymph node, where it is taken up by specialized cells, follicular dendritic cells (FDCs). This is followed by the binding of the virgin B-cells (with surface Ig specific for that antigen) to this antigen.
Following antigenic adherence, B-cells get stimulated to differentiate into antibody-producing plasma cells.23
Though the plasma cells, to begin with, produce IgM, subsequently they undergo a transformation to produce IgG rather than IgM. As soon as the stimulus is off, B-cells B-cell stimulation and division ceases. However, even at this stage, the circulating pool of B lymphocytes contains lot many memory cells.
In case there is another exposure to this very antigen, there immediately occurs a widespread division of B-cells with IgG receptors. This is termed “secondary immune response”. As a result, a large number of IgG antibodies are produced. By combining with the antigen, these antibodies make the antigen harmless. Antigen-antibody reaction triggers the activation of complement. It is the complement that plays a major role in destroying the invading foreign antigen.
SUMMARY AND CONCLUSION
Immunology refers to a biomedical science that deals with the study of all aspects of the immune system, in humans and other living organisms. Immunology has applications in several disciplines of science and as such is further divided into classical, clinical, diagnostic, therapeutic, developmental, evolutionary and reproductive branches. The defense mechanism that protects an individual against invasion by an infection with an extended defense function in the form of immunologic surveillance limiting the development of tumor cells, malignant cell clones, moulds and grafts is termed immunity. Embryologically, the immune system starts with hematopoietic stem cells. The stem cells differentiate into the major players in the immune system, i.e. granulocytes, monocytes and lymphocytes. Finally, immunologic system operates with involvement of lymphocytes (T and B-cells, natural killer cells, plasma cells, phagocytic cells, macrophages and complement proteins). Humoral immunity is concerned with synthesis and release of antibodies (immunoglobulins) secreted by plasma cells, as also complement, interferon and lysozyme. Its functional cell is B-lymphocyte, the bursa-dependent cell, which stems from the precursor in the bone marrow. Antigen-antibody reaction triggers the activation of complement. It is the complement that plays a major role in destroying the invading foreign antigen.
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