Chapter

25

IMMUNE SYSTEM

AND

HUMAN HEALTH

We are continually exposed to various foreign

particles, including infectious agents like bacteria, viruses, protozoa and other parasites. It has long been noticed that survivors of certain diseases, e.g., measles, are not attacked by the same disease again. Clearly, these people have become immune to the concerned disease. The system of our body, which protects us from various infections agents is called immune system. A study of the immune system is known as immunology . The objective of this chapter is to introduce the fundamental concepts of immune system and their use for the improvement of human health and welfare.

Innate and Acquired Immunity

The Latin term Immunis, meaning exempt or freedom, gave rise to the English word immunity. It refers to all the mechanisms used by the body for protection from environmental agents that are foreign to the body. These agents may be microorganisms or their products, certain food items, chemicals, drugs and pollen, etc. Immunity is of two types : (a) innate, and (b) acquired immunity.

25.1 INNATE IMMUNITY

Innate immunity comprises all those defense elements with which an individual is born, and which are always available to protect a living body. One strategy of innate immunity consists of various types of barriers that prevent entry of foreign agents into the body. Even when pathogens enter into the body, they are quickly

killed by some other components of this system. This is the first line of defence of most animals. Innate immunity consists of the following four types of barriers : (a) anatomical, (b) physiological, (c) phagocytic, and (d) inflammatory barriers. Anatomic Barriers These barriers block the entry of organisms into the body. They consist of skin and the mucous membranes. Mucous entraps foreign microorganisms and cilia propel micro-organisms out of the body. Physiological Barriers Factors like body temperature, pH and various body secretions, prevent growth of many pathogenic micro-organisms. For example, fever response inhibits growth of many pathogens. Acidity of the stomach contents kills most ingested micro-organisms. Lysozyme present in secretions, such as tears, digests bacterial cell walls, and interferon induces antiviral state in non-infected cells. Certain kinds of cells, when infected with a virus, respond by releasing a small amount of a class of glycoproteins, called interferons . Interferons, in turn, protect the cells in the vicinity resistant to viral infections. This involves several mechanisms, such as synthesis of antiviral proteins. As a result, the concerned persons exhibit increased resistance to viral infections. Phagocytic Barriers Phagocytosis is an important mechanism of innate immunity. In response to pathogenic infections, the total count of leucocytes increases sharply. Humans contain wandering phagocytes

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Fig. 25.1

A phagocyte with bacteria attached to its surface

Fig. 25.2

A natural killer cell (small one) attacking a tumour cell

(Fig. 25.1), that circulate through the body. The most important phagocytes are the macrophages and the neutrophils. Macrophages (big eaters) are large irregular-shaped cells that engulf microbes, viruses, cellular debris, etc. In response to an infection, monocytes are liberated at the site of infection, and become converted into macrophages. Inflammatory Barriers You might have noticed that an infection or tissue injury often results in redness and swelling, along with pain and production of heat that may result in fever. Such manifestation is localised and is known as inflammatory response . This response occurs due to release of chemical alarm signals, notably histamine and prostaglandins, by the damaged mast cells. There is a leakage of vascular fluid, which contains serum proteins with antibacterial activity. Further, there is an influx of phagocytic cells into the affected area. These responses inhibit and destroy the invading microorganism (Fig. 25.1). Besides the phagocytes, natural killer cells kill virus-infected cells and some tumour cells of the body by creating perforin-lined pores in the plasma membrane of the target cells (Fig. 25.2). These pores allow entry of water into the target cell, which then swells and bursts.

Complement system participates in both innate and acquired immunities. It consists of over 30 proteins that act in various ways to protect the individual from foreign invaders. The member proteins of the complement system function in an orderly manner. Ultimately, there is formation of transmembrane pores in the microbes, which leads to their lysis (Fig. 25.3). Some components

Fig. 25.3

Complement proteins creating a hole in the plasma membrane

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of the complement system coat the invading microbes. This coating enables phagocytes to readily attach to the microbes and destroy them.

25.2 ACQUIRED IMMUNITY

Acquired immunity, also known as adaptive or specific immunity , is capable of recognising and selectively eliminating specific microorganisms. Acquired immunity is found only in vertebrates. It supplements the protection provided by innate immunity. It is generated in response to an exposure to the microorganisms in question. Specific defence mechanisms require several days to be activated, following the breach of non-specific defence mechanisms. Adaptive immunity has the following unique features : (i) Specificity : It is the ability to distinguish differences among various foreign molecules. (ii) Diversity : It can recognise a vast variety of foreign molecules. (iii) Discrimination between Self and Non-self : It is able to recognise and respond to molecules that are foreign or non-self. At the same time, it can avoid response to those molecules that are present within the body (self) of the given animal. (iv) Memory : When the immune system encounters a specific foreign agent, e.g., a microbe, for the first time, it generates immune response and eliminates the invader. The immune system retains the memory of this encounter. As a r esult, a second encounter with the same microbe evokes a heightened immune response. Specific immunity employs two major groups of cells : (a) lymphocytes, and (b) antigen presenting cells. A healthy human being possesses about a trillion lymphocytes. The lymphocytes are of two types, viz., T lymphocytes or T cells and B lymphocytes or B cells. Both the types of lymphocytes, as well as the other cells of the immune response, are produced in bone marrow; the process of their production is called haematopoiesis. Some immature lymphocytes, destined to become thymocytes,

migrate via the blood to the thymus, where they mature as T cells. The B cells, on the other hand, divide and mature in the bone marrow itself. The B and T cells, together, generate the following two types of specific immunity : (a) cell-mediated immunity (by T cells), and (b) antibodymediated or humoral immunity (by B cells). The large and complex foreign molecules (mainly proteins) that activate the specific immunity are known as antigens. Our immune system can recognise a vast variety of antigens readily. Antigenic determinants are those sites on antigens that are recognised by antibodies and receptors present on T and B cells. An antigen triggers a specific immune response against itself. Adaptive immunity may be active or passive. Active immunity is due to the immune response generated in the individual in question by a pathogen or vaccine, whereas passive immunity is conferred by transfer of immune products, like antibodies, etc., from another individual into a non-immune individual. Activation of Adaptive Immunity Every antigen is processed by antigen presenting cells like macrophages, B lymphocytes, etc. The processed antigen is presented on the surface of these cells. A subgroup of T cells called T helper cells, specifically interacts with the presented antigen and becomes activated. The activated T helper cells then activate B cells, and a subgroup of T cells called T cytotoxic cells, in a specific manner. The activated B cells and T cytotoxic cells proliferate to produce clones. All the cells of a clone recognise the same antigen and eliminate it. Cell-mediated Immunity Cell-mediated immunity is the responsibility of a subgroup of T cells, called T cytotoxic cells. An activated T cytotoxic cell is specific to a target cell which has been infected, and kill the target cell by a variety of mechanisms. This prevents the completion of life cycle of the pathogen, since it depends on an intact host cell. Cell-mediated immunity is also involved in killing of cancer cells.

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(a)

(b)

Fig. 25.4

Immunoglobulins : (a) Structure, (b) Antigen binding site

Antibody-mediated Immunity The B cells produce specialised glycoproteins called antibodies. These glycoproteins are highly specific to specific antigens. Antibodies are collectively termed as immunoglobulins or Ig (Fig. 25.4). Each immunoglobulin molecule is made up of 4 polypeptide chains. There are two long chains, called heavy or H chains, and two short chains, called light or L chains. The four polypeptide chains are held together to form a Y-shaped molecule. The top two tips of this Y-shaped molecule bind to the specific antigens in a lock-and-key fashion, forming an antigen-antibody complex. Each antigen has many different antigenic determinants, each of which matches a specific antibody and binds to it (Fig. 25.5). The B cells, thus, direct the antibody-mediated immunity (also called humoral immunity). The antibody molecules may be bound to a cell membrane or they may remain free. The free antibodies have three main functions: agglutination of particulate matter, including bacteria and viruses, opsonisation or coating

of bacteria to facilitate their subsequent phagocytosis by cells, and neutralisation of toxins released by bacteria, e.g., tetanus toxin. In humans, immunoglobulins are grouped into the following five classes : IgA, IgD, IgE, IgG

Antibodies bound to antigenic determinants

Fig. 25.5 Formation of antigen-antibody complex

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Table 25.1 : Functions of Different Immunoglobulin Classes Immunoglobulin Class IgA IgD IgE IgG* IgM Function Protection from inhaled and ingested pathogens. Present on lymphocyte surface as receptors, activation of B cells. Mediator in allergic response. Stimulation of phagocytes and complement system passive immunity to foetus. Activation of B cells.

`*Most abundant Ig (about 75 per cent of human antibodies); only antibody that can cross placenta.

and IgM. The functions of these immunoglobulins are listed in Table 25.1.

25.3 CLONAL SELECTION AND PRIMARY SECONDARY IMMUNE RESPONSES

AND

produced during the primary response; it lasts much longer than primary response. This is why a person surviving a disease like chicken pox or measles becomes immune to subsequent attacks of the same disease.

As already stated, each B and T lymphocyte displays on its surface a specific receptor; the number of cells expressing a given receptor is rather small. In case of a B cell, this receptor is the antibody produced by that cell. When this receptor interacts with the antigenic determinant specific to it, the lymphocyte becomes activated and divides to form a clone of cells. These cells are also transformed into effector cells, i.e., antigen producing B cells and T cytotoxic cells. This phenomenon is called clonal selection , where all the cells in a given T or B cell clone are derived from a single parental cell, and exhibit the same specificity for antigenic determinant. But some of the activated lymphocytes develop into long-lived memory cells, and do not produce antibodies or kill infected cells. However, they divide and produce antibody whenever they get further encounter from the same antigen. The immune response mounted as a result of the first encounter of an animal with an antigen takes relatively longer, is feeble, and declines rapidly. This is known as primary immune response . But a subsequent encounter of this animal with the same antigen results in a hightened immune response much more rapidly. This is referred to as the secondary immune response. The secondary response is due to the memory cells that were

Fig. 25.6

Human lymphatic system

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25.4 LYMPHOID ORGANS

Lymphoid organs are those organs where the maturation and proliferation of lymphocytes take place (Fig. 25.6). There are two types of lymphoid organs. The primary lymphoid organs are those sites where T and B lymphocytes mature, and acquire their antigen-specific receptors. Bone marrow (site of B cell maturation) and thymus (site of T cell maturation) constitute the primary lymphoid organs. After maturation, B and T cells migrate via the circulatory system (blood vascular and lymphatic systems) to the secondary lymphoid organs . These include lymph nodes, spleen and mucosa-associated lymphoid tissues, such as tonsils. These organs are the sites for proliferation and differentiation of lymphocytes, in response to specific antigens. The acquired immune response to antigens usually develops in these organs.

25.5 VACCINATION AND IMMUNISATION

The principle of immunisation or vaccination is based on the property of memory of the immune system. In vaccination, a preparation of antigenic proteins of pathogens or inactivated/ weakened pathogens (vaccine) is introduced into the body. These antigens generate the primary immune response, and the memory B and T cells. When the vaccinated person is attacked by the same pathogen, the existing memory T or B cells recognise the antigen quickly and overwhelm the invaders with a massive production of lymphocytes and antibodies. Edward Jenner, an English physician, in his landmark experiment in 1796, scratched the skin of a boy to introduce into his body the fluid from a sore of a milkmaid who was suffering from cow pox. When the person was later exposed to smallpox, he showed resistance to the disease. Louis Pasteur, a French scientist, found that ageing cultures of cholera bacteria were too weak to cause disease when injected into chickens. But chickens injected with these cultures became immune to fowl-cholera (Fig. 25.7). Using this method,

Fig. 25.7

The classic experiment of Pasteur with chicken (fowl) cholera

Pasteur developed a vaccine (Latin, vacca, meaning : cow) against rabies in 1885. It was later discovered that animals injected with small amounts of the tetanus toxin became immune to the disease. By the end of 1920s, vaccines for diphtheria, tetanus, pertussis (whooping cough) and tuberculosis were available. Some examples of common vaccines are listed in Table 25.2. Traditionally, the vaccine preparations contained either inactivated pathogens, or live but weakened pathogens. Subsequently, antigenic polypeptides prepared from pathogens were used in vaccines. Recombinant DNA technology has allowed the production of antigenic polypeptides of

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Table 25.2 : Vaccine DTP-Hib Disease

Important Vaccines for Babies and Children Age group All babies of 1, 2 and 3 month age Safety Between 90 and 99% Not yet known

Diphtheria, Tetanus, Pertussis (whooping cough) and Haemophilus influenzae type B Hepatitis

Hepatitis B

All babies whose mothers or close family have been infected with hepatitis B All babies of 1, 2 and 3 month age at the same time as DTP-Hib. All children between 10 and 14 years

Polio

Polio

Almost 100%

BCG

tuberculosis (TB)

70%

pathogens in transgenic organisms. Some vaccines produced using this approach are now available, e.g., hepatitis B vaccine produced from transgenic yeast. Attempts are being made to use suitable preparations of the concerned genes themselves from the pathogens as vaccines.

25.6 BLOOD GROUPS

There are 30 or so known antigens on the surface of red blood cells that give rise to different blood groups. In a transfusion, certain blood groups, e.g., ABO blood group, of the recipient and donor must be matched, otherwise the recipients immune system will produce antibodies causing agglutination of the transfused cells and blocking circulation through capillaries. ABO blood groups are determined by the gene I (for isoagglutinin). There are three alleles, IA, IB and IO of this gene. Proteins produced by the IA and IB alleles are known as A and B antigens, respectively. Individuals with blood group A have the A antigen on the surface of their red blood cells (RBCs), and antibodies to antigen B in their plasma. People with blood group B have B antigen on their RBCs, and antibodies against A antigen in their plasma. Individuals with AB blood group have both antigens A and B on their RBCs, and no antibodies for either of the antigens in their

plasma. Type O individuals lack A and B antigens on their RBCs, but have antibodies for both these antigens in their plasma. People with blood group AB can receive blood of A, B or O group, while those with blood group O can donate blood to anyone. This is the most important blood group in transfusion. If a transfusion is made between an incompatible donor and recipient, reaction of antigens on the cells and antibodies in the plasma will produce clots that will clog capillaries. The Rh (Rhesus) blood group is due to a cell surface antigen, which was first discovered in rhesus monkey. Persons having this antigen are called Rh positive (Rh +), whereas Rh negative (Rh) individuals lack this antigen. Rh antigen induces a strong immunogenic response when introduced into Rh individuals. Rh blood group is important in blood transfusion, and is involved in haemolytic disease of the newborn (HDN). When an Rh mother bears an Rh+ foetus, the Rh+ RBCs from the foetus may enter the mothers circulatory system during child birth, causing her to produce anti-Rh antibodies. As a result, subsequent Rh+ foetuses will be exposed to the anti-Rh antibodies produced by the mother, which results in HDN. In order to prevent HDN, Rh mothers are injected with a anti-Rhantibody during all pregnancies carrying Rh+ foetus.

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25.7 ORGAN TRANSPLANTS

AND

ANTIBODIES

Success of organ transplants and skin grafts depends on a proper matching of histocompatibility antigens that occur on all cells of the body. Chromosome 6 of mouse contains a cluster of genes known as the major histocompatibility complex (MHC), which in humans is called human leukocyte antigen (HLA) complex. The alleles of HLA genes are codominant. The products of these genes determine histocompatibility, i.e., compatability between donor and recipient tissues in transplants. The array of HLA alleles on a homologue of our chromosome 6 is known as a haplotype. An individual inherits one HLA haplotype from each parent. The large number of alleles at this locus ensures that only identical twins have the identical haplotype. The best HLA matches would occur within a family. Therefore, the preference order for transplants is as follows : identical twin > sibling > parent > unrelated donor. The procedure carried out to match HLA proteins of donor and recipient is called tissue typing. When HLA types are matched properly, the survival of transplanted organs increases dramatically.

fatal reaction in a sensitive individual; this is called anaphylaxis. Autoimmune Diseases Autoimmune diseases result when the immune system attacks and destroys self cells and molecules. This condition can cause chronic and serious diseases. Examples of autoimmune diseases are insulin-dependent diabetes, multiple sclerosis, rheumatoid arthritis, etc. Multiple sclerosis is caused by antibodies that attack the myelin sheath of nerve cells. Immunodeficiency Diseases Immunodeficiency diseases result from a defect in one or more components of the innate or adaptive immunity. Affected individuals are susceptible to diseases that normally would not bother most people. Immunodeficiency may result from gene mutations, infections, malnutrition or accidents. Severe combined immunodeficiency (SCID) results from one of many genetic defects; one such genetic defect leads to adenosine deaminase deficiency. SCID is characterised by a very low number of circulating lymphocytes. Affected individuals usually die at an early age. AIDS is an example

25.8 IMMUNE SYSTEM DISORDERS

Clearly, the immune system is a multicomponent interactive system. It effectively protects the host from various infections. But an improper functioning of the immune system can cause discomfort, disease or even death. The improper functions fall into the following major groups : (a) hypersensitivity or allergy, (b) auto-immune diseases, and (c) immunodeficiency. Hypersensitivity Allergies result from an inappropriate and excessive immune response to common antigens. Substances that cause allergies are called allergens; they include dust, moulds, pollen, certain foods, and some medicines such as penicillin. Allergy involves mainly IgE antibodies and histamine. A common manifestation of allergy is asthma. Sometimes an allergen may cause a sudden, violent and
Receptor that recognises T -helper cells

Single-stranded RNA

Reverse transcriptase

Fig. 25.8

Schematic representation of HIV

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of immunodeficiency disease caused by the infection from a retrovirus, known as human immunodeficiency virus (HIV) (Fig. 25.8). Retroviruses have RNA genomes that replicate via DNA intermediate. HIV selectively infects and kills T-helper cells. The depletion of Thelper cells weakens the acquired immune response, and may even abolish it completely. The viral RNA genome is converted into DNA

copy by the viral enzyme reverse transcriptase. The DNA copy of HIV becomes inserted into the human chromosome and replicates with the cellular DNA. It may be transcribed to produce RNA copies of the viral genome. The RNA copies are packaged and liberated as virus particles. The infected cell is lysed in this process, and the released virus particles infect new T -helper cells.

SUMMARY

Animal body has elaborate mechanisms for protection from foreign agents and cancer cells (immunity). Immunity is either innate or acquired. Innate or non-specific immunity comprises those mechanisms that are always available to protect animal body, i.e., previous exposure to an antigen is not needed to activate these mechanisms. These mechanisms consist of anatomic, physiologic, phagocytic and inflammatory barriers. Innate immunity is the first line of defence of most animals and plants. Acquired immunity (also called adaptive or specific immunity) is found only in vertebrates. It has the ability to recognise and selectively eliminate specific foreign agents. It is initiated in response to an exposure to the foreign agent in question, and the process takes several days. Acquired immunity has the following unique features : (i) specificity, (ii) diversity, (iii) memory, and (iv) discrimination between self and non-self. It is of two types, viz., active (immune response generated in the concerned individual) and passive (transfer of antibodies, etc. from another individual into a non-immunised individual). Acquired immunity employs two major groups of cells, viz., lymphocytes and antigen presenting cells. Lymphocytes are of two types : (a) B lymphocytes (mature in bone marrow and produce antibodies) and (b) T lymphocytes (mature in thymus and function as cytotoxic or helper cells). Both B and T cells display on their surfaces specific receptors that interact with the antigens. The antigen is processed by antigen presenting cells and its fragments are displayed on the surface of these cells. T helper cells interact with the presented antigen and become activated. These T cells, in turn, activate specific B and T cytotoxic cells. Activated B and T cells proliferate to form clones (clonal selection); some of these cells function in immune response, while some others become memory cells (responsible for secondary response and vaccination). B cells produce antibodies, while T cells kill the target cells (infected cells, cancer cells). Antibodies are glycoproteins (immunoglobulins). Each antibody has two light chains and two heavy chains that form a Y-shaped structure. The top two tips of this Y specifically interact with the antigen to form antigen-antibody complex. Antibodies are grouped into the following five classes : IgA, IgD, IgE, IgG and IgM. The property of memory of immune system is used in vaccination. The vaccine consists of a preparation of antigenic proteins of pathogens, or weakened/inactivated pathogens themselves. The antigenic protein may be prepared from the pathogen, or produced in a transgenic organism, e.g.,

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hepatitis B vaccine produced in yeast. Vaccination has its origin from the works of Edward Jenner and Louis Pasteur. Some examples of commonly used vaccines are BCG, DPT-Hib, hepatitis B, polio etc. Human blood cells display on their surface 30 or more different antigens. These antigens give rise to various blood groups, e.g., ABO, Rh, etc. blood groups. The success of organ transplant depends on proper matching of proteins, called human leucocyte antigens. The preference order for transplants is : identical twin > sibling > parent > unrelated donor. An improper function of the immune system gives rise to the following groups of disorders : (i) allergy (excessive immune response to common antigens), (ii) auto immune diseases (the immune system attacks and destroys self cells and molecules), and (iii) immunodeficiency diseases (inability to mount immune response). Immunodeficiency may result from gene mutations (e.g., SCID), infections (e.g., by HIV), malnutrition or accidents. HIV is a retrovirus; it has a single-stranded RNA genome that is reverse transcribed and incorporated into the host genome. HIV specifically attacks T helper cells.

EXERCISES

1.

Which of the following properties of acquired immunity is the basis of vaccination? (a) Specificity (b) Diversity (c) Memory (d) Discrimination between self and non-self.

2.

Immunodeficiency can result from which of the following? (a) Gene mutation (b) Infection (c) Malnutrition (d) All of the above.

3.

Match the components of the immune system given in column I with the phenomenon listed in column II. Column I (i) (ii) (iv) (v) (vi) Histamines Complement proteins T cytotoxic cells B cells T helper cells (a) (b) (c) (d) (e) (f) (g) (h) Column II Antibody production Activation of B cells Inflammatory response Processing of antigens Passive immunity to foetus Pore formation Killing of specific target cells Allergy

(iii) IgE

(vii) Antigen presenting cells (viii) IgG (ix) IgM

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4.

HIV attacks which of the following? (a) B cells (b) T cells (c) Antigen presenting cells (d) T helper cells. Which of the following is not a component of innate immunity? (a) Antibodies (b) Interferons (c) Complement proteins (d) Phagocytes. Define the following terms : (a) Innate immunity (c) Acquired immunity (e) Haematopoiesis (g) Antigenic determinant (i) Primary immune response (b) (d) (f) (h) (j) Clonal selection Immunology Antigen Vaccine Secondary immune response.

5.

6.

7.

Explain the following in not more than 70 words. (a) Properties of acquired immunity (b) Activation of adaptive immunity (c) Role of lymphoid organs in immune response (d) ABO blood groups (e) Hypersensitivity (f) Autoimmune diseases (g) AIDS. Explain the following in not more than 100 words. (a) Innate immunity (b) Rh blood groups (c) Organ transplants (d) Vaccination. Explain the role of innate immunity in protection from infectious agents.

8.

9.

10. Explain the phenomenon of adaptive immunity with special reference to its properties, activation, clonal selection, and its role in vaccination. 11. Briefly explain the various types of disorders arising from improper function of the immune system. 12. Briefly explain the functions of the following with reference to immunity : (a) Antibodies (b) T helper cells (c) HLA proteins (d) B cells (e) Interferons (f) Mucous membranes (g) Phagocytes (h) Complement proteins