DEFINITION AND TYPES OF IMMUNITY

• It is the ability of the body to resist entry of different types of foreign bodies such as:
• Bacteria
• Virus
• Toxic substances
• Etc.

Types of Immunity

1. Innate immunity
2. Acquired immunity

INNATE IMMUNITY OR NON-SPECIFIC IMMUNITY

• Innate immunity → inborn capacity of body to resist pathogens.
• If any organism enters the body, innate immunity eliminates it before development of any disease.
• It represents the first line of defence against any type of pathogens.
• Therefore, it is called non-specific immunity.

Mechanisms of Innate Immunity

ACQUIRED IMMUNITY OR SPECIFIC IMMUNITY

• Acquired immunity → resistance developed in the body against any specific foreign body like:
• Bacteria
• Viruses
• Toxins
• Vaccines
• Transplanted tissues
• Therefore, this type of immunity is known as specific immunity.
• It is the most powerful immune mechanism which protects the body from invading organisms or substances.
• Lymphocytes are responsible for acquired immunity.

DEVELOPMENT AND PROCESSING OF LYMPHOCYTES

• In fetus, lymphocytes develop from bone marrow.
• After birth, they are released into circulation and differentiated into two categories:

1. T lymphocytes or T cells → responsible for cellular immunity.
2. B lymphocytes or B cells → responsible for humoral immunity.

T LYMPHOCYTES

• T lymphocytes are processed in thymus.
• Processing occurs during the period between just before birth and a few months after birth.
• Thymus secretes thymosin, which accelerates proliferation and activation of lymphocytes.
• Thymosin also increases the activity of lymphocytes in lymphoid tissues.

Processing of T Lymphocytes in Thymus

1. Stem cells from bone marrow enter cortex of thymus and start proliferating.
2. Proliferated cells start maturing into T lymphocytes.
3. Stem cells developing into T cells are called thymocytes.
4. First event during maturation → rearrangement of polypeptide chains on receptor protein called T cell receptor (TCR) present on surface of lymphocytes.
5. T lymphocytes recognize foreign antigen displayed on surface of antigen-presenting cells with the help of their own TCR.

During rearrangement of polypeptide chains:

• In majority of thymocytes, TCR consists of one α chain and one β chain.
• TCR of remaining cells have one δ chain and one γ chain.

Types of T Lymphocytes

1. Helper T cells or inducer T cells.
2. Cytotoxic T cells or killer T cells.
3. Suppressor T cells.
4. Memory T cells.

Storage of T Lymphocytes

• After transformation, all types of T lymphocytes leave thymus.
• They are stored in lymphoid tissues of:
• Lymph nodes
• Spleen
• Bone marrow
• Gastrointestinal (GI) tract.

B LYMPHOCYTES

• B lymphocytes were first discovered in the bursa of Fabricius in birds.
• Hence the name B lymphocytes.
• Bursa of Fabricius is a lymphoid organ situated near the cloaca of birds.
• Bursa is absent in mammals.
• Processing of B lymphocytes in mammals takes place in:
• Bone marrow
• Liver

Types of B Lymphocytes

1. Plasma cells
2. Memory cells

Storage of B Lymphocytes

• After transformation, B lymphocytes are stored in lymphoid tissues of:
• Lymph nodes
• Spleen
• Bone marrow
• GI tract.

ANTIGENS

Types of Antigens

1. Autoantigens or self-antigens
   • Present in the body’s own cells like:
   • A antigen
   • B antigen
2. Foreign antigens or non-self-antigens
   • Enter the body from outside.

Chemical Nature of Antigens

• Antigens are conjugated proteins such as:
• Lipoproteins
• Glycoproteins
• Nucleoproteins.

CELL-MEDIATED IMMUNITY

• Cell-mediated immunity is offered by T lymphocytes.
• It involves several types of cells such as:
• Macrophages
• Lymphocytes
• Natural killer cells
• Other cells which enhance cell-mediated immunity.
• It is also called cellular immunity or T cell immunity.
• It does not involve antibodies.
• Cellular immunity is the major defence mechanism against infections by:
• Viruses
• Fungi
• Few bacteria
• It is also responsible for:
• Delayed allergic reactions
• Rejection of transplanted tissues.
• Cell-mediated immunity starts developing when T cells have contact with antigens.
• Usually, invading microbial and non-microbial organisms carry antigenic material.

ROLE OF ANTIGEN-PRESENTING CELLS

• Antigen-presenting cells are special types of cells in the body which:
• Include release of antigenic materials from invading organisms.
• Later present the antigenic materials to helper T cells.

Types of Antigen-Presenting Cells

1. Macrophages
2. Dendritic cells
3. B lymphocytes

1. Macrophages

• Macrophages are large phagocytic cells which digest invading organisms to release antigen.
• Macrophages are the major antigen-presenting cells.
• They are present along with lymphocytes in almost all lymphoid tissues.

2. Dendritic Cells

• Dendritic cells are nonphagocytic.
• Classified into three categories based on location:

1. Dendritic cells of skin → trap the antigen in blood.
2. Follicular dendritic cells in lymph nodes → trap the antigen in lymph.
3. Langerhans dendritic cells in skin → trap organisms that come in contact with body surface.

3. B Lymphocytes

• B lymphocytes also act as antigen-presenting cells.
• Thus, B cells function as both:
• Antigen-presenting cells
• Antigen-receiving cells
• However, B cells are efficient antigen-presenting cells and need to be activated by helper T cells.

Role of Antigen-Presenting Cells

• Invading foreign organisms are either:
• Engulfed by macrophages through phagocytosis, or
• Trapped by dendritic cells.
• Later, antigen from organisms is released in the form of small peptides.
• Antigenic peptide products are moved towards surface of antigen-presenting cells and loaded on a genetic matter of antigen-presenting cells called human leukocyte antigen (HLA).
• HLA is present in the molecule of class II major histocompatibility complex (MHC) situated on surface of antigen-presenting cells.

Presentation of Antigen

• Antigen-presenting cells present their class II MHC molecules together with antigen-bound HLA to the helper T cells.

Sequence of Events During Activation of Helper T Cells

1. Helper T cell recognizes the antigen bound to class II MHC molecule displayed on the surface of antigen-presenting cell.
2. It recognizes the antigen with help of its own surface receptor protein called T cell receptor.
3. Recognition of antigen by helper T cell initiates a complex interaction between helper T cell receptor and antigen.
4. This reaction activates helper T cells.
5. At the same time, macrophages release interleukin-1, which facilitates activation and proliferation of helper T cells.
6. Activated helper T cells proliferate.
7. Proliferated helper T cells enter circulation for further actions.
8. Simultaneously, antigen bound to class II MHC molecules activates B cells, also resulting in development of humoral immunity.

Role of Helper T Cells

• Helper T cells which enter circulation activate all the other T cells and B cells.
• Helper T cells are of two types:
1. Helper-1 (TH1) cells
2. Helper-2 (TH2) cells

Role of TH1 Cells

• TH1 cells are concerned with cellular immunity.
• They secrete:
• Interleukin-2 → activates the other T cells.
• Gamma interferon → stimulates phagocytic activity of:
  • Cytotoxic cells
  • Macrophages
  • Natural killer (NK) cells.

Role of TH2 Cells

• TH2 cells are concerned with humoral immunity.
• They secrete:
• Interleukin-4
• Interleukin-5
• These are concerned with:
1. Activation of B cells
2. Proliferation of plasma cells
3. Production of antibodies by plasma cells.

OTHER TYPES OF T LYMPHOCYTES

ROLE OF CYTOTOXIC T CELLS

• Cytotoxic T cells activated by helper T cells circulate through:
• Blood
• Lymph
• Lymphatic tissues
• They destroy invading organisms by attacking them directly.

Mechanism of Action of Cytotoxic T Cells

1. Receptors situated on outer membrane of cytotoxic T cells bind antigens of organisms tightly with cytotoxic T cells.
2. Cytotoxic T cells enlarge and release cytotoxic substances such as lysosomal enzymes.
3. Cytotoxic substances destroy the invading organisms.
4. Each cytotoxic T cell can destroy many microorganisms one after another.

Other Actions of Cytotoxic T Cells

1. Cytotoxic T cells also destroy:
   • Cancer cells
   • Transplanted cells such as:
   • Cells of transplanted heart
   • Cells of transplanted kidney
   • Any foreign bodies
2. Cytotoxic T cells also destroy own tissues affected by foreign bodies.
3. Many viruses are entrapped in membrane of affected cells.
4. Antigen of viruses attracts T cells.
5. Cytotoxic T cells kill affected cells along with viruses.
6. Because of this, cytotoxic T cell is called killer cell.

ROLE OF SUPPRESSOR T CELLS

• Suppressor T cells or regulatory T cells suppress activities of cytotoxic T cells.
• They play an important role in preventing cytotoxic T cells from destroying body’s own tissues along with organisms.
• Suppressor cells also suppress activities of helper T cells.

ROLE OF MEMORY T CELLS

• Some T cells activated by an antigen do not enter circulation.
• They remain in lymphoid tissue.
• Such T cells are called memory T cells.
• In later periods, memory cells migrate to various lymphoid tissues throughout the body.
• When body is exposed to same organism for second time:
• Memory cells identify the organism.
• Immediately activate other T cells.
• Invading organism is destroyed very quickly.
• Response of T cells is also more powerful this time.
• During the second exposure, memory cells are activated by antigen and produce more quantity of antibodies at a faster rate than in first exposure.
• Antibodies produced during second exposure to foreign antigen are also more potent than those produced during first exposure.
• This phenomenon forms the basic principle of vaccination against infections.

DEVELOPMENT OF HUMORAL IMMUNITY

• Antibodies are produced by B lymphocytes and released into:
• Blood
• Lymph
• Blood and lymph are body fluids (humours or humors in Latin).
• Since B lymphocytes provide immunity through humours, this type of immunity is called humoral immunity or B cell immunity.
• Antibodies fight against invading organisms.
• Humoral immunity is the major defence mechanism against bacterial infection.
• In cell-mediated immunity, macrophages and other antigen-presenting cells play an important role in development of humoral immunity.

Role of Antigen-Presenting Cells in Humoral Immunity

• Ingestion of foreign organisms and digestion of their antigen by antigen-presenting cells are already explained.

Sequence of Events During Activation of B Cells

1. B cell recognizes antigen bound to class II MHC molecule displayed on surface of antigen-presenting cell.
2. It recognizes antigen with help of its own surface receptor protein called B-cell receptor.
3. Recognition of antigen by B cell initiates a complex interaction between B-cell receptor and antigen.
4. This reaction activates B cells.
5. At the same time, macrophages release interleukin-1, which facilitates activation and proliferation of B cells.
6. Activated B cells proliferate.
7. Proliferated B cells carry out further actions.
8. Simultaneously, antigen bound to class II MHC molecules activates helper T cells, also resulting in development of cell-mediated immunity.

Transformation of B Cells

Proliferated B cells are transformed into two types of cells:

1. Plasma cells
2. Memory cells

Role of Plasma Cells

• Plasma cells destroy foreign organisms by producing antibodies.
• Antibodies are gamma globulin in nature.
• Rate of antibody production is very high.
• Each plasma cell produces about 2,000 molecules of antibodies per second.
• Antibodies are released into:
• Lymph
• Circulation
• Antibodies are produced until the end of lifespan of each plasma cell, which may be from several days to several weeks.

Role of Memory B Cells

• Memory B cells occupy lymphoid tissues throughout the body.
• Memory cells are in inactive condition until the body is exposed to the same organism for second time.

ANTIBODIES OR IMMUNOGLOBULINS

• Antibody is gamma globulin in nature and is also called immunoglobulin (Ig).
• Immunoglobulins form 20% of total plasma proteins.
• Immunoglobulins enter almost all tissues of the body.
• Among antibodies, IgG forms 75% of antibodies in the body.

Types of Antibodies

Structure of Antibodies

• Antibodies are formed by two pairs of chains:
• One pair of heavy or long chains
• One pair of light or short chains.
• Each heavy chain consists of about 400 amino acids.
• Each light chain consists of about 200 amino acids.
• Each antibody has two halves which are identical.
• Both halves are held together by disulfide bonds (S-S).
• Each half consists of:
• One heavy chain (H)
• One light chain (L)
• The two chains in each half are also joined by disulfide bonds (S-S).
• Disulfide bonds allow movement of amino acid chains.
• In each antibody:
• Light chain is parallel to one end of heavy chain.
• Light chain and part of heavy chain parallel to it form one arm.
• Remaining part of heavy chain forms another arm.
• A hinge joins the two arms.
• Each chain of antibody includes two regions:
• Constant region
• Variable region.

Abbreviations

• VL → Variable region of light chain
• VH → Variable region of heavy chain
• CL → Constant region of light chain
• CH → Constant region of heavy chain
• S-S → Disulfide bonds

MECHANISM OF ACTIONS OF ANTIBODIES

Antibodies protect the body from invading organisms by two ways:

1. Direct actions
2. Through complement system

A. Direct Actions of Antibodies

Antibodies directly inactivate invading organisms by:

1. Agglutination
   • Foreign bodies such as RBCs (from a donor) and bacteria with antigens on their surfaces are held together in a clump by antibodies.
2. Precipitation
   • Soluble antigens like tetanus toxin are converted into insoluble forms and then precipitated.
3. Neutralization
   • Antibodies cover the toxic sites of antigenic products.
4. Lysis
   • Antibodies rupture the cell membrane of organisms and then destroy them.

B. Actions of Antibodies Through Complement System

• Complement system accelerates various activities during the fight against invading organisms.
• It is a system of plasma enzymes identified by numbers from C1 to C9.
• Including the three subunits of C1:
• C1q
• C1r
• C1s
• There are 11 enzymes in total.
• All such enzymes are in inactive form.
• They are activated in three pathways:
1. Classical pathway
2. Lectin pathway
3. Alternate pathway

Pathways for Activation of Plasma Enzymes

Classical Pathway

Lectin Pathway

• Mannose-binding lectin combines with:
• Mannose
• Fructose
• Leads to destruction of antigen.

Alternate Pathway

• Binding of factor I with polysaccharide
• Activation of enzymes C3 and C5
• Destruction of antigen.

NATURAL KILLER CELL

• Natural killer (NK) cell → large granular cell with indented nucleus.
• It is considered as a third type of lymphocyte.
• It is not a phagocytic cell.
• Its granules contain hydrolytic enzymes which cause lysis of cells of invading organisms.

Functions of NK Cell

1. Destroys viruses.
2. Destroys viral infected or damaged cells, which might form tumors.
3. Destroys malignant cells and prevents development of cancerous tumors.
4. Secretes cytokines such as:
• Interleukin-2
• Interferons
• Colony-stimulating factor (GM-CSF)
• Tumor necrosis factor-α.

CYTOKINES

• These antibody proteins are secreted by WBCs and some other types of cells.
• Their major function is activation of the regulatory general immune system of the body.
• Cytokines are classified into several types.

IMMUNIZATION

• It is used to induce immune resistance to a body-specific disease.
• Immunization is of two types:

1. Passive immunization
2. Active immunization

PASSIVE IMMUNIZATION

• Passive immunization or immunity is produced without challenging the immune system of body.
• It is done by administration of serum or gamma globulins from a person who is already immunized (affected by a non-immune person).
• Passive immunization is acquired either:
• Naturally
• Artificially

1. Passive Natural Immunization

• Passive natural immunization is acquired from mother before and after birth.
• Before birth: Maternal antibodies (mainly IgG) are transported to fetus through placenta.
• After birth: Antibodies (IgA) are transported through breast milk.

2. Passive Artificial Immunization

• Passive artificial immunization is developed by injecting previously prepared antibodies using serum from:
• Humans
• Animals

ACTIVE IMMUNIZATION

• Active immunization or immunity is acquired by activating the immune system of body.
• Body develops resistance against disease by producing antibodies following exposure to antigens.
• Active immunity is acquired either:
• Naturally
• Artificially

1. Active Natural Immunization

• Naturally acquired active immunity involves activation of immune system in the body to produce antibodies.
• It is achieved during infections.

Toxoids

• It is used to develop immunity against diseases.
• Toxoid consists of weakened components or toxins secreted by pathogens.
• Toxoids are used to develop immunity against diseases like:
• Diphtheria
• Tetanus
• Cholera
• Etc.
• Active artificial immunity may be effective lifelong or for short period.
• It is effective lifelong against diseases such as:
• Mumps
• Measles
• Smallpox
• Tuberculosis
• Yellow fever
• It is effective for a short period against diseases like:
• Cholera → about 6 months
• Tetanus → about 1 year

2. Active Artificial Immunization

• Active artificial immunization → type of immunization achieved by administration of:
• Vaccines
• Toxoids

Vaccines

• Vaccine is prepared from:
• Dead pathogens, or
• Live but attenuated (artificially weakened) microorganisms.
• Vaccine induces immunity against pathogen either by:
• Production of antibodies, or
• Activation of T lymphocytes.
• Vaccines are used to prevent many diseases such as:
• Smallpox
• Measles
• Mumps
• Poliomyelitis
• Tuberculosis
• Smallpox
• Rubella
• Yellow fever
• Rabies
• Typhoid
• Influenza
• Hepatitis B
• Etc.

IMMUNE DEFICIENCY DISEASES

• Normally, defence mechanism protects the body from invading pathogenic organisms.
• When defence mechanism fails or becomes faulty (defective):
  • Organisms even of low virulence produce severe disease.
• Such organisms, which take advantage of defective defence mechanism, are called opportunists.

Types of Immune Deficiency Diseases

1. Congenital immune deficiency diseases.
2. Acquired immune deficiency diseases.

CONGENITAL IMMUNE DEFICIENCY DISEASES

• Congenital diseases → inherited.
• Occur due to defects in:
• B cell
• T cell
• Both.
• Common examples:
• Di George syndrome → due to absence of thymus.
• Severe combined immune deficiency → due to absence of lymphoid tissue.

ACQUIRED IMMUNE DEFICIENCY DISEASES

• Acquired immune deficiency diseases occur due to infection by some organisms.
• Most common disease → Acquired immune deficiency syndrome (AIDS).

Acquired Immune Deficiency Syndrome

• AIDS → infectious disease caused by human immune deficiency virus (HIV).
• AIDS is the most common problem throughout world because of rapid increase in number of victims.
• Infection occurs when a glycoprotein from HIV binds to surface receptors of:
• T lymphocytes
• Monocytes
• Macrophages
• Dendritic cells
• This leads to destruction of these cells.
• It causes slow progressive decrease in immune function, resulting in opportunistic infections of various types.
• Common opportunistic infections which kill AIDS patient:
• Pneumonia
• Skin cancer.

AUTOIMMUNE DISEASES

• Normally, an antigen induces immune response in the body.
• Condition in which immune system does not give response to an antigen is called tolerance.
• This is true with respect to body’s own antigens, called self-antigens or autoantigens.
• Normally, body has tolerance against self-antigens.
• However, sometimes tolerance fails and becomes incomplete against self-antigen.
• This situation is called autoimmunity.
• It leads to activation and production of autoantibodies by B lymphocytes.
• T lymphocytes (cytotoxic T cells) also attack the body’s normal cells whose surface contains the self-antigen or autoantigen.

Common Autoimmune Diseases

1. Diabetes mellitus
2. Myasthenia gravis
3. Hashimoto’s thyroiditis
4. Graves’ disease
5. Rheumatoid arthritis.

IMMUNOLOGICAL HYPERSENSITIVE REACTIONS

• Immunological hypersensitive reactions to an antigen give rise to several allergic conditions and autoimmune diseases.
• Hypersensitive reactions are classified into five types.

TYPE I OR ANAPHYLACTIC REACTIONS

• Anaphylaxis → exaggerated reactions of body to an antigen or other agents to which body is sensitized already.
• It is also called immediate hypersensitivity reaction, because it develops within few minutes of exposure to an allergen.
• Anaphylactic reaction is mediated by:
• IgE
• Other factors involved in inflammation.

TYPE II OR CYTOTOXIC REACTIONS

• Cytotoxic reactions involve mainly IgG antibodies, which bind with antigens on surface of cells, particularly blood cells.
• Affected cells are destroyed.
• Sometimes, IgM and IgA antibodies are also involved.
• Diseases developed due to cytotoxic reactions include:
• Hemolytic diseases of newborn in case of Rh incompatibility.
• Autoimmune hemolytic anemia.

TYPE III OR ANTIBODY-MEDIATED REACTIONS

• Excess amounts of antibodies like IgG or IgM are produced.
• Antigen-antibody complexes are precipitated and deposited in localized areas.
• These cause:
• Arthritis
• Heart causing myocarditis
• Glomeruli of kidney producing glomerulonephritis.

TYPE IV OR CELL-MEDIATED REACTIONS

• Also called delayed type of hypersensitivity.
• It is found in allergic reactions due to:
• Bacteria
• Viruses
• Fungi.
• It is seen in contact dermatitis caused by chemical allergens and during rejection of transplanted tissues.
• Example of type IV reaction:
• Delayed reaction after intradermal injection of tuberculin in persons who are previously affected by tuberculosis.
• Tuberculosis skin test or Mantoux test.
• Delayed type of hypersensitivity is an important feature involving T lymphocytes rather than antibodies.

TYPE V OR STIMULATORY/BLOCKING REACTIONS

• Seen in autoimmune diseases like:
• Graves’ disease → stimulatory reactions.
• Myasthenia gravis → blocking reactions.

IMMUNITY AND CANCER

• Though immune system is very powerful against:
  • Viruses
  • Bacteria
  • Fungi
  • Parasites
  • Other pathogens
• It fails against cancer cells.
• Most often, immune system does not recognize cancer cells which develop from body’s own cells.
• Some cells of immune system may recognize cancer cells as abnormal cells and destroy them.
• Thus, immune system can help body fight against cancer cells on regular basis.
• However, most of the times:
• Immune cells are overpowered by cancer cells.
• They become helpless in preventing development of cancer.
• Cancer cells also can weaken the immune system by encroaching bone marrow.

Cancer of Immune System

• Cancer can develop in immune system itself.
• Cancer of immune system includes:
• Leukemia
• Lymphoma.

Cancer Treatments and Immune System

• Chemotherapy and radiotherapy are useful for certain types of cancer.
• Such treatments may also temporarily weaken the immune system of body.
• Other treatments are:
• Immunotherapy
• Bone marrow transplant (stem cell transplant).

Immunotherapy

• In immunotherapy, substances produced in human body or synthesized in laboratory are used.
• Such substances can:
• Stop growth of cancer cells.
• Stop spreading of cancer to other parts of body.
• Induce immune system of body to destroy cancer cells.

Bone Marrow Transplant

• Bone marrow transplant is used in some types of blood cancer like:
• Leukemia
• Lymphoma
• Myeloma
• High doses of chemotherapy destroy the cancer cell.
• At the same time, stem cells in bone marrow are also killed.
• In these patients:
• Bone marrow transplant is given to replace the destroyed stem cells in bone marrow.
• Transplanted stem cells settle in bone marrow.
• They start growing and later develop into new healthy blood cells.