Immune system

Immunology

Immunology is a branch of biomedical science that covers the study of all aspects of the immune system in all organisms. 

It deals with: the physiological functioning of the immune system in states of

both health and diseases; malfunctions of the immune system in immunological disorder (

autoimmune diseases, hypersensitivities, 

immune deficiency, transplant rejection); the physical, chemical and physiological characteristics of the

components of the immune system in vitro, in situ, and in vivo.

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The Immune System

The immune system is the body's defense against infectious organisms and other invaders.

Each exposure (to the same pathogen) increases the effectivity of the response

Primary Lymphoid organs of the immune system

I. Thymus

II. bone marrow Secondary lymphoid organs

I. Lymph nodes

II. Spleen

III. Skin

IV. liver

V. Tonsils

VI. Small intestine

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Basic Immunology

Depends on the ability of the immune system to distinguish between self and non-self molecules

Self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system Autoimmunity is an immune reaction against self

molecules (causes various diseases) Non-self molecules are those recognized as

foreign molecules One class of non-self molecules are called antigens (

antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response

Immunity

Immunity is the state of having sufficient biological defences to avoid infection, disease, or other unwanted biological invasion. It is the capability of the body to resist harmful microbes from entering it. Components of the Immune systemImmunity involves both specific and non-specific components. 1.The non-specific components act either as barriers or as eliminators of wide range of pathogens irrespective of antigenic specificity. 2.Specific components of the immune system adapt themselves to each new disease encountered and are able to generate pathogen-specific immunity.

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Components of the immune system

Innate immune system Response is non-specific

Exposure leads to immediate maximal response

Cell-mediated and humoral components

No immunological memory

Found in nearly all forms of life (plants & animals)

Adaptive immune system

Pathogen and antigen specific response

Lag time between exposure and maximal response

Cell-mediated and humoral components

Exposure leads to immunologic memory

Found only in jawed vertebrates

Innate immunity, or nonspecific immunity is the natural resistances with which a person is born.

It provides resistances through several physical, chemical and cellular approaches.

Microbes first encounter the epithelial layers, physical barriers that line skin and mucous membranes.

Subsequent general defences include secreted chemical signals (cytokines), antimicrobial substances, fever, and phagocytic activity associated with the inflammatory responses.

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Adaptive immunity

This is inducible and develops slowly than the innate response. This is specific kind of immunity and has memory, therefore providing long term protection. This occurs with contact of foreign particle

Adaptive immunity is often sub-divided into two major types depending on how the immunity was introduced.

I.  Naturally acquired immunity occurs through contact with a disease causing agent, when the contact was not deliberate

II.  Artificially acquired immunity develops only through deliberate actions such as vaccination 9

Types of Adaptive immunity

a. Naturally acquired active immunity occurs when the person is exposed to a live pathogen, develops the disease, and becomes immune as a result of the primary immune response.

b. Artificially acquired active immunity can be induced by a vaccine, a substance that contains the antigen. A vaccine stimulates a primary response against the antigen without causing symptoms of the disease.

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c. Artificially acquired passive immunity is a short-term immunization by the injection of antibodies, such as gamma globulin, that are not produced by the recipient's cells.

d. Naturally acquired passive immunity occurs during pregnancy, in which certain antibodies are passed from the maternal into the fetal bloodstream

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Antigen an antigen is a molecule that induces an

immune response in the body.

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Origin of antigen

Exogenous antigens are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. Endogenous antigens are antigens that have been generated within previously normal cells as a result of normal cell metabolism, or because of viral or intracellular bacterial infection

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An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease.

These antigens should, under normal conditions, not be the target of the immune system, but, due to mainly genetic and environmental factors, the normal immunological tolerance for such an antigen has been

lost in these patients.

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ImmunogenAn immunogen is in analogy to the antigen a substance (or a mixture

of substances) that is able to provoke an immune response if injected to the body. An immunogen is able to initiate an  innate immune response first, later leading to the activation of the adaptive immune response, whereas an antigen is able to bind the highly variable immunoreceptor products (B-cell receptor or T-cell receptor) once these have been produced.

Immunogenicity is the ability to induce a humoral and/or cell-mediated immune response

Antigenicity is the ability to combine specifically with the final products of the immune response (i.e. secreted antibodies and/or surface receptors on T-cells). Although all molecules that have the property of immunogenicity also have the property of antigenicity, the reverse is not true

Epitope – The portion of an antigen that is recognized and bound by an antibody or TCR-MHC combination; also called antigenic determinant.

Antigen(ic) specificity  is the ability of the host cells to recognize an antigen specifically as a unique molecular entity and distinguish it from another with exquisite precision. Antigen specificity is due primarily to the side-chain conformations of the antigen.Hapten is a small molecule that can elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself.Epitope: The portion of an antigen that recognize and bound by antibody also called antigenic determinant..

An antigen-presenting cell (APC) or accessory cell is a cell that displays foreign antigens complexed with major histocompatibility complexes (MHC's) on their surfaces; this process is known as antigen presentation. T-cells may recognize these complexes using their T-cell receptors (TCRs). These cells process antigens and present them to T-cells.

Eg. Dendritic cell,macrophages,B cell,epithelial cells,fibroblast

AntibodyAn antibody (Ab), also known as an immunoglobulin (Ig), is a large

Y-shape protein produced by B cells that is used by the immune system to identify and neutralize foreign objects such as bacteria and viruses.

The antibody recognizes a unique part of the foreign target, called an antigen. 

Each tip of the "Y" of an antibody contains a paratope (a structure analogous to a lock) that is specific for one particular epitope(similarly analogous to a key) on an antigen, allowing these two structures to bind together with precision.

Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly (for example, by blocking a part of a microbe that is essential for its invasion and survival).

The production of antibodies is the main function of the humoral immune system.

Antibodies are secreted by a type of white blood cell called a plasma cell.

Antibodies can occur in two physical forms

1. a soluble form that is secreted from the cell,

2. a membrane-bound form that is attached to the surface of a B cell and is referred to as the B cell receptor (BCR). The BCR is only found on the surface of B cells and facilitates the activation of these cells and their subsequent differentiation into either antibody factories called plasma cells or memory B cells that will survive in the body and remember that same antigen so the B cells can respond faster upon future exposure.

Fig.2. Antibody structure

Mechanism of Actions of AntibodiesAntibodies protect the body from invading organisms in two ways (Fig.b):1. By direct actions2. Through complement system

Direct Actions of Antibodies

Antibodies directly inactivate the invading organism by any one of the following methods:

i. Agglutination: In this, the foreign bodies like bacteria with antigens on their surfaces are held together in a clump by the antibodies.

ii. Precipitation: In this, the soluble antigens like tetanus toxin are converted into insoluble forms and then precipitated.

iii. Neutralization: During this, the antibodies cover the toxic sites of antigenic products.

iv. Lysis: It is done by the most potent antibodies.These antibodies rupture the cell membrane of the organisms and then destroy them.

Complement System The complement system is a biochemical cascade of the innate immune

system that helps clear pathogens from an organism. It is derived from many small plasma proteins that work together to

disrupt the target cell's plasma membrane leading to cytolysis of the cell. The complement system consists of 9 proteins from c1 to c9,  The complement system is involved in the activities of both innate

immunity and acquired immunity. Two biochemical pathways activate the complement system: classical complement pathway,  alternate complement pathway, The classical complement pathway typically requires antibodies for

activation and is a specific immune response, while the alternate pathway can be activated without the presence of

antibodies and is considered a non-specific immune response.  A.Classical complement pathway In this the C1 binds with the antibodies and triggers a series of events.

Byproducts formed during these events produce the following activities:22

1.Opsonization:

Activation of neutrophils and macrophages to engulf the bacteria, which are bound with a protein in the plasma called opsonin.

ii. Lysis:

Destruction of bacteria by rupturing the cell membrane.

iii. Chemotaxis:

Attraction of leukocytes to the site of antigen-antibody reaction.

iv. Agglutination:

Clumping of foreign bodies like RBCs or bacteria.

v. Neutralization:

Covering the toxic sites of antigenic products.

vi. Activation of mast cells and basophils, which liberate histamine: Histamine dilates the blood vessels and increases capillary permeability.So, plasma proteins from blood enter the tissues and inactivate the antigenic products.

B. Alternate pathway:

Activation of Complementary system is due to a protein in circulation called factor I. It binds with polysaccharides present in the cell membrane of the invading organisms.This binding activates C3 and C5, which ultimately attack the antigenic products of invading organism.

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Fig b.,Mechanism of action of antibodies

Functions of Different Antibodies1. IgA plays a role in localized defense mechanism

inexternal secretions like tear2. IgD is involved in recognition of the antigen by Blymphocytes3. IgE is involved in allergic reactions4. IgG is responsible for complement fixation5. IgM is also responsible for complement fixation.

Dual nature of specific immunity Immunization occurs when an individual naturally or artificially

exposed to an antigen and the immune system is activated to produce humoral immunity and cellular immunity.

This means that the effectors of specific immunity are found in both the humoral phase of the body fluids(eg.blood serum)and among the white blood cells in the blood and lymphoid organs.

These two effectors of immunity are different physically and functionally eg they resist different types of pathogens

I. Antibodies(soluble mediators in body fluids)are more effective against pathogen found outside cells

II. Immune cells(cellular elements especially T lymphocytes,macrophages and natural killer cells)are more effective against pathogen found inside cells.

Thus humoral immunity defends the body primarily against bacteria,bacterial toxins and viruses in body fluids.

Cellular immunity defends the host from bacteria and viruses located within infected cells or phagocytic cells as well as from fungi,protozoa and other parasites

Humoral immunity or B cell immunityHumoral immunity is defined as the immunity mediated by

antibodies, which are secreted by B lymphocytes.B lymphocytes secrete the antibodies into the blood and lymph. The blood and lymph are the body fluids (humours or humors in Latin). Antibodies are produced by B lymphocytes. These antibodies fight against the invading organisms. The humoral immunity is the major defense mechanism against the bacterial infection. The macrophages and other antigen-presenting cells play an important role in the development of humoral immunity

Presentation of AntigenAntigen-presenting cells present the antigenic products bound with HLA (which is present in class II MHC molecule) to B cells. This activates the B cells through series of events.Sequence of Events during Activation of B Cells1. B cell recognizes the antigen displayed on the surface of the antigen-presenting cell, with the help of its own surface receptor protein called B cell receptor.2. Recognition of the antigen by the B cell initiates a complex interaction between the B cell receptor and the antigen. This reaction activates B cells.

3. At the same time, macrophages (the antigen-presenting cells) release interleukin-1, which facilitates the activation and proliferation of B cells.4. Activated B cells proliferate and the proliferated cells carry out the further actions.5.Simultaneously, the antigen bound to class II MHC molecules activates the helper T cells, also resulting in development of cell-mediated immunity.ROLE OF HELPER T CELLS

Helper T cells are simultaneously activated by antigen.Activated helper T cells secrete two substances calledinterleukin-2 and B cell growth factor, which promote:1. Activation of more number of B lymphocytes.2. Proliferation of plasma cells.3. Production of antibodies.

Cellular immunity or T cell immunityCell-mediated immunity is defined as the immunity developed by cell-mediated response. Cellular immunity is the major defense mechanism against infections by viruses, fungi and few bacteria like tubercle bacillus. It is also responsible for delayed allergic reactions and the rejection of transplanted tissues.Cell-mediated immunity is offered by T lymphocytesand it starts developing when T cells come in contactwith the antigens. Usually, the invading microbial ornon-microbial organisms carry the antigenic materials.These antigenic materials are released from invadingorganisms and are presented to the helper T cells byantigen-presenting cells .

Presentation of Antigen

Antigen-presenting cells present their class II MHC molecules together with antigen-bound HLA to the helper T cells. This activates the helper T cells through series of events (Fig.a). Sequence of Events during Activation of Helper T cells

1. Helper T cell recognizes the antigen displayed on the surface of the antigen presenting cell with the help of its own surface receptor protein called T cell receptor.2. Recognition of the antigen by the helper T cell initiates a complex interaction between the helper T cell receptor and the antigen. This reaction activates helper T cells.

3. At the same time, macrophages (the antigen-presenting cells) release interleukin-1, which facilitates the activation and proliferation of helper T cells.4. Activated helper T cells proliferate and the proliferated cells enter the circulation for further actions.

Fig a., Antigen presentation. The antigen-presenting cells present their class II MHC molecules together with antigen-bound HLA to the helper T cells.

Cytotoxic T cellsCytotoxic T cells that are activated by helper T cells,circulate

through blood, lymph and lymphatic tissues and destroy the invading organisms by attacking them directly.

Mechanism of Action of Cytotoxic T Cells1. Receptors situated on the outer membrane of cytotoxic T cells

bind the antigens or organisms tightly with cytotoxic T cells.2. Then, the cytotoxic T cells enlarge and release cytotoxic

substances like the lysosomal enzymes.3. These substances destroy the invading organisms.4. Like this, each cytotoxic T cell can destroy a large number of

microorganisms one after another.

WBC(leukocytes) in circulating bloodTypes of leucocyte %age in a normal

leukocyte differential account

Functions

GranulocytesNeutrophilsBasophils

Eosinophils

Agranulocytes

MonocytesLymphocytes

60-700.5-1

2-4

3-820-25

PhagocytosisProduction of heparin and histaminePhagocytosis

PhagocytosisSpecific immunity

LymphocytesLymphocytes are competent to initiat an immune respose

A lymphocyte is any of 3 types of white blood cell in a vertebrate's immune system. All 3 are agranulocytes.

Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow. This process is called haematopoiesis.

All lymphocytes originate, during this process, from a common lymphoid progenitor before differentiating into their distinct lymphocyte types.

The formation of lymphocytes is know as lymphopoiesis.

Following maturation,the lymphocytes enter the circulation and peripheral lymphoid organs (e.g. spleen and lymph nodes) where they survey for invading pathogens and/or tumor cells.

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Types of Lymphocytes 1. T lymphocytes or T cells, which are responsible for the

development of cellular immunity 2. B lymphocytes or B cells, which are responsible for humoral

immunity T cells (thymus cells) and B cells (bursa-derived cells]) are the major cellular

components of the adaptive immune response. Types of B Lymphocytes

After processing, the B lymphocytes are transformed into two types: a. Plasma cells. destroy the foreign organisms by producing the

antibodies b. Memory Bcells. occupy the lymphoid tissues throughout the

body. The memory cells are in inactive condition until the body is exposed to the same organism for the second time.During the second exposure,the memory cells are stimulated by the antigen and produce more quantity of potent antibodies at a faster rate

than in the first exposure eg immunity to chicken pox after you’ve had it Storage of B Lymphocytes After transformation, the B lymphocytes

are stored in the lymphoid tissues of lymph nodes, spleen, bone marrow and the GI tract.

The function of T cells and B cells is to recognize specific “non-self” antigens, Once they have identified an invader, the cells generate specific responses that are tailored to maximally eliminate specific pathogens or pathogen-infected cells.

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Types of T Lymphocytes During the processing, T lymphocytes are transformedinto four types:1. Helper T cells or inducer T cells. These cells are also called CD4 cells because of the presence of molecules called CD4 on their surface. Helper T cells (CD4 cells) which enter the circulation activate all the other T cells and B cells 2. Cytotoxic T cells or killer T cells. These cells are also

called CD8 cells because of the presence of molecules called CD8 on their surface. Cytotoxic T cells that are activated by helper T cells,circulate through blood, lymph and lymphatic tissues and destroy the invading organisms by attacking them directly.

3.Suppressor T cells are also called regulatory T cells.These T cells suppress the activities of the killer T cells.Thus, the suppressor T cells play an important role in preventing the killer T cells from destroying the body’s own tissues along with invaded organisms. Suppressor cells suppress the activities of helper T cells also.

4.Memory T Cells: the memory cells migrate to various lymphoid tissues throughout the body. When the body is exposed to the same organism for the second time,the memory cells identify the organism and immediately activate the other T cells. So, the invading organism is destroyed very quickly. The response of the T cells is also more powerful this time.

Storage of T Lymphocytes

After the transformation, all the types of T lymphocytes leave the thymus and are stored in lymphoid tissues of lymph nodes, spleen, bone marrow and GI tract.

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3.Natural killer cells NK cells are a part of the innate immune system and play a major

role in defending the host from both tumors and virally infected cells. NK cells distinguish infected cells and tumors from normal and

uninfected cells by recognizing changes of a surface molecule called MHC (major histocompatibility complex) class I.

NK cells are activated in response to a family of cytokines called interferons. Activated NK cells release cytotoxic (cell-killing) granules which then destroy the altered cells.They were named "natural killer cells" because of the initial notion that they do not require prior activation in order to kill cells.

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Major histocompatibility complex

The  MHC is a set of cell surface molecules encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, which are immune cells, with other leukocytes or body cells. MHC determines compatibility of donors for organ transplant as well as one's susceptibility to an autoimmune disease via cross reacting immunization.

In humans, MHC is also called human leukocyte antigen (HLA).

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…..MHC molecules in human beings are divided into two types: 1. Class I MHC molecule: It is found on every cell in

human body. It is specifically responsible for presentation of endogenous antigens (antigens produced intracellularly such as viral proteins and tumor antigens) to cytotoxic T cells.

2. Class II MHC molecule: It is found on B cells,macrophages and other antigen-presenting cells. It is responsible for presenting the exogenous antigens(antigens of bacteria or viruses which are engulfed by antigen-presenting cells) to helper T cells.

CD8+ = proteins associated with Tc(cytotoxic or killer T cells)

CD4+ = proteins associated with Th(helper T cells)

Cytokines

 Cytokines are a broad category of small proteins (~5–20 kDa) that are important in cell signaling - they are released by cells and affect the behavior of other cells, and sometimes the releasing cell itself.

Cytokines include chemokines, interferons, interleukins, lymphokines, tumour necrosis factor but not hormones or growth factors.

Cytokines are produced by broad range of cells, including immune cells like macrophages, B lymphocytes and T lymphocytes, mast cells, as well as endothelial cells, fibroblasts,

a given cytokine may be produced by more than one type of cell 43

Chemokines (Greek -kinos, movement) are a family of small cytokines, or signaling proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. 

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Vaccine

A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body'simmune system

 to recognize the agent as foreign, destroy it, and keep a record of it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.

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