CHAPTER 14.0

89An APC engulfs a bacterium and transport a fragment of it to the cell surface via a class II MHC molecule A specific TH cell is activated by binding to the MHC-antigen complex. The CD4 protein of the TH cells enhances the activation, as does interleukin-1 (IL-1) secreted by the APCThe activated TH cell proliferates, giving rise to a clone of identical clones (not shown), all with receptors keyed to the same MHC-antigen combination. These cells The cytokines further stimulate the TH cells and also help activates B cells and TC cells

KEY TERM

The AntigenThe Enemy InvaderUsually a bacteria or virus.Comes in many different forms and attacks the body

The MacrophageBody's RadarType of cell normally present in the bloodDetects the enemy

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The T-Helper CellCommunication LinkBetween the body's macrophages and B-cells

The B-CellThe War FactoryProduces antibodies custom tailored for the type of enemy antigen

AntibodiesAntigen BustersDesigned to seek and destroy the specific enemy antigen

INTRODUCTIONAn animal must defend itself against unwelcome intruders the many potentially dangerous viruses, bacteria and other pathogens it encounters in the air, in food and in waterIt must also deal with abnormal body cells, in some cases , may develop into cancer

5ImmunityIMMUNITY : A state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion.

Antigent:Any substances capable of stimulating an immune response, usually a protein or a large carbohydrate that is foreign to the body.pathogens (disease-causing microorganism or virus)

6Three cooperative lines of defense have evolved to counter this threatsTwo of these are non-specific that is they do not distinguish one infectious agent from another

7Pathogens invade tissuesNonspecific (innate) immune responseSpecific (adaptive) immune responseFirst line of defenseSecond line of defenseThird line of defenseSkin Mucous membranesSecretions of skin and mucous membranePhagocytic white blood cellsAntimicrobial proteinsThe inflammatory responseCell mediated immune responseAntibody mediated (humoral) immunityRapid Requires several hours to several daysLymphocytes Antibodies 8

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Cells of a tissue injured by physical damage or bacteria release chemical signals such as histamine and prostaglandin

In response to the signals, nearby capillaries dilate and became more permeable. Fluid and clotting elements move from the blood to the site and clotting begins.

Chemokines and other chemotactic factors released by various kinds of cells attract phagocytic cells from the blood

When the phagocytic cells arrive at the site of injury, they consume pathogens and cell debris, and the tissue heals

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Cells of a tissue injured by physical damage or bacteria release chemical signals such as histamine and prostaglandinIn response to the signals, nearby capillaries dilate and became more permeable. Fluid and clotting elements move from the blood to the site and clotting begins.Chemokines and other chemotactic factors released by various kinds of cells attract phagocytic cells from the bloodWhen the phagocytic cells arrive at the site of injury, they consume pathogens and cell debris, and the tissue heals11

Antigen (Immunogen)Definition :Any substances capable of stimulating an immune response, usually a protein or a large carbohydrate that is foreign to the body or Any substance that the body regards as foreign and that therefore elicits an immune response, particularly the formation of specific antibodies capable of binding to it.13Characteristics of antigensForeign to host ~ chemical groupings (markers) must be different from those on host cells (receptors) called antigenic determinants or epitopesPossesses two or more antigenic determinants ~ epitopes (2 bivalent, many multivalents)May be soluble, particular, cellular

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A single antigen such as a bacterial surface protein usually has several effective epitopes, each capable of inducing the production of specific antibody15ANTIBODY (immunoglobulin)Definition -protein compounds (immunoglobulins / Igs) produced by plasma cells in response to specific antigens and having the capacity to react against the antigents

Secreted by plasma cells of B cells (B lymphocytes), as a response to antigens.

16One way that an antigen elicits an immune response is by activating B cells to secrete proteins called antibodies

Each antigen has a particular molecular shape and stimulates certain B cells to secrete antibodies that interact specifically for it.Consists of two pairs of polypeptide chains i) Two of the chains are long and are referred to as heavy (H) chains ii) The other two shorter chains are referred to as light (L) chainsThe chains are held together by disulphide (S-S) bridges to form the Y-shaped / T shape molecule

Structure:

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18has two identical antigen binding sites (Fab Portion)These are different for each kind of antibody, which allows the antibody to recognize and attach specifically to a particular antigenEach chain has i) Variable (V) region - antigen binding site ii) Constant (C) region - serves as a basis for distinguishing the classes of antibodies.

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20Five classes of immunoglobulinIgM (pentomer)IgG (monomer)IgA (dimer)IgD (monomer)IgE (monomer)

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IgM ( pentomer)

First circulating antibodies to appear in response to an initial exposure to an antigenTheir concentration in the blood then declines rapidly.The presence of IgM usually indicates a current infectionConsist of 5 Y-shaped monomers arrange in pentagonal structure and therefore, has 10 Fab sites .The numerous antigen binding sites make it very effective in agglutinating antigens and in reactions involving complement.Its too large to cross the placenta

22IgG (monomer)Most abundant of circulating antibodiesIgG is a monomer and has 2 epitope-binding sites It readily crosses the wall of bloods vessels and enters tissue fluidsAlso crosses the placenta and confers passive immunity on the fetus, Its protects against bacteria, virus and toxins in the blood and lymph and triggers action / activate the complement pathway of the complement system

The Fab portion of the antibody has specificity for binding an epitope of an antigen. The Fc portion directs the biological activity of the antibody. 23IgA (dimer)Produced by cells in mucous membranesMain function is to prevent the attachment of viruses and bacteria to epithelial surfacesAlso found in many body secretions, such as saliva, perspiration, and tearsIts presence in the first milk producedHelp protect the infant from gastrointestinal infections

Secretory IgA is a dimer and has 4 Fab sites. A secretory component helps protect it from digestion in body secretions. 24IgD (monomer)Do not activate the complement system and cannot cross the placenta.They are mostly found on the surfaces of B cells,Probably functioning as antigen receptors that help initiate the differentiation of B cells and memory of B cells.

25IgE (monomer)Larger molecules than IgG Represent only a small fraction of the antibodies in the blood The tails attach to mast cells and basophils When triggered by and antigen, cause the cell to release histamine and other chemicals that cause allergic reaction

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Key theme Epitope: The actual portions or fragments of an antigen that react with receptors on B-lymphocytes and T-lymphocytes, as well as with free antibody molecules

Fab portion : Antigen-binding fragment. The actual portions of an antibody molecule that have a shape corresponding to that of an epitope of an antigen. The amino acid sequences of the Fab portion of antibody molecules is hypervariable.28END OF LECTURE 1Sambung sok! Baco dulu..-The roles of Lymphoid organ in immunity.-Antigen-antibody Reaction.-Development of immunity.OBJECTIVESThe roles of lymphoid organ in immunity.Various types of antigen-antibody reactions.The primary & Secondary immune responses to antigen.

30THE ROLES OF LYMPHOID ORGANS IN IMMUNITYOne of the function of the lymphatic system is defense against invading microorganisms and disease.Lymphoid OrgansLymph NodesTonsilsSpleenThymus GlandRed Bone Marrow

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3233Red Bone MarrowIn hollow interior of long bones.Origin of all blood cells.Site of B cells maturation.

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3435- In thoracic cavity, above heart, below thyroid gland.Site of T cells maturation.Contains macrophages.

Thymus3536

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Throughout the body, at the junction of lymphatic vessel. Contains lymphocytes (mostly B cells), macrophages & dendritic cells to filter(traps & fight) antigen in the lymph.Lymph Nodes

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Did you know??

- A kind of lymph node near the pharynx. Contains lymphocytes (mostly B cells). Trap pathogen that enter through nose and mouth.

Tonsil3940

in upper left abdomen, under diaphragm. Contains lymphocytes (mostly T cells). Filter blood and fight infection. Site of old erythrocyte destroyed & removed.Spleen40Lymphoid organ Roles Thymus Produced thymosin, a hormone that plays a role in immune response.The thymus secretes a hormone, thymosin, that causes pre-T-cells to mature (in the thymus) into T lymphocytes.SpleenServes as a reservoir for blood, and filters or purifies the blood and lymph fluid that flows through it. If the spleen is damaged or removed, the individual is more susceptible to infectionsTonsil Protect the respiratory system from infection by destroying bacteria and other foreign matter that enter mouth or nose.Lymph nodesLymph nodes filter the lymph to remove microorganisms and other foreign particles. Each nodule sinus filled contain lymphocytes and macrophages that destroy invading organisms.Bone marrowProduced the lymphocytes that support the body's immune system.Area of maturation for most white blood.41(What do antibodies do?)Antibodies do not directly destroy an antigenic pathogen. The antibody binds to the antigen to form an antigen-antibody complex, which tags the invader for destruction by one of several effectors mechanisms.

42The reaction between antibody and antigenThe antibody becomes attached to the antigen at the antigen binding site like a key in a lockThis causes the antibody to change from a T shape to a Y shapeThis exposes part of the antibody to substances in the plasma that are together known as complement43

Helper T cellvirus44It is the combined effect of antibody and complement that determines the action of antibody The binding of antibodies to antigens to form antigen-antibody complexes is the basis of several antigen disposal mechanisms45Opsonization

The process in which certain antibodies in the blood bind to the surface of an invading microorganism which render it more susceptible to phagocytosisCapsules enable certain bacteria to initially resist phagocytosis. 46Antigen-antibody InteractionNeutralizationAgglutinationPrecipitationComplement-fixation47i. NeutralizationThe antibody binds to and blocks the viral attachment sites or coats bacterial toxin, making them ineffectiveThese microbes, now coated by antibodies,promotes phagocytosis by macrophage.(eliminates by phogocytosis)

48Similarly, antibodies may bind to the surface of a pathogenic bacterium.

These microbes, now coated by antibodies, are readily eliminated by phagocytosis

In a process called opsonization, the bound antibodies enhance macrophage to, and thus phagocytosis of, the microbes

49Neutralization

The Fab portion of the antibodies made against epitopes of the virus attachment site blocks the virus from adsorbing to the receptor site on the host cell membrane. As a result, the virus can not penetrate and replicate. 50ii. AgglutinationAntibody-mediated agglutination of bacteria or viruses effectively neutralizes and opsonizes the microbesAgglutination is possible because each antibody has at least two antigen-binding sitesIgM and IgA has multiple reactive Fab site.

51The cross-linking can result in clumps of bacteria being held together by the antibodies, making it easier for phagocytes to engulf the mass. These large complexes are readily phagocytosed by macrophages

52iii. PrecipitationIn precipitation, the cross-linking of soluble antigen molecules molecules dissolved in body fluids forms immobile precipitates that are disposed of by phagocytosis

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Antibodies combine with complement proteins on surface of foreign cell.This activate the complement system.The membrane attack complex (MAC) make pores (hole) in the foreign cells membrane, causing water & ions enter.The foreign cell then lysed (destroyed). 4. Complement fixation (activation of complement).Types of antigen-antibody reaction Attack cell itself, foreign cell, bacteria etc54

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56Summary of antibody-antigen interaction

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58Explain humoral and cell mediated immune responseExplain the primary and secondary immune responseObjective 59LymphocytesThe vertebrate body is populated by two main types of lymphocytes :B lymphocytes (B cells)T lymphocytes (T cells) ~ Both types of lymphocytes circulate throughout the blood and lymph and are concentrated in the spleen, lymph nodes and other lymphatic tissue. ~ Lymphocytes, like all blood cells, originate from pluripotent stem cells in the bone marrow or liver of a developing fetus.

60Early lymphocytes are all alike, but they later develop into T cells or B cells, depending on where they continue their maturation.

Lymphocytes that migrate from the bone marrow to thymus develop into T cells.

Lymphocytes that remain in the bone marrow and continue their maturation there become B cells.

61T CELLSThere are four main types of T cells:Cytotoxic T cells (TC) (killer cells) ~ destroy the antigen directly by attaching to them and releasing the chemical perforin to kill themHelper T cells (TH) ~ attract and stimulate macrophages and promote the activity of other T- and B- cells to increase antibody production62Memory T-cells ~ have no action but multiply very fast if a second invasion of the antigen occurs, producing an even bigger clone of T-lymphocytes and resulting in rapid destruction of antigen

Suppressor T-cells ~ slow down the vigorous response of the TC and TH cells, so slowing down and the stopping the immune response63B CELLSThere are three different types of B cells :

Plasma B cells ~ secrete antibodies into the circulation

Memory B cells ~ live for a long time in the blood. They do not produce antibodies but are programmed to remember a specific antigen and respond very rapidly to any subsequent infection

Dividing B cells ~ produce more B lymphocyte cells64

65Because lymphocytes recognize and respond to particular microbes and foreign molecules, they are said to display specificity

B cells and T cells specialize in different types of antigens, and they carry out different, but complementary, defensive actions66Lymphocytes B cellsgive rise to plasma cells which produce antibodiesT cellsdirectly attack cells that bear non-self proteinsB and T cells recognize specific antigens through their plasma membrane-bound antigen receptorsLymphocytes are capable of recognizing an antigen as they have antigen receptorsPlasma membrane receptor proteins shape allows them to combine with a specific antigenBoth types of lymphocytes circulate throughout the blood and lymph and are concentrated in the spleen, lymph nodes, and other lymphatic tissue67

To initiate the immune response, the T cells must recognize antigen presented by antigen presenting cell (APC) on MHC.

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696969MAJOR HISTOCOMPATIBALITY COMPLEX (MHC)Major histocompatibality complex (MHC)a collections of cell surface glycoproteins encoded by a family of genes.

Two main classesClass I MHC moleculesfound on almost all nucleated cells - that is, on almost every cell.Class II MHC moleculesrestricted to a few specialized cell types, including macrophages, B cells.

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MHC - Antigen complex on APC or infected body cell bind with T-cell receptor .71

A fragment of foreign protein (antigen) inside the cell associates with an MHC molecule and transported to the cell surface.The combination of MHC molecule and antigen is recognized by a T cell, alerting it to the infection.(CD8)73

A fragment of foreign protein (antigen) inside the cell associates with an MHC molecule and transported to the cell surface.The combination of MHC molecule and antigen is recognized by a T cell, alerting it to the infection.(CD4)747575APC (antigen-presenting cell)APC (Antigen-presenting cell) :

Types : Macrophage, Some B cells, dendritic cell

Function : - Engulf & broken pathogen protein into ANTIGEN FRAGMENT (then bind to MHC molecule to be displayed on cell surface of APC)

- Display the MHC antigen complex to the helper T cells --- to alert immune system.

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Types of immune responseCell-mediated immune responseHumoral (antibody-mediated) immune response78

79Humoral Immune Response (Humoral Immunity)B cells responds to antigens by producing antibodiesAntibodies are secreted into the blood and other body fluids and thus provide humoral immunity(Humor = body fluid)This type of immunity is particularly effective against bacterial & viral infections.

80Cell-mediated Immune Response (Cell-mediated Immunity)T cells do not secrete antibodies but instead directly attack the cells that carry the specific antigensThese cells are described as producing cell-mediated immunityThis type of immunity is particularly effective against fungi, parasites, intracellular viral infections, cancer cell & foreign tissue transplant.

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831. Helper T lymphocytes function in both humoral and cell-mediated immunity84

Both types of immune responses are initiated by interactions between antigen-presenting cells (APCs) and TH cellsThe APCs, including macrophages and some B cells, tell the immune system, via TH cells, that a foreign antigen is in the bodyAt the heart of the interactions between APCs and TH cells are class II MHC molecules produced by the APCs, which bind to foreign antigens86

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An APC engulfs a bacterium and transport a fragment of it to the cell surface via a class II MHC moleculeA specific TH cell is activated by binding to the MHC-antigen complex. The CD4 protein of the TH cells enhances the activation, as does interleukin-1 (IL-1) secreted by the APCThe activated TH cell proliferates, giving rise to a clone of identical clones (not shown), all with receptors keyed to the same MHC-antigen combination. These cells secrete cytokines (eg : Interleukin-2)The cytokines further stimulate the TH cells and also help activates B cells and TC cells92In the cell-mediated response, cytotoxic T cells counter intracellular pathogens 93Antigen-activated TC cells, kill cancers cells and cells infected by viruses and other intracellular pathogensThis is mediated through class 1 MHC moleculesAll nucleated cells continuously produce class 1 MHC molecules, which capture a small fragment of one of the other proteins synthesized by that cell and carries it to the surface94

An infected cell (or cancer cell) displays as an antigen fragment on its surface using a class I MHC molecule. A specific TC cell is activated by binding to the MHC-antigen complex. The CD8 protein of the TC cell enhances the activation, along with IL-2 from TH cells (not shown)The activated TC cell discharges perforin molecules, which create pores in the membrane of the infected cell.Water and ions flow into the infected cell, and the cell lyses.

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The killing action of cytotoxic T cell

Cytotoxic T cell97

98In the humoral response, B cells make antibodies against extracellular pathogens99

After a macrophage engulfs & degrades a bacterium, it displays bacterial antigen fragments complexed with a class II MHC molecule. A helper T cell that recognizes the displayed complex is activated with the aid of cytokines secreted from the macrophage, forming a clone of activated helper T cells (not shown).A B cell that has taken up & degraded the same bacterium displays class II MHC-antigen complexes. An activated helper T cell bearing receptors specific for the displayed antigen binds to the B cell. This interaction, with the aid of cytokines from the T cell, activates the B cell.The activated B cell proliferates & differentiates into memory B cells & antibody-secreting plasma cells. The secreted antibodies are specific for the same bacterial antigen that initiated the response.

A macrophage ingests a pathogenClass II MHC proteins within the cell bind to fragments of the pathogen and transport them to the cell surfaceA TH cell with a receptor specific for the presented antigen contacts the macrophage and is induced to proliferate and secrete cytokinesThe activated TH cell binds with a B cell that has previously taken up antigen. As an APC, the B cells class II MHC molecules present fragments of the antigen. Cytokines help activate the B cell.The B cell proliferates and differentiates into memory cells and plasma cells that secrete antibody molecules specific for the bacterium.101

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103Self and non-self recognitionThe bodys immune defenses do not normally attack tissues that carry a self-marker.

Rather, immune cells and other body cells coexist peaceably in a state known as self-tolerance.

But when immune defenders encounter cells or organism carrying molecule that say foreign, the immune troops move quickly to eliminate intruders.

Non-self includes pathogens and cells from other individuals of the same species.

104Self and non-self cell recognition is governed by major histocompatibility complex (MHC) markers markers that trigger a response from a lymphocyte are called antigens on the plasma membrane of a cell.

All body cells have class 1 MHC markers except red blood cells but class 2 markers are only found on lymphocytes and some macrophages.

Self antigens indicate that the cell is produced within the person and non-self indicate that the material is foreign to the body.

105B-cells and T-cells have self-receptors that briefly bind to a corresponding self antigen of another cell identifying it as self and not requiring destruction.

T-cells have non-self receptors, whereas B-cells have antibodies, which can bond to specific complementary non-self antigens .

Recognition of non-self causes either a cell-mediated response, when T-cell mediated, or humoral response, when B-cell mediatede.g of self and non-self concept :Organ transplantThe MHC is responsible for stimulating the rejection of tissue grafts and organ transplants.

Because MHC creates a unique protein fingerprint for each individual, foreign MHC molecules are antigenic, inducing immune responses against the donated tissue or organ.

To minimize rejection, attempts are made to match MHC of tissue donor and recipient as closely as possible.

In the absence of identical twins, siblings usually provide the closest tissue-type match.

1075. In addition to MHC matching, various medicines are necessary to suppress the immune response to the transplant.

6. However, this strategy leaves the recipient more susceptible to infection and cancer during the course of treatment.

7. More selective drugs, which suppress helper T cell activation without crippling nonspecific defense or T-independent humoral responses, have greatly improved the success of organ transplant

In bone marrow transplants, it is the graft itself, rather than the host, that is the source of potential immune rejection.

Bone marrow transplants are used to treat leukemia and other cancers as well as various hematological diseases.

Prior marrow transplants, the recipient is typically treated with irradiation to eliminate the recipients immune system, leaving little chance of graft rejection.

However, the donated marrow, containing lymphocytes, may react against the recipient, producing graft versus host reaction, unless well matched.

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110PRIMARY & SECONDARY RESPONSE TO INITIAL & LATER DOSE OF ANTIGENDEVELOPMENT OF IMMUNITYAntigens interact with specific lymphocytes, inducing immune responses and immunological memory

A microorganism interacts only with lymphocytes bearing receptors specific for its various antigenic molecules

The selection of a lymphocytes by one of the microbes antigens activate the lymphocyte, stimulating it to divide and differentiate and eventually, producing two clones of cells

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Antigen molecules bind to the antigen receptors of only one of the five B cells shown.The selected B cell proliferates, forming a clone of identical cells bearing receptors for the selecting antigen.Some proliferating cells develop into short-lived plasma cells that secrete antibodies specific for the antigen.Some proliferating cells develop into long-lived memory cells that can respond rapidly upon subsequent exposure to the same antigen.The selective proliferation and differentiation of lymphocytes that occur the first time the body is exposed to an antigen is the primary immune responseAbout 10 17 days are required from the initial exposure for the maximum effector cell response

114During this period, selected B cells and T cells generate antibody-producing effector B cells, called plasma cells, and effector T cells respectivelyWhile this response is developing, a stricken individual may become ill, but symptoms of the illness diminish and disappear as antibodies and effector T cells clear the antigen from the body

115A second exposure to the same antigen at some later time elicits the secondary immune response

This response is faster (only 2 to 7 days), of greater magnitude and more prolonged

The antibodies produced in the secondary response tend to have greater affinity for the antigen than those secreted in the primary response

116The immune systems capacity to generate secondary immune response is called immunological memory, based not only on effector cells, but also clones of long-lived T and B memory cells

These memory cells proliferate and differentiate rapidly when they later contact the same antigen117When a person is exposed to an antigen for the first time, there is a lag of several days before specific antibody becomes detectable.

This antibody is IgM.

After a short time, the antibody level declines.

These are main characteristics of the primary response.

118If, at a later date he or she is re-exposed to the same antigen, there is a far more rapid appearance of antibody, and in greater amount.

It is of the IgG class and remains detectable for months or years.

These are the features of the secondary response.

If, at the same time that he is re-exposed to an antigen, he is exposed to a different antigen for the first time, the properties of the specific response to this antigen are those of the primary response.

119Primary immune responseSecondary immune responseFollowing the first exposure to a foreign antigen, a lag phase occurs in which no antibody is produced, but activated B cells are differentiating into plasma cells. The lag phase can be as short as 2-3 days, but often is longer, sometimes as long as weeks or months.If a second dose of the same antigen is given days or even years later, an accelerated 20 or anamnestic immune response (IR) occurs. This lag phase is usually very short (e.g. 3 or 4 days) due to the presence of memory cells.

The amount of antibody produced is usually relatively low.The amount of antibody produced rises to a high level.120Over time, antibody level declines to the point where it may be undetectable.Antibody level tends to remain high for longer.

The first antibody produced is mainly IgM (although small amounts of IgG are usually also produced).The main type of antibody produced is IgG (although small amounts of IgM are sometimes produced). Vaccination Vaccination is the example of the development of immunity involves both primary and secondary immune response.

Vaccine : A preparation of a weakened or killed pathogen, such as a bacterium or virus, or of a portion of the pathogen's structure that stimulates antibody production.

So vaccine will trigger the primary immune response before our body encounter the same antigen for the second time (secondary immune response).Eg : Rubella, BCG, Hepatitis, triple antigen etc.

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