Immunology Concept, Functions and Types of Immunity

Immunology Concept, Functions and Types of Immunity

Concept, Functions and Types of Immunity
Introduction Concept and functions of Immunity Types of Immunity

Part I Concept and functions of Immunity

I Concept of Immunity 1)Tranditional concept----Immunity refers to protection against infectious diseases. 2)Modern concept---- Immunity is a function of which an individual recognizes and excludes antigenic foreign substances. It is normally beneficial,but sometimes,it is injurious.

II Concept of Immunology
1) Tranditional concept----anti-infection immunity to different types of pathogenic microorganisms. 2) Modern concept----Immunology is an independent subject about composition,functions of immune system; mechanism of immune response and the disease associated with immunity.

III Functions of Immunity
Immune defense Immune homeostasis Immune surveillance

Functions Normal Manifestation Abnormal Manifestation
Functions and Manifestation of Immunity Functions Normal Manifestation Abnormal Manifestation Immune Anti-infection Hypersensitivity Defense Immunodeficiency Immune Eliminate injured and senile cells immune dismodulation Homeostasis Tolerate to self components Autoimmune disease Immune destroy transformed cells Tumor or Surveillance (anti-tumor ) Persistent virus infection Prevent from persistent infection

Part II Types of Immunity
I. Innate Immunity (or native immunity/ non-specific immunity /congenital immunity) II. Adaptive Immunity (or acquired immunity/specific immunity)

I. Innate immunity ( natural immunity/ non-specific immunity )
Protection against infection that relies on mechanisms that exist before infection,are capable of a rapid response to microbes,and react in essentially the same way to repeated infections. Exists at birth Be the first line of defense against infection

1. Characteristics Exists naturally Non–specific
Innate immunity 1. Characteristics Exists naturally Non–specific No immune memory (innate immunity can’t be enhanced by the second stimulation of the same antigen) Immune memory: Exposure of the immune system to a foreign antigen enhances its ability to respond again to that antigen. Hereditable No racial difference

2. Composition Physical barrier : skin and mucosa
Chemical barrier: antimicrobial substances in secretion of skin and mucosa Biotic barrier: normal flora existing on the surface of skin and mucosa Anatomic barrier . blood- brain barrier . blood- placental barrier . blood- tymus barrier

(2) Humoral factors Complement Lysozyme Interferons(IFN) C-reactive protein

(3)Cells participating in innate immunity
Phagocyte: endocytosis and phagocytosis mononuclear phagocytes ----Monocytes,Macrophages (M Φ)----PRR Neutrophils Nature killer cells (NK)—KAR/KIR,IgG Fc receptor Dentritic cells(DC) γδ T cells B1 cells Other cells participating in innate immunity

Macrophages NK cells Neutrophils

Macrophages

Macrophages excluding the pathogen

Over view What are the main types of white blood cells?
Name the two main types of immunity? What are the main distinctions between these two categories? What cells are involved in which aspects of the immune system?

Lymphocytes Many types; important in both humoral and cell-mediated immunity B-cells produce antibodies (APC cell) T- cells Cytotoxic T cells Helper T cells Memory cells

Lymphocytes Natural Killer cells
Large granular lymphocytes (not B or T) Kills tumor cells Kills cells infected with certain viruses (intracellular pathogens)

Monocytes/Macrophage
Phagocytosis and killing of microorganisms Activation of T cells and initiation of immune response Monocyte is a young macrophage in blood There are tissue-specific macrophages APC cells

Dendritic Cells Phagocytosis and killing of microorganisms
Function as antigen presenting cells (APC) In the blood and tissues – mature and migrate to the lymph nodes

Neutrophil Granulocyte Polymorphonuclear Phagocytosis
Cytoplasmic granules Polymorphonuclear Phagocytosis Short life span (hours) Very important at “clearing” bacterial infections Innate Immunity

Eosinophils Kills Ab-coated parasites through degranulation
Involved in allergic inflammation A granulocyte Double Lobed nucleus Orange granules contain toxic compounds

Basophils Might be “blood Mast cells’ A cell-killing cells
Blue granules contain toxic and inflammatory compounds Important in allergic reactions

Antigen-presenting cells (APC)
Highly specialized Process antigen and display peptide fragments on cell surface Involved in T-cell activation Macrophages, dendritic cells and B-cells

Name the two main types of immunity? What are the main distinctions between these two categories? What cells are involved in which aspects of the immune system?

Immune system divisions
Innate immunity First line of defense Adaptive (acquired) immunity Takes time to develop Humoral immunity (antibody–mediated specific immunity) Cell-mediated immunity (The aspect of the adaptive immune response where antigen-specific T cell have a main role) Active immunity Passive or maternal immunity Injection of Immunoglobulin Absorption of maternal antibodies

Innate vs. adaptive immunity
Innate immunity First line of defense (present in all individuals at all times) Immediate (0 – 4 hours) Non-specific Does not generate lasting protective immunity Adaptive immune response (late: > 96 hours) Is initiated if innate immune response is not adequate (> 4 days) Antigen-specific immunity Generates lasting protective immunity (e.g. Antibodies, memory T-cells)

Name the two main types of immunity? What are the main distinctions between these two categories? What white blood cells are involved in which aspects of the immune system?

Immune system cells Adaptive immunity Lymphocyte Memory cells
Innate immunity Granulocytes (i.e. neutrophils) Macrophages Dendritic cells Natural killer (NK) cells Adaptive immunity Lymphocyte B cells T cells Cytotoxic T cells (CTLs) Helper T cells (Th) Memory cells

Innate immune system The first line of defense:
Penetration of the epithelial surface of the body by microorganism (e.g. bacteria) Engulfment of microorganism by macrophages, neutrophils, and dendritic cells Release of cytokines and chemokines Inflammation

Killing by granulocytes
Macrophages and neutrophils recognize pathogen by means of cell-surface receptors Example: mannose receptor, CD14 receptor, scavenger receptors, glucan receptor etc. Binding of MØ/neutrophils with pathogen leads to phagocytosis Bound pathogen is surrounded by phagocyte membrane Internalized (phagosome) Killing of pathogen (Phagolysosome*) Oxidative burst (synthesis of hydrogen peroxide (H2O2)or free oxygen radicals) Acidification Antimicrobial peptides (e.g. defensins) * Phagolysosome = lysosome +phagosome

Phagocytosis Mannose receptor Scavenger receptor LPS receptor (CD14)
Lipid mediators Cytokines Mannose receptor Lysosome Phagosome Scavenger receptor LPS receptor (CD14) Bacteria binding to macrophage receptors initiate the release of cytokines and small lipid mediators of inflammation Phagolysosome The macrophage expresses receptors for many bacterial constituents Macrophages engulf and digest bacteria to which they bind

Phagocytosis (Immunology animation: Janeway) Immune response (IV)
Immune response (IV) 9.1 - Phagocytosis

Humoral immune response
V region; At binding Cell-surface immunoglobulin receptors (BCR) detect extracellular pathogens Once activated, secrete immunoglobulins as soluble antibodies Antibodies Variable region (2 identical antigen-binding sites) Constant region (determines how antibody disposes of the pathogen once it is bound) Fc region

Cell killing – NK cells NK cells do not require prior immunization or activation They attach to ‘target’ cells (ADCC) Cytotoxic granules are released onto surface of cell Effector proteins penetrate cell membrane and induce programmed cell death

Bacteria trigger macrophages to release cytokines and chemokines
Inflammation Cytokines Chemokines Inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain Fluids Proteins Bacteria trigger macrophages to release cytokines and chemokines Vasodilation and increased vascular premeability cause redness, heat, and swelling

Cytokines Adaptive immune system
Low molecular weight, soluble proteins that are produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immune system Innate immune system Macrophages and Dendritic cells Tumor necrosis factor-alpha (TNF-) Interleukin-1 (IL-1) Interleukin-12 (IL-12) Adaptive immune system T-lymphocytes Interleukin-2 (IL-2) Interleukin-4 (IL-4)

II.Adaptive immunity ( acquired immunity/specific immunity)
The form of immunity that is mediated by T or B lymphocytes and stimulated by exposure to infectious agents. Take effects after innate immune response Be the second line of defense against infection

1.Characteristics Specificity Acquired (set up after birth )
Immune memory (Adaptive immunity can be enhanced by the second stimulation of the same antigen) Transferable Self-limitation

2.Composition T cell : Cell-mediated immunity (CMI)
B cell : Humoral immunity(HI) or antibody-mediated immunity

3.The process of immune response in adaptive immunity
Recognition of antigens Activation,proliferation and differenciation of T or B lymphocytes Effector phase of immune response ----Elimination of antigens

Comparison of Adaptive and Innate Immunity
Innate immunity Adaptive immunity Characteristics Exists naturally Acquired by antigen stimulation after birth Responds rapidly in the early develops slowly stage of infection No antigen specificity Has antigen specificity No immune memory Has immune memory Participates in natural defence Participates in specific immune response Cells Neutrophil,Phagocytes,NK cell et al T cell, B cell, APC Molecules Complement.lysozyme,cytokines et al Antibody,cytokines

What is immunology? Immune (Latin- “immunus”)
To be free, exempt People survived ravages of epidemic diseases when faced with the same disease again The study of physiological mechanisms that humans and other animals use to defend their bodies from invading organisms Bacteria - Viruses Fungi - Parasites Toxins

Immunology Terms Antigen Pathogen Antibody (Ab) Immunoglobulin (Ig)
Any molecule that binds to immunoglobulin or T cell receptor Pathogen Microorganism that can cause disease Antibody (Ab) Secreted immunoglobulin Immunoglobulin (Ig) Antigen binding molecules of B cells Vaccination Deliberate induction of protective immunity to a pathogen Immunization The ability to resist infection

Types of Immunity Innate Immunity Adaptive Immunity
Host defense mechanisms that act from the start of an infection but do not adapt to a particular pathogen Recognize “patterns’ of a.a., saccharides, etc.. Adaptive Immunity Response of an antigen specific B and T lymphocytes to an antigen Immunological memory

Types of Immunity Humoral immunity Cell Mediated Immunity
Immunity that is mediated by antibodies Can be transferred by to a non-immune recipient by serum Cell Mediated Immunity Immune response in which antigen specific T cells dominate

Immunology cell histology
Polymorphonuclear Lobed nucleus Mononuclear Non-lobed nucleus Granulocyte Many granules seen in cytoplasm Neutral Does not stain to acidic or basic compounds Acidic (red-pink) Stains to acidic compounds (Eosin) Basic (blue-purple) Stains to basic compounds

Cells of the Immune system
Many cells of the immune system derived from the bone marrow Hematopoetic stem cell differentiation

Components of blood Serum vs. Plasma
Serum: cell-free liquid, minus the clotting factors Plasma: cell-free liquid with clotting factors in solution (must use an anticoagulant)

Components of blood

Lymphocytes Many types; important in both humoral and cell-mediated immunity B-cells produce antibodies T- cells Cytotoxic T cells Helper T cells Memory cells

Lymphocytes Plasma Cell (in tissue) Natural Killer cells
Fully differentiaited B cells, secretes Ab Natural Killer cells Kills cells infected with certain viruses Both innate and adaptive Antigen presentation

Monocytes/Macrophage
Phagocytosis and killing of microorganisms Activation of T cells and initation of immune response Monocyte is a young macrophage in blood There are tissue-specific macrophages Antigen Presentation

Dendritic Cells Activation of T cells and initiate adaptive immunity
Found mainly in lymphoid tissue Function as antigen presenting cells (APC) Most potent stimulator of T-cell response

Mast Cells Expulsion of parasites through release of granules
Histamine, leukotrienes, chemokines, cytokines Also involved in allergic responses

Neutrophil Granulocyte Polymorphonuclear Phagocytosis
Cytoplasmic granules Polymorphonuclear Phagocytosis Short life span (hours) Very important at “clearing” bacterial infections Innate Immunity

Eosinophils Kills Ab-coated parasites through degranulation
Involved in allergic inflammation A granulocyte Double Lobed nucleus Orange granules contain toxic compounds

Basophils Might be “blood Mast cells’ A cell-killing cells
Blue granules contain toxic and inflammatory compounds Important in allergic reactions

Other Blood Cells Megakaryocyte Erythrocyte Platelet formation
Wound repair Erythrocyte Oxygen transport

Major Tissues Primary Lymph tissues Secondary Lymph Tissues
2º 2º Major Tissues 1º 2º Primary Lymph tissues Cells originate or mature Secondary Lymph Tissues 2º 2º 2º 2º 1º

Immunity Immunity The ability of the body to fight infection and/or foreign invaders by producing antibodies or killing infected cells. Immune System The system in the body responsible for maintaining homeostasis by recognizing harmful from nonharmful organisms and produces an appropriate response.

Foreign Invaders Called Pathogens Antigens
Viruses, bacteria or other living thing that causes disease/immune response. Antigens Toxins that pathogens produce that cause harm to an organism.

Parts of the Immune System
Blood - White Blood Cells in particular. Lymph nodes Thymus Gland – Produces T Lymphocytes Bone Marrow – Produces B Lymphocytes

How does the body fight infection/foreign invaders?
The Body’s THREE lines of Defense First Line of Defense – The Skin Provides Physical and Chemical barriers Physical – hard to penetrate, made of indigestible keratin Chemical – tears, sweat

Second Line of Defense – Nonspecific Immune Response
These are defenses the body uses no matter what the invader may be. These defenses include: Phagocytosis – done by Macrophages Natural Cell Killers Inflammation - caused by release of Histamine from leukocytes Fever – caused by histamines. The fever (high temp) kills invaders by denaturing their proteins. Macrophage: A phagocytic cell found in the liver, spleen, brain and lungs. Travels to all areas of the body to find and eat pathogens.

Third Line of Defense – Specific Immune Response
This is a specific response to a specific pathogen/antigen. The response involves the creation of Antibodies.

Y-shaped protein molecule. Made up of variable and constant regions.
Antibodies Y-shaped protein molecule. Made up of variable and constant regions. Made up of Heavy and Light chains. Produced by B-Lymphocytes Function: Recognize antigens, bind to and deactivate them. Note: Variable region recognizes the anitgens.

How an antibody operates/works?
Deactivation of a bacterium by an antibody.

The Pathway of Specific Immune Response
Pathogens Pathogens eaten by Macrophage Displays portion of Pathogen on surface Helper-T cell recognizes Pathogen Step 1 Step 2 Step 3

Activates B- Cell Activates Cytotoxic T- Cell Memory B-Cell Memory T-Cell Kills Infected Cells Antibodies

Cellular Immunity .vs. Antibody Immunity
Cellular Immunity Antibody or Humoral Immunity Carried out by T-Cells Infected cells are killed by Cytotoxic T –Cells. Carried out by B-cells Antibodies are produced and dumped into blood stream. Antibodies bind to antigens and deactivate them.

Immune Response Explained
Antigen infects cells. Macrophage ingests antigen and displays portion on its surface. Helper T- Cell recognizes antigen on the surface of the macrophage and becomes active. Active Helper T-Cell activates Cytotoxic T-Cells and B-Cells. Cytotoxic T-Cells divide into Active Cytotoxic T-cells and Memory T – Cells. Active Cytotoxic T-Cells kill infected cells. At the same time, B-Cells divide into Plasma Cells and Memory B- Cells. Plasma cells produce antibodies that deactivate pathogen. Memory T and Memory B cells remain in the body to speed up the response if the same antigen reappears. Supressor T-Cells stop the immune response when all antigens have been destroyed.

Immune Response Summary
Displays copy of antigen on surface of cell Antibody Immunity Cellular Immunity

Primary .vs. Secondary Immune Response
Primary Immune Response This is a response to an invader the First time the invader infects the body. No measurable immune response for first few days. Next 10 – 15 days antibody production grows steadily Secondary Immune Response A more rapid response to an invader the 2nd time it invades the body. Antibody production increases dramatically and in a much shorter time period..

Primary .vs. Secondary Immune Response

Passive .vs. Active Immunity
This is immunity where the body is “actively” producing antibodies to fight infection. Ex: You have a throat infection and you are actively creating antibodies to fight it. Vaccination: An injection of a weakened strain of an infectious microbe (pathogen) that causes the body to undergo active immunity (produce antibodies). Passive Immunity This is immunity where antibodies are given to a person from the blood of another person or animal. This immunity only lasts for a short period of time. ex: Breastfeeding mothers pass antibodies to their children through the milk.

Autoimmune Disease Autoimmune diseases are diseases where the immune system begins to attack itself. Ex: Rheumatoid Arthritis – crippling disease of the joints. Lupus – disease of blood and organs. Multiple Sclerosis – disease of nervous system Cause(s): unknown Cures/Treatments: No known cures. Usually treated with drugs.

Allergies Allergy - An exaggerated response by the immune system to an allergen. Allergen: a normally harmless substance that causes an allergic reaction. ex: dust, pollen, mould, food, insect stings Types of Allergic reactions There are two types of allergic reactions. a. Immediate – occurs within seconds and normally lasts for about 30 mins. b. Delayed – takes longer to react and can last for a much longer time.

What happens during an allergic reaction?
During an allergic reaction antibodies cause histamines to be released from certain cells. Histamines cause: a. Swelling of tissues b. Release of fluids (runny noses and eyes) c. muscle spasms (some cases) Anaphylaxis or anaphylactic shock: This is the sudden and severe allergic reaction to a substance that can cause death. Treatments for Allergies Avoidance of material – especially food. Epinephrine – “epi – pen” Antihistamines -- benadryl

Antibodies – structure, classes and function
Objectives By the end of the session you should be able to: illustrate and describe the basic structure of antibodies in terms of heavy and light chains explain the structure in relation to function of the molecules define the terms ‘isotype’, ‘allotype’ and ‘idiotype’ describe the structure of each of the five main classes of antibody describe the location and function of each class of antibody define the terms ‘affinity’ and avidity’ of antibodies

Basic structure of antibodies

Primary antibody structure

The fragment antigen binding (Fab fragment) is a region on an antibody which binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope—the antigen binding site—at the amino terminal end of the monomer. The two variable domains bind the epitope on their specific antigens.

An epitope, also know as antigenic determinant, is the part of a macromolecule that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope. Although epitopes are usually thought to be derived from nonself proteins, sequences derived from the host that can be recognized are also classified as epitopes.

Antibody structure

Binding of lysozyme to V domains of heavy and light chains
Heavy Chain Lysozyme (antigen) Light chain

Antibody heterogeneity
Isotypes Two light chain isotypes – k and l : Five heavy chain isotypes - m,g,d,a and e Allotypes Genetic markers- (rather like blood groups and usually the result of minor amino acid differences) on immunoglobulins that segregated within the species and inherited in Mendelian fashion eg. Km (on k light chains) and Gm (on IgG heavy chains) Idiotypes Each antibody varies in its amino acid sequences in the variable regions of both heavy and light chains to create different specificities

Different classes of antibody have:
Different distribution within the body Different primary functions (but with some overlaps) ie. There is ‘division of labour’ within the antibody system

Ig class Heavy chain Light chain
IgM m (mu) k (kappa) or l (lambda) IgG g (gamma) k (kappa) or l (lambda) IgA a (alpha) k (kappa) or l (lambda) IgE e (epsilon) k (kappa) or l (lambda) IgD d (delta) k (kappa) or l (lambda)

IgM Large molecule, pentameric structure: mainly confined to the circulation: prominent in early responses to most antigens: provides first line of defence against bacteraemia

Antibodies - electron micrographs
IgM (pentameric) IgA (dimeric)

IgG Predominant antibody in internal body fluids, including extravascular sites where it combats microbes and toxins; only class of antibody to cross the placenta to provide the newborn with protection

IgA Provides the primary defence against local infections owing to its abundance in saliva, tears, bronchial secretions, nasal mucosa, prostatic fluid, vaginal secretions and mucous secretions in the small intestine

IgE Provides protection at mucosal surfaces where it enhances acute inflammation through mast cells and recruits anti-microbial agents; is raised in parasitic infections; is responsible for the symptoms of allergies

IgD Mostly present on the surface of B lymphocytes with monovalent IgM where it acts as an antigen receptor controlling lymphocyte activation and suppression

Summary of different classes and subclasses of antibodies

Antigenic determinants (epitopes) recognised by antibodies

Physical forces holding antibodies and antigen together

Affinity and avidity of antibodies
The tightness with which the antigen binding site attaches to an antigen determinant (epitope) Avidity The tightness of binding when several antigen binding sites attach to several antigenic determinants

Immunoglobulin

Immunoglobulin Element of adaptive immune mechanism
Better known as antibody It recognize the foreign objects How they work (examples) Animation1 Animation2 There are 5 classes of human antibodies: IgG, IgM, IgA, IgD, and IgE. The simplest antibodies, such as IgG, IgD, and IgE, are "Y"-shaped macromolecules called monomers An antibody or immunoglobulin is a large Y-shaped glycoprotein belonging to the immunoglobulin superfamily; used by the immune system to identify and neutralize foreign objects like bacteria and viruses. An antibody contains two sites called paratopes that recognize a specific target, which is called an antigen. Paratopes can be thought of as similar to locks and are specific for just one particular part of the antigen called an epitope, which can be considered similar to a key. This specific lock and key interaction allows an antibody to tag a microbe or an infected cell for attack by other parts of the immune system. The binding of an antibody can also neutralize its antigen target directly by, for example, blocking a part of a microbe that is essential for its survival and growth in the body. Demonstration of antibody activity against diphtheria and tetanus toxins. Beginning of humoral theory of immunity. The HV regions of a Fab, representing both light and heavy chains, are highlighted in purple. The antigen is green. The part of the antigen in direct contact with the antibody is called the antigenic determinant, or epitope. This ribbon structure shows the antibody's HV (purple) and FR (yellow) regions of the Fab, and their interaction with an epitope of the antigen.

Structure of immunoglobulin
Two identical heavy (H) chains and two identical light (L) chains combine to form this Y-shaped antibody molecule Heavy chains α and γ have approximately 450 amino acids. (50kDa) Heavy chains μ and ε have approximately 550 amino acids. Light chain 250 amino acid (25kDa) a variable region that differs between different B cells, but is the same for all immunoglobulins produced by the same B cell or B cell clone. The variable domain of any heavy chain is composed of a single immunoglobulin domain. These domains are about 110 amino acids long

Disulfide bonds Bonds between two amino acids result of the SH (sulfhydral) group of one amino acid covalently bonding to the SH group of another amino acid Stronger than hydrogen bonds Eg. Hair proteins are held together by disulfide bonds Disulfide bonds play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium. Used to stabilize many proteins that play structural roles, such as hair. In fact, getting a "permanent" is all about breaking and reforming disulfide bonds in hair to make straight hair curly.

Heavy chains The heavy chains each have four domains
Variable domains (VH) Constant domains (CH1,2,3) The heavy chains each have four domains. The amino terminal variable domains (VH) are at the tips of the Y. These are followed by three constant domains: CH1, CH2, and the carboxy terminal CH3, at the base of the Y's stem. A short stretch, the switch, connects the heavy chain variable and constant regions. The hinge connects CH2 and CH3 (the Fc fragment) to the remainder of the antibody (the Fab fragments). The two identical protein chains in an antibody molecule that contain the most amino acids and, therefore, have the greater molecular weight. An immunoglobulin fold is a common all-β protein fold that consists of a 2-layer sandwich of ~7 antiparallel β-strands arranged in two β-sheets. The backbone switches repeatedly between the two β-sheets. Typically, the pattern is (N-terminal β-hairpin in sheet 1)-(β-hairpin in sheet 2)-(β-strand in sheet 1)-(C-terminal β-hairpin in sheet 2). The cross-overs between sheets form an "X", so that the N- and C-terminal hairpins are facing each other.

Light chain The light chains are constructed of two domains
Variable (VL) Constant (CL)

The fragment antigen binding (Fab fragment) The fragment crystallizable region (Fc region) Antibodies bind to antigens by reversible, noncovalent interactions, including hydrogen bonds and charge interactions The fragment antigen binding (Fab fragment) is a region on an antibody which binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope—the antigen binding site—at the amino terminal end of the monomer. The two variable domains bind the epitope on their specific antigens. The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system. In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains; IgM and IgE Fc regions contain three heavy chain constant domains (CH domains 2-4) in each polypeptide chain Antibodies are capable of binding a wide variety of antigens, including macromolecules and small chemicals. The reason for this is that the antigen - binding region of antibody molecules forms a flat surface capable of accommodating many different shapes. Antibodies bind to antigens by reversible, noncovalent interactions, including hydrogen bonds and charge interactions. The parts of antigens that are recognized by antibodies are called epitopes, or determinants. Different antigenic determinants may be recognized based on sequence (linear determinants) or shape (conformational deter- determinants). Some of these epitopes are hidden within antigen molecules and are exposed as a result of a physicochemical change (neodeterminants).

How variety is maintained
The variable heavy chain is coded combining 3 genes (VH, DH, JH) The variable light chain is coded combining 2 genes (VL, JL) Most likely humans produce between 107 and 109 different shaped Fabs The variable heavy chain portion of the Fab is coded for by a combination of 3 genes, called VH, DH, and JH. The variable light chain portion of the Fab consists of either a kappa chain or a lambda chain coded for by a combination of 2 genes, VL and JL. In the DNA of each B-lymphocyte there are multiple forms of each one of these variable determinant genes. Although the exact number of each gene isn't known, there are probably around 65 VH genes; 27 DH genes; 6 JH genes; 40 kappa VL genes; 5 kappa JL genes; 40 lambda VL genes; and 4 lambda JL genes. Through random gene-splicing, any combination of the multiple forms of each gene can join together resulting in billions of possible gene combinations! However, all gene recombinations are not equally likely. Most likely humans produce between 10^7 and 10^9 different shaped Fabs. This is known as combinatorial diversity. Additionally, specialized enzymes in the B-lymphocyte cause splicing inaccuracies or add additional nucleotides at the gene junctions to generate further diversity. This is called junctional diversity.

Antibody Fab region Antibody (Fab) molecular surface, with the PorA antigen superimposed. The dark colored groove on the surface of the antibody matches precisely the shape of the PorA antigen Any changes in the sequence of PorA in this region can disrupt antibody binding

Antigen binding some pictures

Functional consequences: (VH) and (VL) are positioned to stereochemically react with antigen The stem is good for mediate effector functions The structural features discussed so far have important functional consequences. The variable regions of both the heavy and light chains, (VH) and (VL), lie at the tips of the Y, where they are positioned to stereochemically react with antigen. The stem of the Y projects in a way to efficiently mediate effector functions such as the activation of complement. Its CH2 and CH3 domains bulge to facilitate interaction with effector proteins. Geometric fit and a chemical (electrostatic charge) fit, often called complementarity -- the antibody has + charge where the antigen is -, and the antibody has knobs where the antigen has indentations Constant fragment. The portion of an antibody molecule that carries out the biological activities of that class of antibody. Biological activity includes binding to receptors on phagocytes and activating the classical complement pathway. The amino acid sequence of the Fc portion of an antibody is the same for every antibody in that class.

Hinge Two disulfide bonds in the hinge region unite the two heavy chains The hinge allows the two antigen-binding Fab regions of each antibody molecule to move Two disulfide bonds in the hinge region, between cys235 and cys238 pairs, unite the two heavy chains. The hinge allows the two antigen-binding Fab regions of each antibody molecule to move, enabling them to simultaneously bind antigen epitopes that are separated from one another by varying distances

Conclusion Changes in the antigen binding site conformation are vital for antigen recognition Herewith the variety of antibody conformation is vital for our health

Reference Abul K. Abbas, Andrew H. Lichtman. Basic Immunology Functions and Disorders of the Immune System. Second Edition 2004

Humoral Immunity Results in production of proteins called “immunoglobulins” or “antibodies”. Body exposed to “foreign” material termed “antigen” which may be harmful to body: virus, bacteria, etc. Antigen has bypassed other protective mechanisms, ie, first and second line of defense.

Dynamics of Antibody Production
Primary immune response Latent period Gradual rise in antibody production taking days to weeks Plateau reached Antibody level declines

Initial antibody produced in IgM Lasts days Followed by production of IgG Lasts 4-5 days Without continued antigenic challenge antibody levels drop off, although IgG may continue to be produced.

Secondary Response Second exposure to SAME antigen.
Memory cells are a beautiful thing. Recognition of antigen is immediate. Results in immediate production of protective antibody, mainly IgG but may see some IgM

Humoral Immune Response

Cellular Events Antigen is “processed” by T lymphocytes and macrophages. Possess special receptors on surface. Termed “antigen presenter cell” APC. Antigen presented to B cell

Basic Antibody Structure
Two identical heavy chains Gamma Delta Alpha Mu Epsilon

Two identical light chains Kappa OR Lambda

Basic Structure of Immunoglobulins

IgG Most abundant Single structural unit Gamma heavy chains
Found intravascularly AND extravascularly Coats organisms to enhance phagocytosis (opsonization)

IgG Crosses placenta – provides baby with immunity for first few weeks of infant’s life. Capable of binding complement which will result in cell lysis FOUR subclasses – IgG1, IgG2, IgG3 and IgG4

IgA Alpha heavy chains Found in secretions Produced by lymphoid tissue
Important role in respiratory, urinary and bowel infections. 15-10% of Ig pool

Secretory IgA Exists as TWO basic structural units, a DIMER
Produced by cells lining the mucous membranes.

Secretory IgA

IgA Does NOT cross the placenta. Does NOT bind complement.
Present in LARGE quantities in breast milk which transfers across gut of infant.

IgM Mu heavy chains Largest of all Ig – PENTAMER 10% of Ig pool
Due to large size restricted to intravascular space. FIXES COMPLEMENT. Does NOT cross placenta. Of greatest importance in primary immune response.

IgE Epsilon heavy chains Trace plasma protein Single structural unit
Fc region binds strongly to mast cells. Mediates release of histamines and heparin>allergic reactions Increased in allergies and parasitic infections. Does NOT fix complement Does NOT cross the placenta

IgD Delta heavy chains. Single structural unit.
Accounts for less than 1% of Ig pool. Primarily a cell bound Ig found on the surface of B lymphocytes. Despite studies extending for more than 4 decades, a specific role for serum IgD has not been defined while for IgD bound to the membrane of many B lymphocytes, several functions have been proposed. Does NOT cross the placenta. Does NOT fix complement.

Cellular Immune Response
Important in defending against: fungi, parasites, bacteria. Responsible for hypersensitivity, transplant rejection, tumor surveillance. Thymus derived (T) lymphocytes

Cell Mediated Reaction
Helper T cells – turn on immune response Suppressor T cells – turn off immune response Cytotoxic T cells directly attack antigen

Cell Mediated Immunity

The Immune System: Innate and Adaptive Body Defenses

Also called immunoglobulins
Antibodies Also called immunoglobulins Constitute the gamma globulin portion of blood proteins Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen Are capable of binding specifically with that antigen There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE

Classes of Antibodies IgD – monomer attached to the surface of B cells, important in B cell activation IgM – pentamer released by plasma cells during the primary immune response IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces IgE – monomer that binds to mast cells and basophils, causing histamine release when activated

Consists of four looping polypeptide chains linked together with disulfide bonds Two identical heavy (H) chains and two identical light (L) chains The four chains bound together form an antibody monomer Each chain has a variable (V) region at one end and a constant (C) region at the other Variable regions of the heavy and light chains combine to form the antigen-binding site

Figure 21.12a, b

Antibody Structure Antibodies responding to different antigens have different V regions but the C region is the same for all antibodies in a given class C regions form the stem of the Y-shaped antibody and: Determine the class of the antibody Serve common functions in all antibodies Dictate the cells and chemicals that the antibody can bind to Determine how the antibody class will function in elimination of antigens

Mechanisms of Antibody Diversity
Plasma cells make over a billion different types of antibodies Each cell, however, only contains 100,000 genes that code for these polypeptides To code for this many antibodies, somatic recombination takes place Gene segments are shuffled and combined in different ways by each B cell as it becomes immunocompetent Information of the newly assembled genes is expressed as B cell receptors and as antibodies

Random mixing of gene segments makes unique antibody genes that:
Antibody Diversity Random mixing of gene segments makes unique antibody genes that: Code for H and L chains Account for part of the variability in antibodies V gene segments, called hypervariable regions, mutate and increase antibody variation Plasma cells can switch H chains, making two or more classes with the same V region

All antibodies form an antigen-antibody (immune) complex
Antibody Targets Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction All antibodies form an antigen-antibody (immune) complex Defensive mechanisms used by antibodies are neutralization, agglutination, precipitation, and complement fixation

Complement Fixation and Activation
Complement fixation is the main mechanism used against cellular antigens Antibodies bound to cells change shape and expose complement binding sites This triggers complement fixation and cell lysis Complement activation: Enhances the inflammatory response Uses a positive feedback cycle to promote phagocytosis Enlists more and more defensive elements

Other Mechanisms of Antibody Action
Neutralization – antibodies bind to and block specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells

Other Mechanisms of Antibody Action
Agglutination – antibodies bind the same determinant on more than one antigen Makes antigen-antibody complexes that are cross-linked into large lattices Cell-bound antigens are cross-linked, causing clumping (agglutination) Precipitation – soluble molecules are cross-linked into large insoluble complexes

Mechanisms of Antibody Action
Figure 21.13

Monoclonal Antibodies
Commercially prepared antibodies are used: To provide passive immunity In research, clinical testing, and treatment of certain cancers Monoclonal antibodies are pure antibody preparations Specific for a single antigenic determinant Produced from descendents of a single cell

Monoclonal Antibodies
Hybridomas – cell hybrids made from a fusion of a tumor cell and a B cell Have desirable properties of both parent cells – indefinite proliferation as well as the ability to produce a single type of antibody

Cell-Mediated Immune Response
Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed Two major populations of T cells mediate cellular immunity CD4 cells (T4 cells) are primarily helper T cells (TH) CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy cells harboring foreign antigens Other types of T cells are: Suppressor T cells (TS) Memory T cells

Major Types of T Cells Figure 21.14

Importance of Humoral Response
Soluble antibodies The simplest ammunition of the immune response Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph

The Humoral Immune Response (HIR) is the aspect of immunity that is mediated by secreted antibodies (as opposed to cell-mediated immunity which involves T lymphocytes) produced in the cells of the B lymphocyte lineage (B cell). Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction.[1] Humoral immunity is called as such, because it involves substances found in the humours, or body fluids.

Importance of Cellular Response
T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells T cells are best suited for cell-to-cell interactions, and target: Cells infected with viruses, bacteria, or intracellular parasites Abnormal or cancerous cells Cells of infused or transplanted foreign tissue

Antigen Recognition and MHC Restriction
Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen T cells must simultaneously recognize: Nonself (the antigen) Self (a MHC protein of a body cell)

The major histocompatibility complex (MHC) is a large genomic region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system, autoimmunity, and reproductive success. The proteins encoded by the MHC are expressed on the surface of cells in all jawed vertebrates, and display both self antigens (peptide fragments from the cell itself) and nonself antigens (e.g. fragments of invading microorganisms) to a type of white blood cell called a T cell that has the capacity to kill or co-ordinate the killing of pathogens, infected or malfunctioning cells.

Both types of MHC proteins are important to T cell activation
Class I MHC proteins Always recognized by CD8 T cells Display peptides from endogenous antigens

Endogenous antigens are:
Class I MHC Proteins Endogenous antigens are: Degraded by proteases and enter the endoplasmic reticulum Transported via TAP (transporter associated with antigen processing) Loaded onto class I MHC molecules Displayed on the cell surface in association with a class I MHC molecule

Class I MHC Proteins Figure 21.15a

Class II MHC Proteins Class II MHC proteins are found only on mature B cells, some T cells, and antigen-presenting cells A phagosome containing pathogens (with exogenous antigens) merges with a lysosome Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum

Class II MHC Proteins Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 cells

Class II MHC Proteins Figure 21.15b

Antigen Recognition Provides the key for the immune system to recognize the presence of intracellular microorganisms MHC proteins are ignored by T cells if they are complexed with self protein fragments

Antigen Recognition If MHC proteins are complexed with endogenous or exogenous antigenic peptides, they: Indicate the presence of intracellular infectious microorganisms Act as antigen holders Form the self part of the self-antiself complexes recognized by T cells

T Cell Activation: Step One – Antigen Binding
T cell antigen receptors (TCRs): Bind to an antigen-MHC protein complex Have variable and constant regions consisting of two chains (alpha and beta)

MHC restriction – TH and TC bind to different classes of MHC proteins TH cells bind to antigen linked to class II MHC proteins Mobile APCs (Langerhans’ cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen

TC cells are activated by antigen fragments complexed with class I MHC proteins APCs produce co-stimulatory molecules that are required for TC activation TCR that acts to recognize the self-antiself complex is linked to multiple intracellular signaling pathways Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition)

Figure 21.16

T Cell Activation: Step Two – Co-stimulation
Before a T cell can undergo clonal expansion, it must recognize one or more co-stimulatory signals This recognition may require binding to other surface receptors on an APC Macrophages produce surface B7 proteins when nonspecific defenses are mobilized B7 binding with the CD28 receptor on the surface of T cells is a crucial co-stimulatory signal Other co-stimulatory signals include cytokines and interleukin 1 and 2

Depending on receptor type, co-stimulators can cause T cells to complete their activation or abort activation Without co-stimulation, T cells: Become tolerant to that antigen Are unable to divide Do not secrete cytokines

T cells that are activated: Enlarge, proliferate, and form clones Differentiate and perform functions according to their T cell class

Primary T cell response peaks within a week after signal exposure T cells then undergo apoptosis between days 7 and 30 Effector activity wanes as the amount of antigen declines The disposal of activated effector cells is a protective mechanism for the body Memory T cells remain and mediate secondary responses to the same antigen

Some are co-stimulators of T cells and T cell proliferation
Cytokines Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages Some are co-stimulators of T cells and T cell proliferation Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to: Release interleukin 2 (IL-2) Synthesize more IL-2 receptors

Other cytokines amplify and regulate immune and nonspecific responses
IL-2 is a key growth factor, which sets up a positive feedback cycle that encourages activated T cells to divide It is used therapeutically to enhance the body’s defenses against cancer Other cytokines amplify and regulate immune and nonspecific responses

Examples include: Cytokines Perforin and lymphotoxin – cell toxins
Gamma interferon – enhances the killing power of macrophages Inflammatory factors

Regulatory cells that play a central role in the immune response
Helper T Cells (TH) Regulatory cells that play a central role in the immune response Once primed by APC presentation of antigen, they: Chemically or directly stimulate proliferation of other T cells Stimulate B cells that have already become bound to antigen Without TH, there is no immune response

Helper T Cells (TH) Figure 21.17a

Helper T Cell TH cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors TH cells stimulate B cells to divide more rapidly and begin antibody formation B cells may be activated without TH cells by binding to T cell–independent antigens Most antigens, however, require TH co-stimulation to activate B cells Cytokines released by TH amplify nonspecific defenses

Helper T Cells Figure 21.17b

Cytotoxic T Cell (Tc) TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized Their targets include: Virus-infected cells Cells with intracellular bacteria or parasites Cancer cells Foreign cells from blood transfusions or transplants

Bind to self-antiself complexes on all body cells
Cytotoxic T Cells Bind to self-antiself complexes on all body cells Infected or abnormal cells can be destroyed as long as appropriate antigen and co-stimulatory stimuli (e.g., IL-2) are present Natural killer cells activate their killing machinery when they bind to MICA receptor MICA receptor – MHC-related cell surface protein in cancer cells, virus-infected cells, and cells of transplanted organs

Mechanisms of Tc Action
In some cases, TC cells: Bind to the target cell and release perforin into its membrane In the presence of Ca2+ perforin causes cell lysis by creating transmembrane pores Other TC cells induce cell death by: Secreting lymphotoxin, which fragments the target cell’s DNA Secreting gamma interferon, which stimulates phagocytosis by macrophages

Mechanisms of Tc Action
Figure 21.18a, b

Other T Cells Suppressor T cells (TS) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells Gamma delta T cells (Tgd) – 10% of all T cells found in the intestines that are triggered by binding to MICA receptors

Summary of the Primary Immune Response
Figure 21.19

The four major types of grafts are:
Organ Transplants The four major types of grafts are: Autografts – graft transplanted from one site on the body to another in the same person Isografts – grafts between identical twins Allografts – transplants between individuals that are not identical twins, but belong to same species Xenografts – grafts taken from another animal species

Prevention of Rejection
Prevention of tissue rejection is accomplished by using immunosuppressive drugs However, these drugs depress patient’s immune system so it cannot fight off foreign agents

A marked deficit in B and T cells
Immunodeficiencies Congenital and acquired conditions in which the function or production of immune cells, phagocytes, or complement is abnormal SCID – severe combined immunodeficiency (SCID) syndromes; genetic defects that produce: A marked deficit in B and T cells Abnormalities in interleukin receptors Defective adenosine deaminase (ADA) enzyme Metabolites lethal to T cells accumulate SCID is fatal if untreated; treatment is with bone marrow transplants

Acquired Immunodeficiencies
Hodgkin’s disease – cancer of the lymph nodes leads to immunodeficiency by depressing lymph node cells Acquired immune deficiency syndrome (AIDS) – cripples the immune system by interfering with the activity of helper T (CD4) cells Characterized by severe weight loss, night sweats, and swollen lymph nodes Opportunistic infections occur, including pneumocystis pneumonia and Kaposi’s sarcoma

AIDS Caused by human immunodeficiency virus (HIV) transmitted via body fluids – blood, semen, and vaginal secretions HIV enters the body via: Blood transfusions Contaminated needles Intimate sexual contact, including oral sex HIV: Destroys TH cells Depresses cell-mediated immunity

HIV multiplies in lymph nodes throughout the asymptomatic period
AIDS HIV multiplies in lymph nodes throughout the asymptomatic period Symptoms appear in a few months to 10 years Attachment HIV’s coat protein (gp120) attaches to the CD4 receptor A nearby protein (gp41) fuses the virus to the target cell

AIDS HIV enters the cell and uses reverse transcriptase to produce DNA from viral RNA This DNA (provirus) directs the host cell to make viral RNA (and proteins), enabling the virus to reproduce and infect other cells

AIDS HIV reverse transcriptase is not accurate and produces frequent transcription errors This high mutation rate causes resistance to drugs Treatments include: Reverse transcriptase inhibitors (AZT) Protease inhibitors (saquinavir and ritonavir) New drugs currently being developed that block HIV’s entry to helper T cells

Loss of the immune system’s ability to distinguish self from nonself
Autoimmune Diseases Loss of the immune system’s ability to distinguish self from nonself The body produces autoantibodies and sensitized TC cells that destroy its own tissues Examples include multiple sclerosis, myasthenia gravis, Graves’ disease, Type I (juvenile) diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis

Mechanisms of Autoimmune Diseases
Ineffective lymphocyte programming – self-reactive T and B cells that should have been eliminated in the thymus and bone marrow escape into the circulation New self-antigens appear, generated by: Gene mutations that cause new proteins to appear Changes in self-antigens by hapten attachment or as a result of infectious damage

Mechanisms of Autoimmune Diseases
If the determinants on foreign antigens resemble self-antigens: Antibodies made against foreign antigens cross-react with self-antigens

Hypersensitivity Immune responses that cause tissue damage
Different types of hypersensitivity reactions are distinguished by: Their time course Whether antibodies or T cells are the principle immune elements involved Antibody-mediated allergies are immediate and subacute hypersensitivities The most important cell-mediated allergic condition is delayed hypersensitivity

Immediate Hypersensitivity
Acute (type I) hypersensitivities begin in seconds after contact with allergen Anaphylaxis – initial allergen contact is asymptomatic but sensitizes the person Subsequent exposures to allergen cause: Release of histamine and inflammatory chemicals Systemic or local responses

Immediate Hypersensitivity
The mechanism involves IL-4 secreted by T cells IL-4 stimulates B cells to produce IgE IgE binds to mast cells and basophils causing them to degranulate, resulting in a flood of histamine release and inducing the inflammatory response

Acute Allergic Response
Figure 21.20

Reactions include runny nose, itching reddened skin, and watery eyes
Anaphylaxis Reactions include runny nose, itching reddened skin, and watery eyes If allergen is inhaled, asthmatic symptoms appear – constriction of bronchioles and restricted airflow If allergen is ingested, cramping, vomiting, or diarrhea occur Antihistamines counteract these effects

Anaphylactic Shock Response to allergen that directly enters the blood (e.g., insect bite, injection) Basophils and mast cells are enlisted throughout the body Systemic histamine releases may result in: Constriction of bronchioles Sudden vasodilation and fluid loss from the bloodstream Hypotensive shock and death Treatment – epinephrine is the drug of choice

Subacute Hypersensitivities
Caused by IgM and IgG, and transferred via blood plasma or serum Onset is slow (1–3 hours) after antigen exposure Duration is long lasting (10–15 hours) Cytotoxic (type II) reactions Antibodies bind to antigens on specific body cells, stimulating phagocytosis and complement-mediated lysis of the cellular antigens Example: mismatched blood transfusion reaction

Subacute Hypersensitivities
Immune complex (type III) hypersensitivity Antigens are widely distributed through the body or blood Insoluble antigen-antibody complexes form Complexes cannot be cleared from a particular area of the body Intense inflammation, local cell lysis, and death may result Example: systemic lupus erythematosus (SLE)

Delayed Hypersensitivities (Type IV)
Onset is slow (1–3 days) Mediated by mechanisms involving delayed hypersensitivity T cells and cytotoxic T cells Cytokines from activated TC are the mediators of the inflammatory response Antihistamines are ineffective and corticosteroid drugs are used to provide relief

Delayed Hypersensitivities (Type IV)
Example: allergic contact dermatitis (e.g., poison ivy) Involved in protective reactions against viruses, bacteria, fungi, protozoa, cancer, and rejection of foreign grafts or transplants

Developmental Aspects
Immune system stem cells develop in the liver and spleen by the ninth week Later, bone marrow becomes the primary source of stem cells Lymphocyte development continues in the bone marrow and thymus system begins to wane

Developmental Aspects
TH2 lymphocytes predominate in the newborn, and the TH1 system is educated as the person encounters antigens The immune system is impaired by stress and depression With age, the immune system begins to wane

Immunology Concept, Functions and Types of Immunity

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Immunology Concept, Functions and Types of Immunity

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