the doctrine of immunity . immunoprophylaxis and immunotherapy
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The doctrine of immunity . Immunoprophylaxis and immunotherapy. Acquired ( Adaptive) Immunity Active Passive Natural Artificial Natural Artificial (Infection) (Immunizing agents) Clinical Subclinical (Placental transfer, - PowerPoint PPT PresentationTRANSCRIPT
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Acquired ( Adaptive) Immunity
Active Passive
Natural Artificial Natural Artificial (Infection) (Immunizing agents)
Clinical Subclinical (Placental transfer, colostrum)
(administration of immune sera)
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First Line of Defense• Epidermis• Mucous membranes
– Mucous– Cilia– Lacrimal apparatus of eyes– Saliva– Urine flow– Vaginal secretions– Defecation and vomiting
• Sebum• Perspiration• Lysozyme• Gastric juice
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Second Line of Defense
• Antimicrobial proteins1. Interferons (IFNs)
– Antivirals that prevent replication of virus
2. Complement system– Enhance immune reactions
3. Transferrins– Inhibit bacterial growth by reducing available
iron
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• Interferons (IFNs) are antiviral proteins produced in response to viral infection.
• alpha-IFN, • beta-IFN, • gamma-IFN.
• The mode of action of -IFN and -IFN is to induce uninfected cells to produce antiviral proteins (AVPs) that prevent viral replication.
• Interferons are host-cell–specific but not virus-specific.• Gamma-interferon activates neutrophils and macrophages
to kill bacteria.
Interferons (IFNs)
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Complement System Summary
Series of 30 plasma (serum) proteins, activated in a cascade
Three effects of complement system:
1. Enhances inflammatory response, e.g.: attracts phagocytes
2. Increases phagocytosis through opsonization or immune adherence
3. Creates Membrane Attack Complexes (MACs) Cytolysis
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Classical Pathway of Complement ActivationClassical Pathway of Complement Activation
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IgA and IgE cannot activate complement
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Alternative Pathway of Complement ActivationAlternative Pathway of Complement Activation
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Figure 21.8a
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• When an NK cell recognizes a cell as “non-self” it releases cytotoxic perforins and granzymes
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ADCC by NK Cells
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Destruction of Virus-Infected Cells by NK Cells through Antibody-Dependent Cellular Cytotoxicity
(ADCC)
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The name antigens (Gk. anti against, genos genus) is given to
organic substances of a colloid structure (proteins and
different protein complexes in combination with lipids or
polysaccharides) which upon injection into the body are
capable of causing the production of antibodies and reacting
specifically with them.
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Antigens, consequently, are characterized by the following main properties:
(1) the ability to cause the production of antibodies (antigenicity), and
(2) the ability to enter into an interaction with the corresponding antibodies (antigenic specificity).
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The features of molecules that determine antigenicity and immunogenicity are as follows.
A. Foreignness: In general, molecules recognized as "self” are not immunogenic; ie, we are tolerant to those self-molecules. To be immunogenic, molecules must be recognized as "nonself," ie, foreign.
B. Molecular Size: The most potent immunogens are proteins with high molecular weights, ie, above 100,000.
C. Chemical-Structural Complexity:
D. Antigenic Determinants (Epitopes): Epitopes are - small chemical groups on the antigen molecule that can elicit and react with antibody.
Most antigens have many determinants; ie, they are multivalent. In general, i determinant is roughly 5 amino acids or sugars in size. The overall three-
dimensional structure is the main criterion of antigenic specificity.
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Antigenic substances must have also certain properties: a colloid structure, and solubility in the body fluids. Antigenic properties are pertinent to toxins of a plant origin (ricin, robin, abrin, cortin, etc.), toxins of an animal origin (toxins of snakes, spiders, scorpions, phalangia, karakurts, bees), enzymes, native foreign proteins, various cellular elements of tissues and organs, bacteria and their toxins, rickettsiae and viruses.
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Hapten is a molecule that is not immunogenic by itself but can react with specific antibody. Haptens are usually small molecules, but some high-molecular-weight nucleic acids, lipids, complex carbohydrates and other substances are haptens as well. Many drugs, eg, penicillins, are haptens, and the catechol in the plant oil that causes poison oak and poison ivy is a hapten. The addition of proteins to haptens even in a small amount gives them the properties of complete antigens. In this case the protein carries out the function of a conductor.
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Vi
O
K
H
Antigen structure of bacteria cell
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N
H
Antigens of influenca virus
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• Collection of genes on chromosome 6
• Three regions: class I, class II, class III
• Highly polymorphic!
• Gene products:• class I molecules• class II molecules• class III molecules (and other stuff)
MHC complex Major histocompatibility complexMajor histocompatibility complex
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class I MHC moleculeclass II MHC molecule
class II MHC genes class I MHC genesclass III MHC genes
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• Encoded by three loci: HLA-A, HLA-B, HLA-C• Display antigens from within the cell (e.g., viral antigens) to CD8+ T cells.
• Present on all nucleated cells! (Good idea.)
Class I MHC molecules
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• Encoded by three loci: HLA-DP, HLA-DQ, HLA-DR
• Display extracellular antigens (e.g., bacterial antigens the cell has eaten) to CD4+ T cells
• Present mainly on antigen presenting cells, like macrophages! (Makes sense.)
Class II MHC molecules
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ANTIBODIES (IMMUNOGLOBULINS) Antibodies are globulin proteins (immunoglobulins) that react specifically with the antigen that stimulated their production. They make up about 20% of the protein in blood plasma.. There are five classes of antibodies: IgG, IgM, IgA, IgD, and IgE.
IMMUNOGLOBULIN STRUCTURE
Immunoglobulins are glycoproteins made up of light (L) and heavy (H) polypeptide chains. The terms "light" and heavy" refer to molecular weight; The simplest antibody molecule has a Y shape and consists of four polypeptide chains: two H chains and two L chains. The four chains are linked by disulfide bonds. An individual antibody molecule always consists of identical H chains and identical L chains.
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Heavy (H) polypeptide
chains
Class of immunoglobulin
Ig G
Ig M
Ig A
Ig E
Ig D
The Immune system includes 5 classes of Immunoglobulin (Ig)
Ig M - (22)5, (22)5Ig A - (22)n , (22)n,,
Ig E - 22, 22
IgD - 22, 22
Ig G - 22,,22
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If an antibody molecule is treated with a proteolytic enzyme such as papain, peptide bonds in the "hinge" region are broken, producing two identical Fab fragments, which carry the antigen-binding sites, and one Fc fragment, which is involved in placenta! transfer, complement fixation, attachment site for various cells, and other biologic activities
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IgG. Each IgG molecule consists of two L chains and two H chains linked by disulfide bonds (molecular formula H2L2). Because it has two identical antigen-binding sites, it is said to be divalent.
IgG is the predominant antibody in the secondary-response and constitutes an important defense against bacteria and viruses. IgG is the only antibody to cross the placenta only its Fc portion binds to receptors on the surface of placental cells. It is therefore the most abundant immunoglobulin in newborn. IgG is one of the two immunoglobulins that can activate complement and opsonizes.
IMMUNOGLOBULIN CLASSESIMMUNOGLOBULIN CLASSES
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IgM is the main immunoglobulin produced early in the primary response. It is present as a monomer on the surface of virtually all B cells, where it functions as an antigen-binding receptor. In serum, it is a pentamer composed of 5 H2L2 units plus one molecule of J (joining) chain. Because the pentamer has 10 antigen-binding sites, it is the most efficient immunoglobulin in agglutination, complement fixation (activation), and other antibody reactions and is important in defense against bacteria and viruses. It can be produced by the fetus in certain infections. It has the highest avidity of the immunoglobulins; its interaction with antigen can involve all 10 of its binding sites.
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IgA is the main immunoglobulin in secretions such as colostrum, saliva, tears, and respiratory, intestinal, and genital tract secretions. It prevents attachment of bacteria and viruses to mucous membranes. Each secretory IgA molecule consists of two H2L2 units plus one molecule each of J (joining) chain and secretory component. The secretory component is a polypeptide synthesized by epithelial cells that provides for IgA passage to the mucosal surface. It also pretects IgA from being degraded in the intestinal tract. In serum, some IgA exists as monomeric H2L2.
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IgE is medically important for two
reasons: (1) it mediates immediate
(anaphylactic) hypersensitivity,
and
(2) it participates in host defenses
against certain parasites, eg,
helminths (worms). The Fc region
of IgE binds to the surface of mast
cells and basophils. Although IgE
is present in trace amounts in
normal serum (approximately
0.004%), persons with allergic
reactivity have greatly increased
amounts, and IgE may appear in
external secretions. IgE does not
fix complement and does not cross
the placenta.
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IgD. This immunoglobulin has no known antibody function but may
function as an antigen receptor; it is present on the surface of many B lymphocytes. It is present in small
amounts in serum.
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Major Functions of Human ImmunoglobulinsMajor Functions of Human Immunoglobulins• Function IgM Main Ig during Primary Response (Early antibody).
Fixes Complement most effectively).
• IgG Main Ig during Secondary Response (late antibody).Opsonization.Fixes Complement.Neutralizes Toxins, Viruses.
• IgA Secretory mucosal IgPrevents invasion from gut mucosa.
• IgE Immediate Hypersensitivity.Mast cell and Basophil reactions.Activates Eosinophils in helminth infection
• IgD Function Unknown.Mostly on the Surface of B cells.
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• Antibody-mediated mechanisms of antigen disposalBinding of antibodies to antigens
inactivates antigens by
Viral neutralization(blocks binding to host)
and opsonization (increasesphagocytosis)
Agglutination ofantigen-bearing particles,
such as microbes
Precipitation ofsoluble antigens
Activation of complement systemand pore formation
Bacterium
Virus Bacteria
Solubleantigens Foreign cell
Complementproteins
MAC
Pore
Enhances
Phagocytosis
Leads to
Cell lysis
Macrophage
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PRIMARY OR CENTRAL LYMPHOID ORGANSare responsible for synthesis and maturation of immunocompetant cells.These include the bone marrow and the thymus.
PERIPHERAL OR SECONDARY LYMPHOID ORGANS are sites where the lymphocytes localise, recognise foreign antigen and mount response against it. These include the lymph nodes, spleen, tonsils, adenoids, appendix, and clumps of lymphoid tissue in the small intestine known as Peyer's patches. They trap and concentrate foreign substances, and they are the main sites of production of antibodies.
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Lymphocytes
• Live in blood, bone marrow, lymphoid tissues
• Basic function: make antibodies (immunoglobulins)
• B-cell receptor complex recognizes antigens• binds antigen• sends signals to T cells
• Antigens can be free and circulating (don’t have to be bound to MHCs or displayed by other cells to be recognized!)
B lymphocytes
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The B-Cell Receptor
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Lymphocytes
• Live in blood, bone marrow, lymphoid tissues
• Two basic functions:• kill stuff• help other cells do their jobs
• T-cell receptor (TCR) complex recognizes antigens• binds antigen• sends signals to the T cell
• Antigens must be:• displayed by other cells…• …AND bound to an MHC receptor
T lymphocytes
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The T-Cell Receptor
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Antigen-presenting cells
• Main job: catch antigens and display them to lymphocytes
• Dendritic cells• Have fine cytoplasmic projections• Present all over body: skin, lymph nodes, organs• Capture bug antigens, display to B and T cells
• Other APCs• Macrophages eat bugs and present antigens to T cells, which tell
macrophages to kill bugs • B cells present antigens to helper T cells, which tell B cells to
make antibodies
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Antigen-presenting cells (APC) activate T helper cells
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Humoral immune response
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Cell-mediated immune response
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Immunizations
2 artificial methods to make an individual immune to a disease
Active immunizationadministration of a vaccine so that the patient actively mounts a protective immune response
Passive immunization
individual acquires immunity through the transfer of antibodies formed by an immune individual or animal
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Brief history of immunologyBrief history of immunologyRelatively new science; origin
usually attributed to Edward Jenner, but has
deep roots in folk medicineJenner discovered in 1796 that
cowpox (vaccinia) induced protection against
smallpoxJenner called his procedure
“vaccination”
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Louis Pasteur developed a vaccine against Pasteurella multocida
Practice of transferring protective antibodies was developed when it was discovered that vaccines protected through the action of antibodies
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• In the 1880s, Louis Pasteur devised a vaccine against cholera in chickens and developed a rabies vaccine that proved a spectacular success upon its first use in a boy bitten by a rabid dog
• These practical triumphs led to a search for the mechanisms of protection and the development of the science of immunology
• In 1890 Emil von Behring and Shibasaburo Kitasato discovered that the serum of vaccinated individuals contained “antibodies” that specifically bound to the relevant pathogen
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3 general types of vaccines
attenuated (live) microbe “treated” to lose virulence but retain antigenicity
killed (inactivated)
Toxoidtoxin treated with heat or formaldehyde to lose toxicity but retain antigenicity
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Also called modified live vaccinesUses pathogens that are living but have reduced virulence so they don’t cause disease
Attenuation is the process of reducing virulence
viruses often attenuated by raising them in
tissue culture cells for which they aren’t
adapted until they lose the ability to produce
disease bacteria can be made avirulent by
culturing under unusual conditions or through
genetic manipulation
Attenuated Vaccines
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Attenuated Vaccines
Can result in mild infections but no disease
Contain replicating microbes that can stimulate a strong immune response due to the large number of antigen molecules
Viral vaccines trigger a cell-mediated immune response dominated by TH1 and cytotoxic T cells
Vaccinated individuals can infect those around them, providing herd immunity
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Problems with Attenuated Vaccines
Attenuated microbes may retain enough virulence to cause disease, especially in immunosuppressed individuals
Pregnant women should not receive live vaccines due to the risk of the modified pathogen crossing the placenta
Modified viruses may occasionally revert to wild type or mutate to a virulent form
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Inactivated Vaccines
Can be either whole agent vaccines produced with deactivated but whole microbes, or subunit vaccines produced with antigenic fragments of microbes
Both types are safer than live vaccines since they cannot replicate or mutate to a virulent form
When microbes are killed must not alter the antigens responsible for stimulating protective immunity
Formaldehyde is commonly used to inactivate microbes by cross-linking their proteins and nucleic acids
Recognized as exogenous antigens and stimulate a T2H response that promotes antibody-mediated immunity
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Problems with Inactivated Vaccines
Do not stimulate herd immunity Whole agent vaccines may stimulate a inflammatory response due to nonantigenic portions of the microbeAntigenically weak since the microbes don’t reproduce and don’t provide many antigenic molecules to stimulate the immune response
Administration in high or multiple doses, or the incorporation of an adjuvant, can make the vaccine more effective
adjuvants are substances that increase the antigenicity of the vaccineadjuvants may also stimulate local inflammationhigh and multiple vaccine doses may produce allergic reactions
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General Properties of Attenuated (Live) and Inactivated Vaccines
InactivatedAttenuated (Live)
• Virulent pathogen grown under adverse conditions or continued passage through different hosts
• Single boost• Can be unstable• Induces both humoral and
cellular immunity• Reversion to virulent form
possible (eg. Sabin vaccine 1 case per 4 million doses)
• Contamination with other viruses (eg. SV-40 from Monkey present in Sabin Vaccine)
Inactivation of virulent pathogen by chemicals (formaldehyde) or irradiation with X-rays
Multiple boosts
Stable (important for 3rd world)
Induces primarily humoral immunity
No reversion (provided the inactivation is complete)
Attenuated organisms confer better immunity but are less “safe”
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Live attenuatedLive attenuated vaccines are the major class of vaccines for intracellular pathogens. As these agents lead to active infections and propagate in the body, suitably attenuated strains require low doses of vaccine and lead to a lasting form immunity that is both
antibody and cytotoxic. Live attenuated vaccines, therefore, are ideal vaccines if attenuation can be achieved and can be maintained, ie if attenuation is stable and
reversion to the virulent phenotype occurs.
inactivated attenuated
cost higher (greater mass required) lower (agent replicates in the body)
administration parenteral oral
adjuvant needed not needed
stability good poor
reversion absent possible
immunity mucosal immunity absent
antibody-mediated
short-lasting
mucosal immunity present
antibody-mediate and cytotoxic T cells
long-lasting
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Toxoid Vaccines
Chemically or thermally modified toxins used to stimulate active immunity
Useful for some bacterial diseases
Stimulate antibody-mediated immunity
Require multiple doses because they possess few antigenic determinants
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Modern Vaccine Technology
Research attempts to make vaccines that are more effective, cheaper, and safer
A variety of recombinant DNA techniques can be used to make improved vaccines
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