MCD Immunology Alexandra Burke-Smith 1 1. Introduction to Immunology Professor Charles Bangham ( [email protected]) 1. Explain the importance of immunology for human health. The immune system What happens when it goes wrong? persistent or fatal infections allergy autoimmune disease transplant rejection What is it for? To identify and eliminate harmful “non-self” microorganisms and harmful substances such as toxins, by distinguishing ‘self’ from ‘non-self’ proteins or by identifying ‘danger’ signals (e.g. from inflammation) The immune system has to strike a balance between clearing the pathogen and causing accidental damage to the host (immunopathology). Basic Principles The innate immune system works rapidly (within minutes) and has broad specificity The adaptive immune system takes longer (days) and has exisite specificity Generation Times and Evolution Bacteria- minutes Viruses- hours Host- years The pathogen replicates and hence evolves millions of times faster than the host, therefore the host relies on a flexible and rapid immune response Out most polymorphic (variable) genes, such as HLA and KIR, are those that control the immune system, and these have been selected for by infectious diseases 2. Outline the basic principles of immune responses and the timescales in which they occur. IFN: Interferon (innate immunity) NK: Natural Killer cells (innate immunity) CTL: Cytotoxic T lymphocytes (acquired immunity)
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MCD Immunology Alexandra Burke-Smith
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1. Introduction to Immunology Professor Charles Bangham ([email protected])
1. Explain the importance of immunology for human health.
The immune system What happens when it goes wrong?
persistent or fatal infections
allergy
autoimmune disease
transplant rejection What is it for?
To identify and eliminate harmful “non-self” microorganisms and harmful substances such as toxins, by distinguishing ‘self’ from ‘non-self’ proteins or by identifying ‘danger’ signals (e.g. from inflammation)
The immune system has to strike a balance between clearing the pathogen and causing accidental damage to the host (immunopathology).
Basic Principles
The innate immune system works rapidly (within minutes) and has broad specificity
The adaptive immune system takes longer (days) and has exisite specificity
Generation Times and Evolution Bacteria- minutes Viruses- hours Host- years
The pathogen replicates and hence evolves millions of times faster than the host, therefore the host relies on a flexible and rapid immune response
Out most polymorphic (variable) genes, such as HLA and KIR, are those that control the immune system, and these have been selected for by infectious diseases
2. Outline the basic principles of immune responses and the timescales in which they occur.
50-70% of circulating WBC 1-3% of circulating WBH <1% of circulating WBC
Phagocytic Not phagocytic- release granules containing histamines, serotonin, prostaglandins
Required for immune response to parasites, helminths and allergic responses
Important in Th2 responses- kick starting acquired immune reponse
3. Define the terms antigen, antibody, B lymphocyte, T lymphocyte, primary and secondary immune
responses, and innate and acquired immunity.
Acquired/Adaptive Immunity
Characteristics
Antigen specific
Can form memory
Requires priming- specific cells help to start the acquired immune response Cellular Immunity: T and B cells Humoral immunity: antibodies
Antigens are glycoprotein molecules which react with antibodies or T cells. However not all antigens can induce an immune response in the host: those that can are termed immunogens Antibody molecules can be found in the blood stream and the body fluids and bind specifically to particular molecules termed antigens. They are the acquired component of the humoral immune response.The most basic antibody molecule is bivalent- with two antigen binding sites. Immunoglobulins
IgG - 75% of our serum - Crosses placenta, therefore important in protecting newborns - Long serum hal-life - Part of secondary immune respons
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- Bivalent- two identical antigen binding sites IgM - 10% of total serum Ig - Complex of 5 linked bivalent monomeric antibodies, therefore 10 identical binding sites- multivalent - Star-like shape - Important in primary immune response - Slightly lower affinity to antigens compared to IgG, which is compensated for by number of binding sites
IgA - 2 basic monomers; dimer with secretory piece - Found in body secretions, e.g. mucus membranes in GI tract - Contains a secretory component which protects it from digestive enzymes
IgE - Involved in allergic response and the response to helminths - Binds to basophils and mast cells - Triggers release of histamines
IgD - Complete function not known
A particularly antibody ‘recognizes’ an antigen because that antibody’s binding site it complementary to the EPIPTOPE (region approx 6 amino acids long) on the antigen. This forms the basis of the specificity of antigen recognition. How does an antibody kill a virus? Four important mechanisms:
1. Binds to the virus and prevents attachment to the cell
2. Opsonisation: virus-antibody complex is recognised and phagocytosed by macrophage
3. Complement- mediated lysis of enveloped viruses: cascade of enzymes in the blood which leads to the
destruction of cell membranes, and the destruction of the viral envelope
4. Antibody-dependant cell-mediated cytotoxicity (ADCC) mediated by NK-like cells (see earlier for explanation)
Cells of the acquired immune system
Lymphocytes
Agranular leukocytes
20-40% of the circulating WBC
99% of the cells in lymphatic circulation
T (thymus-derived) cells - Helper T cells: recognize antigen, help B cells to make antibodies and T cells to kill - Cytotoxic T cells: poisonous to cells,kill cells infected by viruses and intracellular bacteria
B (bone marrow-derived) cells - Make antibodies - Have insoluble antigen-binding receptor on its surface. In fact have multiple clones of this receptor;
monoclonal antibodies
NK (natural killer) cells - See earlier in notes
Each subset has distinct cell-surface molecules, e.g. CD4 on helper T-cell which is the receptor for HIV molecules
Lymphocyte precursors are produced in the haematopoietic tissue in the bone marrow
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T cells are then transported to the thymus, where they undergo THYMAL EDUCATION. Here 95-99% get destroyed as they have the potential to recognise host cells
4. Outline the role of clonal selection in immune responses.
Lymphocyte antigen receptors
B cell antigen receptor is a membrane-bound antibody, i.e. surface immunoglobulin which binds intact
antigens; recognises surface of protein, therefore antigen must be in native conformation
Expressed on the T cell surface are 2 protein chains (alpha and beta) which together make the t cell antigen
receptor (TCR). This binds to digested antigen fragments.
Each antigen receptor binds to an epitope on a different antigen, and is unique to a cell. There are many
copies of the receptor on the cell surface
The T-cell antigen receptor (TCR)
Recognizes complex of antigen peptide and HLA (MHC) molecule
HLA (Human leukocyte antigen) binds to little fragments of the pathogen, transports them to the surface so they can be recognized, e.g. so a virus cannot hide inside a host cell. Combination of short peptide from microorganism + HLA = recognition by TCR
MHC denotes the Major Histocompatibility Complex (also known as HLA) Generation of clonal diversity in lymphocytes
During B and T cell development, random genetic recombinations occur within each cell among multiple copies of immunoglobulin genes (B cells) or TCR genes (T cells). There are parallel genes, but they undergo random splicing and recombination which leads to a large repertoire of antigen receptors
These processes generate the diversity of clones of lymphocytes: each clone is specific to a different antigen. Primary Immune Response: clonal selection
A typical antigen is recognized by 1 in ~105 naive T cells
98% of T cells are in the lymph circulation and organs; 2% in blood.
Antigen binds to surface receptor on the B cell (Ig) or the T cell (TCR) and causes selective expansion of that clone.
The receptors which bind with highest affinity to the antigen are selected for, outcompete the other receptors , proliferate and survive to form effector lymphocytes
What happens when the antigen is removed?
Most lymphocytes that have proliferated recently will die after fulfilling their function (involves 2 or 3 mechanisms)
Some survive as memory cells. These are epigenetically modified so that next time the host is infected, the frequency of the receptors will increase.
How does the immune response clear a pathogen?
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Cytotoxic T lymphocytes (CTLs) kill cells infected by viruses or intracellular bacteria. It recognizes antigen peptide and HLA complex, releases granules of enzymes including proteases which digest DNA. The cell is therefore destroyed- APOPTOSIS
Antibodies bind to pathogens: the complex is destroyed or ingested by cells.
5. Understand the role of the physical organization of the immune system in its function.
How does a T cell meet its antigen?
Antigens are taken up by specialized ANTIGEN-PRESENTING CELLS (class of cells which are capable of taking
up particles, ingesting them and presenting proteins on their surface)
transported from the tissues into secondary lymphoid organs, where they meet T cells
initiate the acquired immune response
Antigen-presenting cells include B lymphocytes, macrophages and dendritic cells (which are most efficient)
Lymphoid Organs
Organized tissue in which lymphocytes interact with non lymphoid cells
Sites of initiation and maturation of adaptive immune responses.
Primary lymphoid organs produce the lymphocytes, e.g. bone marrow and thymus
Secondary lymphoid organs include lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT)
Lymphocytes and antigen-presenting cells circulate continuously blood and lymphatic vessels from
tissues via lymph nodes/spleen into the blood
T cells spend around 1-2 hours in the blood, but the rest of the day in the lymph
The tissues are patrolled by lymphocytes, antibodies and antigen-presenting cells.
For example, the skin contains lymphatic vessels that drain into local lymph nodes.
Gut lymphoid tissue controls responses in the intestinal tract.
Antigens present in the blood are taken to the spleen.
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Definitions Lymphocytes are mononuclear cells which are part of the leukocyte (white blood) cell lineage. They are subdivided into B (Bone marrow-derived) and T (Thymus-derived) lymphocytes. Lymphocytes express antigen receptors on their surface to enable recognition of a specific antigen Naïve lymphocytes have never encountered the antigen to which their cell surface receptor is specific and thus have never responded to it. Memory lymphocytes are the products of an immune response, enabling the specificity of their specific receptor to remain in the pool of lymphocytes in the body. Innate immunity An early phase of the response of the body to possible pathogens, characterized by a variety of non-specific mechanisms (e.g. barriers, acids or enzymes in secretions) and also molecules and receptors on cells which are Pattern Recognition Molecules which recognize repeating patterns of molecular structure found on the surface of microorganisms. The innate immune response does not generate memory. Adaptive immunity is the response of antigen-specific lymphocytes to antigen, and includes the development of immunological memory. Adaptive responses can increase in magnitude on repeated exposure to the potential pathogen and the products of these responses are specific for the potential pathogen. Also known as Specific Immunity or Acquired Immunity. Active Immunity is the induction of an immune response by the introduction of antigen. Passive Immunity is immunity gained without antigen induction i.e. by transfer of antibody or immune serum into a naïve recipient. Primary Response is the response made by naïve lymphocytes when they first encounter their specific antigen. Secondary Response is the response made by memory lymphocytes when they re-encounter the specific antigen. T cells originate in the thymus. They recognize antigen presented at the cell surface by MHC/HLA molecules. Surface markers on T cells are CD3, CD4 & CD8 B cells originate in the bone marrow. They recognize free antigen in the body fluids. Surface markers associated with B cells are CD19, surface immunoglobulin class II MHC
- Hassalls’ corpuscle secretes soluble factors, and is important in regulatory T cells
Secondary Lymphoid Organs
Lymphatic System
- Fluid drained from between tissue cells absorbed into lymph
- 2 to 3 litres of lymph are returned to the blood each day (via superior vena cava)
- In the process of draining, lymph can “capture” pathogens
- Fluid passes through lymph nodes which survey for pathogens
LYMPH NODES
- Kidney shaped organs > 1cm
- During immune response, swell in size
- Fluid enters through AFFERENT vessel
- Fluid leaves via EFFERENT vessel
- Lymph perculates through all lymphocytes before
leaving the node
- Usually a SUMMATIVE junction, i.e. there are many
afferent vessels but one efferent vessel
- Rich blood supply lets lymphocytes into the lymph
nodes via the HIGH ENDOLTHELIAL VENUES
- T-cell zone: parafollicular cortex
- B-cell zone: lymphoid follicle- mostly on the
periphery of the lymph node
- During immune response, there is a massive proliferation of B cells, which leads to the formation of a
GERMINAL CENTRE
- Specific chemokines target their respective lymphocytes to their specific areas, e.g. T-cells to the
parafollicular cortex
- The lymph entering lymph nodes may also contain cells such as dendritic cells and macrophages
Spleen
- Filter for antigens in the blood
- Large organ in the abdomen
- Separated into
white pulp: lymphoid cells around blood vessels, full
of lymphocytes
red pulp: contains old damaged RBC
- Any diseases involving RBC, i.e. sickle-cell, often
results in an enlargement of the spleen
- T cell area: peri-arteriolar lymphatic sheath (PALS)
- B cell area is located further away from blood vessels
- Not a vital organ: Individuals who do not have a spleen are highly susceptible to infections with encapsulated
bacteria
Mucosal Associated Lymphoid Tissue (MALT)
• Epithelium is the first line of defence • mucosae and skin form a physical barrier • very large surface area, in large part a single layer of cells • heavily defended by the immune system in case it breaks
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Gut Associated Lymphoid Tissue
- Many villi, plus smoother regions - Involved in the mesenteric lymphatic drainage
system to mesenteric lymph nodes, including intraepithelial lymphocytes
- PEYER’S PATCH: non-capsulated aggregation of lymphoid tissue- predominantly B lymphocytes and contain germinal centres during immune responses
- M-CELLS: sample contents of the intestine,
surveying for pathogens which they can then deliver to immune cells
Cutaneous Immune System - I.e. the skin - Epidermis contains keratinocytes, Langerhans cells
and intraepidermal lymphocytes - The dermis heavily guards the epidermis with
immune cells, e.g. macrophages, T lymphocytes etc - The demis also consists of venules and lymphatic
vessels, providing entry to the blood circulation and drainage to regional lymph node
3. Outline the recirculation of lymphocytes. PROBLEM: There are a very large number of T cells with different specificities There are a very large number of B cells with different specificities There may only be limited amounts of antigen How does the body ensure that the antigen meets lymphocyte with specific receptor? SOLUTION:
Lymphocyte recirculation - Pathogen on mucosal surface - Naive lymphocytes leave BM and Thymus and enter the bloodstream - Recirculate through peripheral lymphoid tissue - Recognition of antigen- massive B cell proliferation in secondary lymphoid tissue (lymphocyte activation) - Otherwise the lympcytes die
Extravasion of naive T cells into the lymph nodes (occurs during immune response)
- The naive T cell “rolls” along the epithelium
- These are then stopped and activated by specific chemokines at a particular place on the epithelium. This “right place” is determined by SELECTINS
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- INTEGRINS then increase adhesion of the T cell to the epithelium, leading to arrest of the cell - Transendothelial migration of the T cell from the bloodstream into the lymph node then occurs - Antigens also enter the lymph nodes via the draining lymphatics - Naive lymphocytes recirculate approx once per day -- enter lymph node—high endothelial venue –
lymphocyte is activated by antigen – stops recirculatng – massive proliferation of B lymphocytes – reenter the blood via the superior vena cava (via the efferent vessel) – target invading microbes/pathogens
Anatomical structure of the immune system
4. Explain the use of CD (cluster of differentiation) markers for discrimination between lymphocytes. Lymphocytes
• Small cells with agranular cytoplasm and a large nucleus • Can be subdivided into 2 groups depending on where they were produced
- B lymphocytes (Bone Marrow) - T lymphocytes (Thymus)
• These express different CD molecules, which are recognised by different antibodies CD Markers
• an internationally recognised systematic nomenclature for cell surface molecules • used to discriminate between cells of the haematopoietic system • more than 300 CD markers • clinical importance e.g. CD4 in HIV
5. Compare and contrast phenotypic characteristics of B and T cells. Relative Quantities
T cells B cells
7.5 x 109 in the blood
Blood contains 2% of the total pool, therefore 50 x 7.5 x 109 = 3.75 x 1011
~ 1012, but mostly in the gut
T Lymphocytes
• all express CD3- antigen specific receptor (TCR)
• TCR, about 10% in blood
• TCR, about 90% in blood: ~2/3 express CD4, ~1/3 express CD8. All mature T cells express one or the other CD4+ = T helper cells, regulatory T cells- Secrete cytokines CD8+ = cytotoxic T cells- Lyse infected cells, secrete cytokines • Thymic output of naive T cells declines with age, and the thymus atrophies. Therefore older people have a
reduced ability to respond to new infections. However the total number of T cells does not change, there are just more memory cells. ANTIGEN RECOGNITION
• only recognise processed antigen presented at the surface of another cell using T cell receptor • antigen is presented by an MHC molecule
B lymphocytes
• Produced by and develop in bone marrow • Surface antigen receptor (B cell receptor) : immunoglobulin like molecule • Express CD markers CD19 & CD20 (not CD3, CD4 or CD8) • Express MHC Class II (can present antigen to helper T cells) • Effector function is to produce antibodies
ANTIGEN RECOGNITION
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• recognise intact antigen free in body fluids (so not presented by another molecule)
• Use B cell receptor, a membrane anchored form of antibody linked to signalling subunits
6. Give examples of antigen presenting cells (APCs) and their locations. Antigen presenting cells (APC) cells that can present processed antigen (peptides) to T lymphocytes to initiate an acquired (adaptive) immune response:
Dendritic cells (DC) - Location: Widely spread e.g. Skin & mucosal tissue - Presents to T cells
B lymphocytes - Location: lymphoid tissue - Presents to T cells
Macrophages (activated) - Location: lymphoid tissue - Presents to T cells
Follicular dendritic cells - Location: lymph node follicles - Presents whole antigens to B cells
- Bacteria bind to macrophage receptors- initiate a response release of cytokine (soluble mediators SIGNAL
INFECTION)
- Phagocytosis then occurs: Engulf and digest bacteria
Cytokines
• Small secreted proteins
• Cell-to-cell communication
• Generally act locally
• Powerful at low concentrations
• Short-lived
INTERLEUKINS (IL-x) Between leukocytes approx 35 different types
INTERFERONS (IFN) Anti-viral effects approx 20-25 different types
CHEMOKINES Chemotaxis, movement approx 50 different types
GROWTH FACTORS development of immune system
CYTOTOXIC Tumor necrosis factor (TNF)
Mechanism
• Inducing stimulus – transcription of gene for soluble protein in cytokine-producing cell – cytokine binds to
receptor on target cell -- Binding generates signal – changes in gene transcription and gene activation –
biological effect
• Cytokines are usually released in a mixture, therefore have a wide range of effects on a range of different
target cells
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Autocrine Action
same cell
e.g. Interleukin 2
Paracrine Action
nearby cell
e.g. interferon
Endocrine action
circulate in bloodstream distant cell
e.g. interleukin 6
Important Cytokines
IL-1
alarm cytokine
fever
TNF-
alarm cytokine
IL-6
acute phase proteins
liver
IL-8
chemotactic for neutrophils
IL-12
directs adaptive immunity
activates NK cells
Bacterial Septic Shock
• Systemic infection
• Bacterial endotoxins cause massive release of the TNF- and IL-1 by activated macrophages
• Increased vascular permeability
• Sever drop in blood pressure
• 10% mortality
Dendritic Cells
• Network of cells located at likely sites of infection, in the skin and near mucosal epithelia
• Recognise microbial patterns, secrete cytokines
• engulf pathogens, and migrate to local lymph node to present antigens to adaptive immune system
Complement
“describe the activity in serum which could complement the ability of specific antibody to cause lysis of bacteria”
Ehrlich (1854-1915)
• major role in innate and antibody-mediated immunity
• complex series of ~30 proteins and glycoproteins, total serum conc. 3-4 mg/ml
• triggered enzyme cascade system; initially inactive precursor enzymes, and as a few enzymes are activated,
they catalyse the cleaving of secondary components etc
• rapid, highly amplified response
• very sensitive
• components produced mainly in the liver, but also by monocytes and macrophages
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Activation
The Classical Pathway
initiated by antigen-antibody complexes
The Alternative Pathway
direct activation by pathogen surfaces
The Lectin Pathway
antibody-independent activation of Classical Pathway by lectins which bind to carbohydrates only found on
pathogens, e.g. MBL and CRP
• Classical & Alternative Pathways converge at C3
• C3 leads to the final Common Pathway
• late phase of complement activation
• Ends with the formation of the Membrane Attack Complex (MAC)
• As a bi-product of the classical pathway, fragments cleaved are
pro-inflammatory molecules
• Principle opsonin is C3b
Control Mechanisms
Acheieved by: • Lability of components, i.e. their short half-life
• Dilution of components in biological fluids
• Specific regulatory proteins:
- Circulating/soluble, eg C1-inhibitor, Factor I, Factor H, C4-binding protein
- membrane bound, eg CD59 (interferes with MAC insertion) and DAF (competes for C4b)
Function
1. Lysis
2. Opsonisation
3. Inflammation/chemotaxis
Mast Cells
• Secrete histamine and other inflammatory mediators, including cytokines
Mucosal mast cell lung
Connective tissue mast cells skin and peritoneal cavity near blood vessels
• Recognise, phagocytose and kill bacteria • activated to degranulate by complement products (ANAPHYLATOXINS) leading to vasodilation and increased
vascular permeability. Local Acute Inflammatory Response
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• tissue damage trigger cascades:
• invasion of pathogens recognition by macrophages phagocytosis release of soluble cytokines + chemokines Diapedesis and Chemotaxis (slowing down of neutrophils in blood vessels and migration towards site of infection)
• complement activation mast cell degranulates release of pro-inflammatory fragments + histamines • endothelial damage change in nature of endothelium signals site of infection to neutrophils
Systemic “Acute-Phase” Response
• May accompany local inflammatory response 1-2 days after • Fever, increased white blood cell production (LEUKOCYTOSIS) • Production of acute-phase proteins in the liver • Induced by cytokines
ACUTE PHASE PROTEINS Required to enhance immune response
C-reactive protein (CRP) - C polysaccharide of pneumococcus - Activates complement - Levels may increase 1000 fold Mannan Binding Lectin (MBL) - Opsonin for monocytes - Activates complement Complement Fibrinogen - clotting
Importance of Cytokines
Signal liver: - produce acute-phase proteins Signal bone marrow: - Increase Cerebrospinal fluid (CSF) by stromal cells and macrophages - Increase leukocytosis (WBC production) Signal Hypothalamus: - Prostaglandins production – fever - Via pituitary gland and adrenal cortex, release corticosteroids – signals liver again
Natural Killer (NK) cells
• Large granulated lymphocytes
• Cytotoxic: lyse target cells ad secrete INTERFERON-
• 5-10% peripheral blood lymphocytes
• No antigen-specific receptor
• Complex series of activating and inhibitory receptors
• Have receptors which bind to antibody-coated cells (ADCC- ANTIBODY DEPENDENT CELL-MEDIATED
CYTOTOXICITY)
• Important in defence against tumour cells and viral infections, especially Herpes
Target Cell Recognition
Missing self recognition
- Ligation of inhibitory NK receptors = inhibition of target cell killing
- Involves recognition of lack of MHC molecules
Induced self recognition
- Ligation of activating NK receptors = target cell killing
• This allows the angle between the two antigen binding sites to change
angle depending on the proximity of cell surface determinants, i.e.
how close together antigens are
Note: • Both light and heavy chains can be divided into variable (where the
sequences are different) and constant (same sequence) regions
• Each IG (immunoglobulin/antibody) domain, e.g. variable light, has
INTRAMOLECULAR DISULPHIDE BONDS to maintain their specific 3D
structure required for antigen binding
• Many cell surface proteins also have IG-like domains, and are said to belong to the IG super family
• The constant region binds to Fc receptors, which can lead to cell activation, e.g. NK cells (secondary effector
functions in immune response)
Antigen-binding site
• Antigen binding occurs at 3 HYPERVARIABLE regions, known as COMPLEMENTARITY DETERMINING REGIONS
(CDR’s)
• These have specific residue positron numbers
• The region of binding is a large undulating 3D structure (~750A = 10-10m), so is highly specific and there are a
significant number of interactions between the antibody and antigen surface
Forces involved • Hydrogen bonds
• Ionic bonds
• Hydrophobic interactions
• Van der Waals interactions
Are non-covalent, therefore are relatively weak. This means that in order to have a HIGH AFFINITY, there can only be
a short distance between the antigen and antibody, highly complementary nature, and a significant number of
interactions.
Antibody Affinity The strength of the total non-covalent interactions between a single antigen binding site and a single epitope on the
antigen.
The affinity association constant K can be calculated:
K varies from 104 to 1011 L/mol
Antibody Avidity The overall strength of multiple interactions between an antibody with multiple binding sites and a complex antigen
with multiple epitopes
• This is a better measure of binding capacity in biological systems
• Monovalent interactions have a low affinity
• Bivalent interactions have a high affinity
• Polyvalent interactions have a very high affinity
Cross-Reactivity Antibodies elicited in response to one antigen can also recognise a different antigen, for example:
1. Vaccination with cowpox induces antibodies which are able to recognise smallpox
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2. ABO blood group antigens are glycoproteins on red blood cells. Antibodies made against microbial agents on
common intestinal bacteria may cross-react with the glycoproteins, which poses a problem for blood
transfusions.
Isotypes and Allotypes • Isotypes are antibodies who are present in everybody, with a constant region.
• Allotypes are antibodies that contain single amino acid mutations, giving allelic polymorphisms which vary in
the population
Immunoglobulin Classes
Different classes of antibodies differ in the constant regions of their heavy chains
Class IgG IgA IgM IgD IgE
Heavy chain γ α µ δ ε
CH Domains 3 3 4 3 4
Light Chain κ/λ κ/λ κ/λ κ/λ κ/λ
IgG and IgA have subclasses
Class IgG IgA
Subclass IgG1, IgG2, IgG3, IgG4 IgA1, IgA2
H chain γ1, γ2, γ3, γ4 Α1, α2
IgG IgA IgM
• γ heavy chain • most abundant • monomer • 4 subclasses- variability mainly
located in hinge region and effector function domains
• Actively transported across the placenta- protection from mother to newborn
• Found in Blood and extracellular fluids
• Major activator of classical complement pathway (mainly IgG1 and IgG3)
• Subclasses decrease in proportion from 1-4
• heavy chain • Second most abundant • monomer (blood) • dimer (secretions) • Major secretory
immunoglobulin • Protects mucosal surfaces from
bacteria, viruses and protozoa • Secretory IgA: joined by J chain
and secretory component. Plasma cell secretes dimeric form without secretory. This bonds to poly-Ig receptor and is endocytosed and secreted into lumen. The poly-Ig receptor is cleaved and becomes the secretory component
• The secretory component
protects IgA from being degraded in the lumen, by proteases etc
• µ heavy chain • pentameric • 5 monomers joined by J chain
(10 x Fab) • mainly confined to blood
(80%) • first Ig synthesised after
exposure to antigen (primary antibody response)
• multiple binding sites compensate for low affinity
• efficient at agglutination of bacteria
• activates complement
IgD IgE
• δ heavy chain • extremely low serum concentrations • least well characterised • surface IgD expressed early in B cell
development • involved in B cell development and activation
• heavy chain • present at extremely low levels • produced in response to parasitic infections and
in allergic diseases • binds to high affinity Fc receptors of mast cells
and basophils
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• cross-linking by antigen triggers mast cell activation and histamine release
Selective Immunoglobulin Distribution
• IgG and IgM in blood
• IgG in extracellular fluid
• Dimeric IgA in secretions across epithelia, including breast milk
• Maternal IgG in foetus via placental transfer
• IgE with mast cells below epithelium
• Brain devoid of antibodies
Antibody effector functions
Summary
Antibodies: In defence
- targeting of infective organisms
- recruitment of effector mechanisms
- neutralisation of toxins
- removal of antigens
- passive immunity in the new born
In medicine
- levels used in diagnosis and monitoring
- pooled antibodies for passive therapy/protection
In laboratory science
- vast range of diagnostic and research applications
Effector Function Activity Example Antibody Class
Neutralization of toxins Inhibits toxicity Tetanus toxin Mainly IgG
Neutralization of viruses Inhibits infectivity Measles Mainly IgG