Adaptive immunity

what are antibodies

soluble serum proteins

What are the different antibodiy classes?

IgA

IgG

IgM

IgE

IgG

what is IgG

the most abundant antibody in human serum

what is IgM

beta globulin

what is IgE and IgA

secreted across mucosal surfaces

what is IgG used for

vaccine components

describe the structure of antibodies

-              Four polypeptide chains where 2 are identical

-              2 light chains and 2 heavy chains, joined together by disulphide linkages, in a Y shape configuration, which is characteristic of IgG

-              FAB region is the fragment for antigen binding (N-terminal region)

o   Here there are 2 fragments, which are identical to one another

-              C-terminal or FC region has a different function (FC stands for first crystallised)

describe the secondary protein structures of igG1

o   Has hairpin loop structures

o   Every given antibody will only recognise one antigen, which is encoded for by the amino acid sequence (in the variable region – N-terminal)

o   This is why the antigen binding site is also known as the variable region

o   There are conserved regions in the N-terminal as well as the C-terminal

what type of antibody can join to form IgA?

o   2 IgG can be joined by a disulphide bridge at the C terminus forms a IgA antibody, which is secretory

when ing join, what determines what antibody is formed?

the position of the disulphide bridge determines whether IgD or IgE is formed

how is IgM formed and why is this beneficial?

o   IgM is 5 IgG joined by disulphide bridges – creates 10 antigen binding sites

§  Creates a faster response and more likely for pathogen to bind

what are epitopes?

the different sequences on an antigen that is exposed to the external environment

what do vaccines target?

the different epitopes on a given antigen

what causes variation on antibodies between species?

-              The idiotype on the N terminus is very variable and there is variation here between different species

o   Isotype on the N terminus varies between species but is species specific

what is the C-terminus like on antibodies between species?

more or less the same with little variation

what is an allotype?

the inter-species variation between a species’ isotope

what produces antibodies?

-              Antibodies are produced by B-cells on contact with non-self (antigen)

-              Bone marrow produces stem cells for B-cells (B-cells are myeloid stem cell precursors)

What is bursa processing and where does it occur?

-              Bursa processing occurs in the spleen (primary lymphoid tissue) – this is where B-cells mature and are stored

describe the clonal selection theory

-              B-cells that encounter an antigen, only then they produce an antibody

o   This forms a plasma cell – this forms the antibody and does so until it reaches clonal exhaustion

o   Memory B cell – laid down in secondary lymphoid tissue for when you encounter the same antigen

o   B-cells can produce an antibody of one specificity – one clone of B-cell will only produce antibodies of one specificity

what type of antibody is produced first when an antibody encounters a B-cell?

o   IgM antibody is always produced as there are more antigen binding sites present

§  This can take a while to happen, which is why the first immune response is slow (time taken for the correct clone of B-cell to be selected and then it has to proliferate and differentiate)

describe what type of antibody is produced during the second response when an antigen is encountered by a B-cell?

§  The second response produces IgG antibodies via memory cells (and then plasma cells) and is much faster due to the volume of memory cells

This determines vaccination success

How can antibodies generate diversity?

-              B-cells are produced and stored in the bone marrow

-              Each B-cell produces only one specificity of antibody, which is formed by splicing different constant and variable region genes together

-              Here, B-cells that produce antibodies that would recognise ‘self’ would also be destroyed

what is gene segment recombination?

-              Antibody genes are organized into segments—V (variable), D (diversity), and J (joining) segments for the heavy chain, and V and J segments for the light chain. During B-cell development, these segments randomly combine to create a unique variable region that determines the specificity of the antibody. This recombination process alone creates a substantial variety of possible antibodies.

what is junctional diversity?

-              During recombination, additional diversity is introduced at the V-D and D-J junctions (in heavy chains) and the V-J junctions (in light chains). Enzymes add or remove nucleotides at these junctions, resulting in slightly different amino acid sequences even among antibodies with the same V, D, and J segments.

what is somatic hypermutation?

-              After encountering an antigen, B cells undergo somatic hypermutation in their antibody genes. This process introduces random mutations, especially in the complementarity-determining regions (CDRs), which are the parts of the antibody that bind antigens. These mutations can improve the antibody's binding affinity for its target.

what is class switch recombination?

-              B cells can also switch the constant (C) region of their antibody, changing the antibody's isotype (e.g., IgM, IgG, IgA) without altering its antigen-binding specificity. This switch allows the immune system to tailor its response depending on the location and type of infection.

How do antibodies work?

-              Antibodies have a conserved region of amino acids

-              Phagocytes also have a FC receptor to detect this sequence when the same antigen is encountered

-              The conserved region at the C-terminal region will be detected by phagocytic cells when the same antigen is encountered

Antibodies can also activate the classical complement pathway

Describe the classical complement pathway

o   The antibody opsonises the bacterial cell surface

o   C1 binds to the antibody in the FC region, forming AC1 (antibody C1)

o    C4 and C2  bind to AC1, giving an enzyme with esterase activity (AC142) – this is sort of equivalent to C3 convertase

o   AC142 splits C3 to C3a and C3b

o   C3a has a chemotactic role and causes degranulation of the mast cells

o   C3b is a target for phagocytic cells

o   If the molecule is gram negative, C5 cascade occurs

o   C5 convertase releases C5a, which is chemotactic and leads to mast cell degranulation

o   C5b leads to a membrane attack complex

How do antigens trigger B cells to make antibodies?

• the antibody on the surface of the B cell encounters an antigen

• B cells recognise two types of antigens, thymus independent antigen and T-helper cells

• B cells present the antigen on the surface via MHC class II via endocytosis

• CD4 stabilises this complex

• Increasing the number of T-helper cells increases the likelihood of collision between T helpers and B cells

• Macrophages stimulate T-helper cells to divide by presenting the antigens on the macrophage surface

• The antigen is presented on the surface with MHC class II

• Macrophages phagocytose and expel the bacteria antigens into the plasma

• These reach the liver and up regulates C3, amplifying the immune response

• Macrophages secrete IL-1 and stimulate more T-helpers to divide which triggers activation and proliferation of B cells.

What is the role of thymus independent antigen?

§  This gives a critical signalling mass to allow for a cascade to then occur in the B-cell

§  Cross-linking can occur between different B-cell receptors (epitopes), increasing the reactivity

§  Few antigens are like this and cannot turn on B-cells directly

Direct induction

Where do T-cells mature and differentiate?

Thymus gland

What happens to T helper cells in the presence of an antigen?

·      Can turn into different types of T-cells

·      Can differentiate into memory cells or effector cells (these cooperate with B-cells)

What do you calculate when measuring the extent of an infection?

ratio of CD4 to CD8

What interleukins are produced by T-helper cells and what is the effect of these?

·      Interleukins 2, 4 and 5 are produced by T-helper cells and these turn on the B-cell

What is the role of TH-1 cells?

• turn on macrophages to stimulate more phagocytosis, leading to more antigen presentation on the macrophage surface

• These recognise the macrophages with the MHC class II complex

• These then secrete interferon gamma, which turns on macrophages and stimulates more phagocytosis

• This stimulates the innate immune system

  • Can be used to overcome bacteria that have adapted to evade phagocytosis

What is the connection between TH1 cells and T8 cells?

§  Very important for dealing with intracellular pathogens such as viruses

§  These recognise infected cells and recruit cytotoxic T-cells and kill the infected cells with the help of TH-1 cells

§  Here, the MHC I on the cell is still intact but some of the viral membrane may be left on the host membrane or some of the virus is presented on the surface of the cell after processing

what are the 5 steps of vaccination success?

-              Direct induction of adaptive cell mediated immunity (differentiation of memory cells to plasma cells) is key to vaccination success

-              T-cell induction of plasma cells to produce antibody is key to vaccination success

-              Induction of cell mediated immunity via innate (macrophage) and adaptive (T-helper) arms to produce antibody is key to vaccination success

-              Induction of cell mediated immunity (innate arm) in the absence of an antibody is also the key to vaccination success

o   A good vaccine would stimulate the humoral component of adaptive immunity and the cell-mediated arm in innate immunity

Induction of cell mediated immunity (adaptive arm) in the absence of antibody is also key to vaccination success

What can hypersensitivity reactions be classified as?

immediate or delayed

what is an allergic reaction?

-              when someone produces IgE when they encounter a certain antigen

what is a type I hypersensitivity reaction?

• anaphylaxid or allergy

  • When an individual encounters the allergen/antigen for the second time

how does a type I hypersensitivity reaction occur?

o   When an individual encounters the allergen/antigen for the second time

o   During the first encounter, B-cells are stimulated to form plasma cells to secrete IgE (also known as a reagent)

o   The individual has a hereditary predisposition for this production

o   Once the IgE is synthesised, they bind to the FC receptor on mast cells, basophils and eosinophils, causing sensitivity

o   Upon the 2^nd time encountering this allergen, IgE binds to the FC receptors on the mast cells rapidly, causing degranulation

o   Degranulation leads to the release of inflammatory mediators such as histamine, leukotrienes, heparin, prostaglandins, platelet activation factor and eosinophil chemoattractant factor for anaphylaxis

o   These trigger smooth muscle contraction, vasodilation, increased vascular permeability and mucus secretion

what is systemic anaphylaxis?

o   generalised response to an allergen when an individual has had a subsequent exposure to the allergen

§  Normally leads to respiratory impairment due to smooth muscle contraction in the bronchioles

§  The arterioles dilate, causing decreased blood pressure and increases capillary permeability, causing increased fluid in tissue spaces

§  The person can die very quickly due to reduced venous return, asphyxiation, reduced blood pressure and circulatory shock

what is localised anaphylaxis?

o   atopic allergy, which is dependent by the route of which the allergen enters the body eg hayfever, which sensitises the mast cells located in the mucus membranes       

§  Eg bronchial asthma – lower respiratory tract, which has similar allergens to asthma

§  In bronchial asthma, the air sacs become over distended and become filled with mucus

§  Smooth muscle in bronchi contract, producing wheezing or a whistling sound upon exhalation

§  Food allergies causing hives is also an example of this

what is desensitisation?

§  injecting allergens beneath the skin to produce IgG antibodies

·      These act as a blocker so can intercept and block the allergen if encountered before they have the chance to react with mast cell bound IgE

§  Suppressor T-cell selectivity may also cause a decrease in IgE sensitivity

what is a type II hypersensitivity reaction?

-              (antibody dependent cytotoxic hypersensitivity):

o   Results in the destruction of host cells by lysis or toxic mediators

o   IgE or IgM are direct against cell surface or tissue associated antigens

o   This usually activates the complement pathway (via complement) and effector cells (via FC receptors)

o   Eg receiving blood from a donor with a different blood group

what is a type III hypersensitivity reaction?

-              (complex mediated hypersensitivity):

o   Involves the formation of immune complexes

How do type III hypersensitivity reactions occur?

o   Normally, immune complexes are removed by monocytes

o   When there are too many immune complexes (antibody-antigen), they may not be as effectively removed

o   The accumulation can lead to the activation of complement, causing a hypersensitivity reaction

o   This can cause damage to blood vessels (vasculitis), kidney glomerular basement membranes (glomerular nephritis), arthritis as well as reactions to skin

What are the types of type III hypersensitivity reactions?

o   Persistent bacterial, viral or protozoal infection with a weak antibody response – leads to chronic immune complex formation and eventual deposition of complex in the host tissues

o   Continued formation of autoantibodies to self-antigens in autoimmune disease – this overloads the reticular endothelial system and can lead to complex deposition eg SLE

o   Immune complexes can form at body surfaces – eg lungs due to constant inhalation of antigens eg farmers’ lungs where the farmer has repeated inhalation of fungi from moudly hay

§  Most antibodies produced are IgE – deposition occurs at the alveoli, leading to alveolar inflammation

§  Eg streptococcal infections – can produce glomerular nephritis as it believed that complexes deposit in the kidney glomeruli

what is a type IV hypersensitivity reaction?

-              (cell mediated or delayed type hypersensitivity):

o   Delayed T-cell mediated reactions

o   Takes time for the delayed type hypersensitivity T-cell to accumulate at the antigen (~1 day)

how do type IV hypersensitivity reactions occur?

o   Occurs when antigens, especially the ones at tissue cells, phagocytose via macrophages and then present these antigens to receptors on the delayed type hypersensitivity T cell surface

o   This contact causes the cell to proliferate and release cytokines, which attract basophils, lymphocytes, macrophage to the effected tissue

o   This can cause damage to tissue sites

o   Eg Tb skin test, allergic contact dermatitis, some autoimmune diseases, transplantation reactions and the killing of cancer cells

what is tuberculin hypersensitivity?

Type 4 hypersensitivity

o   a partially purified protein (tuberculin) is obtained from the bacillus that causes Tb

§  This is then injected into the forearm of the individual being tested

§  Positive person for this has a reaction that occurs within 8 hours and the area around the injection becomes red and firm and hard within 12-24 hours

§  The reaction reaches its peak at 48 hours

§  The reaction is linked to the amount of antigen introduced and the sensitivity of the individual

Similar testing for leprolin for leprosy , histoplasmin for histoplasmosis, brucella antigen for brucellosis

What type of hypersensitivity reaction is allergic contact dermatitis?

o   caused by haptins that bind with proteins in the skin forms the allergen that illicit the immune response

o   The haptins examples are cosmetics, plant materials, topical chemotherapeutic agents, jewellery

o   This can cause skin tissue destruction

o   Caused by viruses, bacterial cells, fungi and protozoa that produce chronic infections where the macrophage and T-cells are continuously stimulated

o   Eg leprosy, Tb, candida, herpes simplex virus,