Factors Influencing Immunogenicity

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Factors Influencing Immunogenicity
Immune system protects against bacterial, viral,
fungal and parasitic infections.
It recognises macromolecules in the structure of
these infectious agents (Proteins/polysaccharides
)
Proteins are most potent immunogens with
polysaccharides ranking second
Lipids and nucleic acids do not serve as
immunogens
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In cell-mediated immunity, ONLY proteins serve as
immunogens
Must be processed to small peptides in
association with MHC molecule
Immunogenicity is not intrinsic property
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Immunogen Contribution To Immunogenicity
Immunogenicity is determined by five properties
of immunogen
1) Foreignness
2) Molecular weight
3) Chemical Composition
4) Complexity
5) Degradability
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1) Foreignness
Ability of lymphocyte to recognise self antigen
occurs during MATURATION
Any molecule not exposed to immature lymphocytes
during this critical period nonself or foreign

Degree of immunogenicity depends on degree of
foreignness
The greater the phylogenetic distance between two
species, the greater the genetic and antigenic
disparity between them
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Bovine serum albumin (BSA) more immunogenic in
chicken than goat
Exceptions
_at_ Some macromolecules that are conserved cross
species
_at_ Sperm/corneal tissue are very sequestered from
immune system
_at_ If sperm or corneal tissue were to be injected
into the same animal from which they originated
? Immunogenic
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2) Molecular Weight
Molecular weight of 100,000 Da (100 kDa) The
best
Molecular weight lt 500-10,000 Da are poor
3) Chemical Composition Heterogeneity
Synthetic homopolymers (single amino acid or
sugar) lack immunogenicity regardless of
molecular weight.
Copolymers composed of different amino acids
are immunogenic
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Addition of aromatic amino acids (e.g. tyrosine
or phenylalanine) increases immunogenicity
Primary, secondary, tertiary and quaternary
structures of proteins affect immunogenicity
4) Degradability
Macromolecules that cannot be degraded and
presented by APC are poor immunogens
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Polymers of D amino acids cannot b degraded by
macrophage enzymes ? therefore poor immunogens
Large, insoluble macromolecules more immunogenic
than small soluble ones
Why ? More readily phagocytosed and processed
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Viral Antigens
Virus nucleic acid protein
Protein subunit Capsomers
Complete viral particle Virion
It is these proteins that are recognised as
antigen by humoral and cell-mediated pathways
Therefore, surface sequence generated by tertiary
conformation of viral proteins function as
immunodominant B cell epitopes
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During viral infection, antibody levels increase.
Antibodies clear virus by
1) Opsonization (coat virus to help its
phagocytosis)
2) Activate complement cascade (lysis of virus)
3) Bind to virus surface ? prevent further
infection
Viruses cause minor changes to their amino acid
sequence (antigenic drift) or major one
(antigenic shift) that allows them to escape
immune response. (e.g. influenza and aids)
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Bacterial Antigens
Bacteria simple prokaryotes
Immunogen is mainly epitope on surface
Gram positive bacteria composed largely of
peptidoglycans
Peptidoglycans Polysaccharide cross-linked by
short peptide chains
Structural differences in these ? unique epitopes
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Gram negative bacteria thin peptidoglycan layer
covered with protein and LPS.
LPS major antigenic component in gram negative
bacteria
Bacterial capsule loose polysaccharide or
polypeptide layer
Associated with virulence as it interferes with
phagocytosis
However, repeating sequence of high molecular
weight sugars allow generation of a significant
humoral antibody response
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F(ab)2 region consists of two 50,000 Da molecular
weight polypeptide chains (heavy chains) and two
25,000 Da chains (light chains)
Immunoglobulin Subtypes
Five different Ig subtypes
IgM
5-10 of total serum immunoglobulins
Monomeric IgM is membrane-bound antibody
Secreted IgM is pentamer (I.e. five monomeric
subunits held together by disulphide bonds)
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First Ig produced in response to an antigen
First Ig synthesized by neonates
Can bind multidimensional antigens such as viral
particles and RBC
IgM causes clumping of RBC AGGLUTINATION
More potent at this and at activation of
complement system than other Ig
Large size hinders diffusion into intercellular
fluids
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IgA
10-15 of Ig in serum
Predominant Ig in external secretions such as
breast milk, saliva, tears, mucus of bronchial,
genitourinary and digestive tracts.
In serum IgA Monomer
IgA of external secretion called secretory IgA.
IgA binds to poly Ig receptor on mucosal and
glandular epithelium
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Transported by receptor-mediated endocytosis into
coated pits
Therefore, IgA serves an important effector
function at mucous membranes (main entry sites
for pathogens)
IgG
Most abundant in serum (80)
Monomer
Four IgG subclasses IgG 1-4
IgG1, 3 and 4 Cross the placenta and protect
developing foetus
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IgG activates complement system
IgG Opsonins by binding Fc receptors on
phagocytic cells
IgE
Very low serum concentration
Mediate hypersensitivity reactions responsible
for hay fever, asthma and anaphylactic shock
IgE binds to Fc receptors on membranes of
basophils and mast cells.
Cross linking of IgE molecules by allergens ?
degranulates basophils and mast cells
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IgD
0.2 of total Ig
Unknown function
Membrane-bound Ig
Expressed on mature B cells