Transcript Kuby Immunology 6/e

Immunology
Lecture 1
Antigens
Based on
Kuby IMMUNOLOGY (6ed)
Kindt • Goldsby • Osborne
• Essence of immune response is to
distinguish self from nonself
• Antigen can be distinguished by two
properties:
a) Induce an immune response
b) React specifically with what they induce
• When Ag is introduced into a cell:
• B-cell + Ag = Effector B cells (plasma) +
memory B cells
• T-cells + Ag = Effector T cells (CTLs, TH)
+ Memory T cells
• Abs: Humoral response
• Activated T cells: Cell mediated response
• Humoral: mediated by Ag specific blood
proteins called Ag
• This immunity protects against circulating
extracellular Ag (bacteria, exotoxins, virus
etc.)
• Cell mediated: primary effector mechanism
is mediated by Ag specific T cells
• Two subpopulations (Tc –killer cells & THrelease communication molecuces,
cytokines)
• Substance that induces specific immune
response is called an antigen immunogen
• Ability of a substance to induce humoral or
cell mediated immunity is called
immunogenicity
• The inducing substance is called
immunogen
• The ability of a substance to react with the
specific Abs or activated T cells that it
induces is called antigenicity.
• All immunogens are antigens; but all
antigens are not immunogens
• Some small molecules called haptens are
antigenic but incapable of inducing specific
immune response (no Immunogenicity)
• Many biological molecules can function as
haptens: Drugs, peptide hormones, steroid
hormones etc.
• Antihapten antibodies against hCG is used
to detect pregnacy
Factors that influence
immunogenicity
• To protect against infectious disease, the IS
must recognize bacteria, bacterial products,
fungi, parasites and viruses as immunogens.
• IS recognize particular macromolecules of
an infectious agent: their proteins and PS
• NA and lipids: not good immunogens
unless complexed with proteins /PS
• Scientists use Proteins and PS in experimental
studies of humoral immunity
• For cell mediated immunity studies: only
proteins and some lipids, and glycolipids serve
as immunogens
• These molecules are not recognized directly
• Must be processed and presented together with
MHC (proteins)/ with CD1 (Lpds and GL)
Humoral (Ab mediated)
Cell mediated
B cell dependent
T cell dependent
Can recognise Ag without support
molecules (Not MHC restricted)
Recognise Ag in asosication with MHC
Produce Effector B cells (plasma) +
memory B cells
Produce memory T cells and Effector T
cells
Molecualr weight of some common
experimetnal Ags used in immunology
Antoigen
Mol Mass (Da)
Bovine gamma globulin
150,000
BSA
69,000
Flagellin (monomer)
40,000
Hen eggw white lysozyme
15,000
Ovalbumin
44,000
Sperm whale myoglobin
17,000
Tetanus toxoid
150,000
Characteristics of immunogen
• Foreignness
• Recognise as non self
• Unresponsiveness to self antigens: during
lymphocyte development
• Ag not exposed to immature lymphocyres
will eb recognised as nonself
• Degree of immunogencity depends on
degree of foreignness
• Greater phylogenietic distance between two
sepcies
• BSA in Cow! Vs BSA in rabbit
• BSA in chicken is more immunogenci than
in sheep
• MHC-I is a good immunogen even in same
species (HLA typing)
• Conserved proteins (Collagen/ Cyt c)
• Sequested proteins (corneal tissue, sperm)
act as immunoigen in same animal
Molecular Size
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Minmum 100 KDs
Less than 10Kd: poor immunogen
Less than 1Kd not immunogenic
Buildiign block of macromoleuces
(aa,nt,fa,ms) not immunogenic
Chemical composition
• Must not be inorganic in nature
• Kidney stones
• Biggest thread to integrity of an organism is
organic molecules
• Large synthetic homopolymers: X
• Collagen (many tyrosine residues), nylon,
polyacralamide, teflon
• Polypeptides of D-aa is as immunogenic as L-aa?
• Will Abs against D-a.a react with L-a.a
polypeptide?
• Aromatic more immunogenic than nonaromatic
amino acids
• Four levels of protein organisation: more
complexity
• Pure lipids: not immunogenic
• But mix with proteins (cardiolipin in
Wasseman test)
• Specific Abs are raised agiant sterids, fat
soluble vitamins like E, complex lipids (LT)
• Level of leukotriene is determined using Abs
(evaluating asthma)
• Anti-lipid Abs used in transplnataion assays
• Lipid antigens in recognising Mycobacterium
tuberculosis and Mycobacterium leprae
• Pure NA vs nucleoproteins
• Abs to NA appear in serum of patients with
SLE
• Penicillin-Protein conjugate
– Drugs become allergen (sulfadrugs)
Biodegradability
• Intact Ag must be broken down
• APC degrade Ag (antigen processing)
• Large insoluble macromolecules better than
small soluble molecules
• Large molecules are readily phagocytosed
and processed
Charge
• Molecules need not to be charged to
function as immunogens
• Excessive high charge depress immune
response
Conformation
• Denatured molecules can be immunogenic
• Native molecules are better as all antigenic
determinants are intact
Role of biological system
• Genotype of the recipient
– Hereditary absence of the lymphocyte receptor
recognizing a particular Ag
– Failure of an Ag to be presented by a given
MHC
Dosage
• Insufficient dose will not stimulate IR
– Failure to activate lymphocytes
– Immunological tolerance
• High dose also induce tolerance
• Booster dose require for clonal proliferation
of B and T cells
Route of Administration
• Intravenous (into vein): moves to spleen
• Intradermal (into the skin): lymph nodes
• Subcutaneous (beneath the skin): moves to
lymph cells/local lymph nodes
• Intramuscular (into a muscle): lymph nodes
• Intraperitoneal (into the peritoneal cavity):
spleen
Adjuvants
• Substances that enhances immunogenicity of Ag
– When Ag has low immunogenicity
– When small amount of Ag is available
• It works by:
– Ag persistence is prolonged
– Co-stimulatory signals are enhanced (B7 of
Macrophages and CD28 of TH cells)
– Local inflammation is increased
– The nonspecific proliferation of lymphocytes is
stimulated
• Aluminum potassium sulphate
• Freund’s incomplete adjuvants (Ag in aqueous
solution, mineral oil, mannide monooleate)
• Freund’s complete adjuvants (heat killed
mycobacteria for muramysl dipeptide, Ag in
aqueous solution, mineral oil, mannide
monooleate)
• Mycobacterium tuberculosis
• Bordetella pertusus
• Bacterial lipopolysachharide
• Synthetic polynucleotides (poly IC, AU)
Epitopes
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Whole Ag is not immunogenic
Ag has two regions: Hapten and carrier
Haptens are antigenic, but not immunogenic
Hapten portion is called AD
Ag advertise its foreignness through epitopes
Can purified AD induce IR?
At least one AD make a molecule
immunogenic
• It is at least 6 sugars or 15-22 a.a
• Dextran (homopolymer of glc) is a good Ag
• It must be accessible to Abs
– On surface/ hydrophilic
• It can be continuous or discontinuous
• Mb (16.7Kd) has 5 AD of 6-10aa
• Rich in basic amino acid: Ab binding is
through hydrophilic interaction
Egg white lysozyme:
discontinuous epitopes
129aa
Discontinuous
1-12 and 122-129
• Some residues are more important (immuno
dominant)
• Lysozyme: 60-83
• B cells and T cell recognize different
epitopes on the same antigenic molecule
• Human Glucagon (29aa): B cells of mice
identify the amino terminal portion and T
cells identify the carboxy terminal portion
Ag recognition by T and B lymphocytes (qualitative differences)
Based on the studies of PGH Gell and Baruj Benaceraff (1959)
Primary
Immunization
Secondary
immunization
Secondary immune response
Ab Production
Cell mediated T
Response
Native Protein
Native Protein
+
+
Native Protein
Denatured Proteins
-
+
Check your leraning
• Write down the characteristics of ADs