Transcript Antigen Structure and Immunogenicity

Antigen Structure and
Immunogenicity
Folder Title: Antigens(NoTP)
(Without TP Slides)
Updated: September 16, 2014
Antigen Recognition by the Specific
Immune System:
Recognition by B-cell and T-cell Receptors
Antigen (Ag): Binds specifically to an antibody
binding site (Ab), or to a T-cell receptor (TCR)*
• (* When the antigen is being presented to the TCR on a
specific set of cell-membrane proteins called MHC)
Immunogen: Binds specifically to an antibody
binding site or to a T-cell receptor*,
and generates a humoral or cellular immune response.
All immunogens must be antigens,
Not all antigens can generate a response.
Haptens and Epitopes
Haptens: Small organic molecule
(e.g. 1-Fluoro-2,4-dinitrobenzene)
Not Immunogenic by themselves
Can be immunogenic when attached to an immunogenic
macromolecular carrier
The Anti-hapten antibody so generated will bind the Hapten
Epitope: A region of a macromolecular antigen
that is actually an antigenic determinant,
a molecular sub-region that is actually recognized and
bound by an Antibody or T-Cell Receptor
Antigen-Antibody Complementarity
Antibody Light Chain
Variable Region
Fig.
4-6b
Kuby
3rd Ed
AgAb
Sep
Influenza Virus Antigen
Antibody Heavy
ChainVariable Region
Antigen - Antibody Binding
Antibody Light Chain
Variable Region
Fig.
4-6a
Kuby
3rd Ed
AgAb
Kiss
Antibody Heavy Chain
Influenza Virus Antigen
Variable Region
Prot2nd
Primary
sequential
epitopes in
sperm whale
myoglobin
(Epitopes are
antigenic
determinants in
Macromolecules)
Conformational
(non-sequential)
Epitope in Hen
Egg White
Lysozyme.
(Colors show amino
acid side chains
contacting the two
different chains of the
antibody, or
contacting both
chains. Antibody
structure to be
covered later)
Myoglobin
Single Polypeptide
17,000 MW (Tertiary
Structure)
About 7 secondary
domains. One bound
Heme in hydrophobic
pocket
Hemoglobin: a2b2 Tetramer
64,000 MW
One heme per subunit
What Determines Immunogenicity of
an Antigen?
1. Properties of the immunogen
(See detailed breakdown next slide)
2. Properties of the Host (Slides 12 and 18)
a. Genetic
b. Physiological
3. Mode of Antigen Exposure
ImGenFx1
ImGenFx2
Called “H2” in Mice; “HLA” in Human
HLA = Human Leucocyte-associated Antigens
Immunogenicity of Antigens and the MHC Gene Collection:
MHC = Major Histocompatibility Complex
Haplotype = a set of closely linked genes controlling the immune response.
Haplotype is usually transferred to progeny as a linked set
Antigen #1
Antigen #2
Two different antigens
Ag&MHCb
Ag 1
Ag 2
Two different antigens
Ag&MHCc
Ag 1
Ag 2
Two different antigens
Ag&MHCd
Ag 1
Ag 2
Two different antigens
Ag&MHC
Ag 1
Ag 2
ImGenFx3
ImAdmin
Conformational Properties of
Epitopes for Antibodies
64
80
Hen Egg-White Lysozyme: Conformations of Sequence 62 to 80
Anti-hapten Antibodies
See Figure 4-1
p. 77
Kuby, 6th Edition
AbHapten
To Here Sept. 11
AgByB&Ta
AgByB&Tb
AgByB&T
Conformational (nonsequential) Epitope in
Hen Egg White
Lysozyme.
Antigens in Immunologically-Based Clinical Diagnosis and Pathology
Cancer Antigens in Diagnosis of Cancer
Carcino-Embryonic Antigen (CEA)
Prostate Specific Antigen (PSA)
Ovarian Cancer Antigen (CA 125)
Whole-body Imaging of Metastatic Colon Carcinoma
A33 Antigen
Anti-Human Chorionic Gonadotropin Pregnancy Test
(Early Home Pregnancy Test)
Type II Allergic Hypersensitivity
Blood Group Antigens in Transfusions
Hemolytic Disease of New-Borns: Rh Antigen incompatibility
Super-Antigens in Toxic Shock Syndrome
Antigens in Immunologically-Based
Treatment of Cancers and Other Pathologies:
(Specifics Later)
Cancer Antigens as Targets for Therapy
Radioactively-labeled Antibodies
Cytolytic Antibodies
Specifically Activated Antigen-presenting Cells.
Imaging with Antibodies Carrying
“Reporter Groups”
Radioactive Isotopes
Fluorescent Groups (“Chromophores”)
Metals
Antigen-Antibody Interactions in Research and Clinical
Medicine
e.g. Radioactively labeled monoclonal antibody
reacting with tumor cell antigens in detection of
metastatic colon cancer
Imaging on Metastatic Colon Carcinoma with
Radioactive-Iodine-Labelled Monoclonal Ab to A33 Ag
Lloyd Old, Scientific American, August, 1996, p. 138)
SeeMets
Arm
Head
Antihapten Antibodies in the Detection and
Measurement of Small Molecules
For example:
Anti-HCG (Human chorionic gonadotrophin) antibody
in the detection of soluble HCG in urine
AntiHCG
What will happen
when concentration of
Anti-HCG-Ab is about
equal to Haptencarrier conjugate?
What will happen when you put excess soluble hapten in the
way of the anti-HCG-Ab?
PregTest
Antibodies in Blood Transfusions
Antibodies to A, B, O Blood Group Antigens
Pre-existing Antibodies to Non-tolerated (Unmatched)
Blood Group Antigens : “Isohemagglutinins”
ABOTypes
Pre-existing serum antibodies from exposure to bacterial
antigens that mimic antigens on red blood cells
ABO Blood Group Genotypes, Phenotypes, Antigens and
Serum Antibodies Present
Not a hexasaccharide
(No terminal sugar)
ABOSugar
See Figure 15-13 (a), p. 389,
Kuby, 6th Edition
Galactose
Antibodies in Hemolytic Disease of the New-born
(HDNB)
(Rh-Factor Sensitization)
Rh-Factor positive baby – Rh Negative Mother
HDNB
See Figure 15-14
p. 390, Kuby
6th Edition
HDNBPhoto
AntiRhAb
Following are three Turning Point short answer questions.
Please put all notes on the floor.
Do not have any electronic devices other than your NXT transmitter.
No consulting with other students.
If you have a problem with your device, I can provide you with a
loaner NXT device.
If you have a problem using your NXT device, please ask Elisabeth
for help.
It is imperative that the integrity of these in-class Turning Point
quizzes be maintained at the same level as we will do with the three
written exams.
Immunopathology of Bacterial Septic Shock
Caused by Gram Negative Bacterial Endotoxins:
Examples E. coli
Pseudomonas aeruginosa
Neisseria meningitidis
Meningococcus
70,000 Deaths per year
Diarrhea, Fever, Blood Clotting, Blood Pressure Drop
Macrophage Activation by Endotoxin:
Generates systemic cytokine production IL1 and TNF-alpha (Tumor necrosis factor)
Immunopathology of Bacterial Toxic Shock
Exotoxins Secreted or Presented Membrane Bound:
Act as "Superantigens"
Examples Staphylococcus aureus:
TSST1 (Toxic Shock Syndrome Toxin)
Streptococcus pyrogenes - Rheumatic fever and shock
Staphylococcus enterotoxins: Food poisoning
Superantigens cross-link TCR with Antigen-presenting
Cell MHC Class II Proteins
Generates systemic cytokine production - IL1 and TNFalpha (Tumor necrosis factor)
SuperAg
Staphylococcal enterotoxins (food poisoning)
Streptococcal pyrogenes exotoxins (rheumatic
fever, toxic shock)
See Table 11-2, p. 367, 7th Edition
See Figure 11-6
7th Edition p. 367
Mitogens and Lectins
Mitogens: Stimulate mitosis and cell division non-specifically
(non-specific therefore stimulate polyclonally)
Lectins: Proteins that bind to carbohydrate in glycoproteins
(Can be potent mitogens)
Glycoproteins: Conjugated protein with covalently attached
carbohydrate residues
Examples of Mitogens
Concanavalin A (Con A) : Non-specific T-cell mitogen
Phytohemaglutinin (PHA): Non-specific T-cell mitogen
Pokeweed Mitogen (PWM): Non-specific T- and B-cell
Mitogen
Lipopolysaccharide (LPS): Gram negative bacterial cell wall
component
Potent Polyclonal (non-specific) B-Cell Mitogen
Immune Adjuvants and the Immunogenicity of Vaccines
(See Scientific American, October, 2009)
Boosting Vaccine Power, pp 72 to 79
Activating Antigen-presentation by Cells of the Innate
Natural Immune Response
e.g. Purified derivatives of bacterial lipo-polysaccharides
Bacterial DNA derivatives
Bacterial flagellin protein
Specific Activation of Antigen-presenting Cells
Extra-corporeally (outside of the body)
Dendritic Cell Vaccines
See Dendreon
Innate Natural Immunity and Systemic Sepsis:
NOVA Video on Meningitis (Meningococcal Meningitis,
Endotoxin, and Systemic Sepsis)
http://www.pbs.org/wgbh/nova/meningitis/
Has video links to steps in meningococcal sepsis
“Amy’s Story”
and related NOVA Stories
tpfondy.mysite.syr.edu
The Story of the Oakwood Children
See “Song of the Oakwood Children” as a self-running
presentation
Following are two Turning Point short answer questions.
Please put all notes on the floor.
Do not have any electronic devices other than your NXT transmitter.
No consulting with other students.
If you have a problem with your device, I can provide you with a
loaner NXT device.
If you have a problem using your NXT device, please ask Elisabeth
for help.
It is imperative that the integrity of these in-class Turning Point
quizzes be maintained at the same level as we will do with the three
written exams.
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