Lecture 3 Slides Flashcards
(151 cards)
0
Q
Antigen
A
Any substance that reacts with T or B lymphocytes
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Q
Immunogen
A
Substances that generate immune response
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Q
Simple to macromolecules
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Carbohydrates, phospholipids, nucleic acids and proteins
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Immunologic properties of antigens (Ag)
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Immunogenicity
Antigenicity
Allerogenicity
Tolerogenicity
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Q
Is immunogenic same as antigenic
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Yes, but antigenic does not equal immunogenic
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Q
Types of antigens
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Alloantigen
Mitogen
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Q
Alloantigen
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Antigen determinants found on a molecular structure of some members of the species, but not on the corresponding molecular structure of other members of the species. Inherited as simple Mendelian traits. Are usually detected when one member of a species is immunized with a molecule from member of same species
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Q
Mitogens
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Polyclonal activator, e.g., PHA, ConA, LPs
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Q
Superantigen
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Among the most potent t-cell mitogens known
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Q
What do super antigens bind to?
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Residues in the variable domain of the T-cell receptor and to residues in class II MHC molecules outside of the antigen-binding cleft
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What can super antigens cross link a t-cell to?
A
A class II MHC molecule even when the TCR does not recognize the bound antigenic peptide, leading to activation of the T-cell.
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Q
How does a super antigen activate all t-cells?
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Expressing the V domain to which that super antigen binds
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Q
Common super antigens include
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Staphylococcal enterotoxemia (Ses) and toxic shock syndrome toxin 1 (TSST1)
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Q
Hapten
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Type of antigen
Small molecules which could never induce an immune response unless coupled to a carrier molecule (foreign protein) e.g. Dinitrophenyl, amino benzene sulphonate, arsonate
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Q
Haptein
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Carrier molecule, unlike free haptein, can act as an immunogen
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Q
Hapten-carrier conjugate
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Carrier and hapten combined
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Q
When hapten-carrier conjugate side to immunize rabbit, rabbit creates antibodies to
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Hapten and carrier and conjugate of hapten and carrier
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Q
What antibodies form when one is injected with hapten
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None
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Q
What antibodies form when one is injected with protein carrier (BSA)
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Anti-BSA
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What antibodies form when one is injected with hapten-carrier conjugate
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Anti-DMP (major)
Anti-BSA (minor)
Anti-DNP/BSA (minor)
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Q
What do adjuvants do
A
Enhance immune response
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Q
Freund’s incomplete adjuvant
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Prolongs antigen persistence
Enhances costimulatory signal
Induces granulosa formation
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Q
Freund’s complete adjuvant
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Prolongs antigen persistence
+Enhances costimulatory signal
+Induces granulosa formation
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Q
Insoluble aluminum slats
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Prolongs antigen persistence
Induces granulosa formation
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Mycobacterium tuberculosis
Induces granuloma formation
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Bordetella pertussis
Stimulates lymphocytes nonspecifically
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Bacterial lypopolysaccaride (LPS)
Enhances costimulatory signal
| Stimulates lymphocytes nonspecifically
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Synthetic polynucleotides (poly IC/poly AU)
Stimulates lymphocytes nonspecifically
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What factors of immunogenic influence immunogenicity
Immunogenic foreignness
Size
Chemical composition
Physical form (particulate>soluble; denatured>native;degradability Ag processing by Ag presenting cells)
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What are biological contributions to immunogenicity
System genetics
Species
Individual responders vs non-responders
Age
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How does method of admission contribute to immunogenicity
Dose
Route. Subcutaneous>intravenous>intra gastric
Adjuvant substances that enhance an immune response to an Ag
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Epitope
Small,site on antigen which is recognized by antibody
| Usually between one and six sugars or amino acids on the surface of the antigen
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Antigenic determinant
Cluster of epitopes on the surface of an antigen
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How many determinants does antigen have? Are they different?
Several and they are structurally different from each other
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What does a monoclonal antibody react with
Only one determinant on the same antigen
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What does antigenic determinant bind
Receptors on T cells or antibodies (B cells)
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How does B cell interact with antigen? T cell?
B cell - involves binary complex of membrane Ig and Ag
| T cell - involves ternary complex of T cell receptor, Ag, and MHC molecule
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Do B cells and T cells bind with soluble antigen?
B cells - yes
| T-cells - no
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How are B cells and T cells involved with MHC molecules
B-cells - non requires
| t-cells- required to display processed antigen
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Chemical nature of antigens that react with B cells and T cells
B cells - protein, polysaccharide, lipid
| T cells - mostly proteins, but some lipids and glycolipids presented on MHC-like molecules
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Epitope properties recognized by B cells and T cells
B cells - accessible, hydrophobic, mobile peptides, containing sequential or no sequential amino acids
t-cells - internal linear peptides produced by processing of antigen and bound to MHC molecules
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Antibodies
Immune-system related proteins that bind antigen
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Where are antibodies present
On B cell membrane or secreted by plasma B cells
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What do membrane bound antibodies confer
Antigen specificity
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What do secreted antibodies serve as
The effector of the humoral immunity
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Where are antibodies found
Electrophoresis separates plasma proteins into albumin and globulin. most antibodies are found in the gamma globulin fraction
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Immunoglobulin
Ig
Proteins of molecular weight 150,000 - 900,00 Kd
Unique molecules, derived from immunoglobulin super gene
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How does Ig bind
One end of Ig binds to antigens (the Fab portion) and other end is responsible for effector functions
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fab portion of Ig
So called because it is the fragment of the molecule which is antigen binding
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Fc portion of Ig
Crystallizable
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Immunoglobulins are composed of
Two H chains and two L chains. They are heterodimers.
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Where are disulfide bonds in IgG
Between heavy chains and bet, each heavy and light chain
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What is variable region
Includes ends of light and heavy chains
Composed of 100-110 aa, give antibody it's specificity for binding antigen
Fab or fragment antigen binding that include in the variable ends of an antibody
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What is variable region further subdivided into
Hyper variable (HV) and framework (FR) regions
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Hyper variable regions
Have a high ratio of different aa in a given position, relative to the most common amino acid in that position
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Constant region
```
Does not contain antigen binding domain
Sequence in constant region of the light chain are either lambda or kappa
There are five different sequences in heavy chain constant region and they determine the class or isotype of the antibody.
```
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Hinge region
Constant region of light chain has one domain of homology
CH has homology domains (CH1, CH2 and CH3)
Extended peptides are found between CH1 and CH2 called hinge region
Make antibody more flexible
Found only in IgG, IGA, and IgD (3 CH)
IgM and IgE have no hinge but 4 CH
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Where is hinge region found?
IgG, IgA, and IgD
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What is subunit structure of immunoglobulin
4 polypeptide chains
2 heavy chains
2 light chains
Form a Y shaped unit
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What bridges the two heavy chains
Interchain SS bond
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How are light chains linked to heavy chains
Interchain SS bonds
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What two regions do heavy chains have
Amino acid homology constant region (CH)
| Regions with variation in sequence (VH)
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CL chains of Ig are either
Kappa or lambda
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Regions of constant sequence homology are
CLkappa or CL lambda
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Regions of variable sequence homology are
VLkappa or VLlambda
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What does each CL or VL region have
Intrachain S-S bond
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What are H and L chains folded into
Globular domains
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What is different between IgG, IGA and IgD and IgE and IgM
First have hinge region. Second don't.
| First don't have extra domain. Latter do.
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Primary structure
Accounts for variable and constant regions (domains) of the heavy and light chains
Amino acid sequence of polypeptide chain
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Secondary structure
Folding into antiparallel Beta sheets that are stabilized by hydrogen bonds
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Tertiary structure
Globular domains connected by polypeptide chains and stabilized by hydrophobic interactions and the disulfide bonds
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Quaternary structure
Globular domains of adjacent heavy and light chains interact forming the functional Ig molecule
No covalent bonding
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Is there covalent bonding in quaternary structure
No
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Two roles of immunoglobulin
Antigen receptor
| Effector molecule
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Role of antigen receptor
- recognition of and binding to antigens such as toxins, viruses, and exposed molecules on the surface of pathogenic organisms
- V domain function
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Role of effector molecule
Elimination or inactivation of the foreign antigen or the cell that bears the antigen
C domain function
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Where are antibodies made
T cells release cytokines that make B lymphocytes evolve into plasma cells
Plasma cells secrete antibodies in greater amounts, but do not divide
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Where do plasma cells exist
In lymphoid tissues, not blood.
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Where do memory cells from B cells circulate
In blood?
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CDR
Complementarity determining region
-is the Ag binding site
Hyper variable region is not conserved
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What causes wide range of CDR specificities
Variation in length and sequence of the CDRs in each Fab fragment
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Antigenic determinants
Epitopes on antigen. Antibodies recognize and react with epitopes.
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Can immunoglobulins be immunogens
Yes
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Three antigenic determinants of immunoglobulin
Isotypic, allotypic, and idiotypic
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Isotopic determinants
Constant region determinants that distinguish Ig class and subclass within a species
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Allotypic determinants
Subtle amino acid differences encoded by different alleles of isotype genes. Can be detected by comparing the same antibody class among different inbred strains.
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Idiotypic determinants
Generated by conformation of amino acid sequences of heavy and light chain variable region specific for each antigen
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What is each idiotypic determinant called
Idiotope. Sum of individuals idiotopes is idiotype.
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Difference between primary and secondary responses
Primary is slow in onset, low in magnitude, shirt lived, and IgM
Secondary is rapid on onset, high in magnitude, long lived, IgG (or IgA or IgE)
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What does B cell do when it encounters its matching antigen
It is triggered. It engulfs the antigen and digests it. Then it displays antigen fragments bound to its unique MHC molecules.
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What do combination of MHC and antigen attract?
The help of a mature matching T cell
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What does T cell secrete
Cytokines that help the B cell to multiply and mature into antibody producing plasma cells
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What do antibodies do once they've been secreted?
They are released into the blood. They lock onto matching antigens. The antigen-antibody complexes are then cleared by the complement cascade or by the liver or the spleen
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Heavy chain, no. Of Ch Ig domains, subclasses, light chain, J chain, molecular formula:
IgG
```
Gamma H
3CH
Human, gamma 1,2,3,4
L kappa or lambda
No J
Gamma2kappa2
```
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Heavy chain, GH Ig domains, subclasses, light chain, J chain, molecular formula:
IgM
```
Mu H
4 CH
None
Kappa or lambda L
Yes J
Gamma2lambda2
```
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Heavy chain, GH Ig domains, subclasses, light chain, J chain, molecular formula:
IgA
```
Alpha H
3
Alpha 1 and 2
K or lambda L
Yes J
(a2k2)n or (a2lamvda2)n n=1,2,3,4
```
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Heavy chain, GH Ig domains, subclasses, light chain, J chain, molecular formula:
IgE
```
Epsilon
Four
None
Kappa or lambda
None
E2k2
```
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Heavy chain, GH Ig domains, subclasses, light chain, J chain, molecular formula:
IgD
```
Delta
Three
None
Kappa or lambda
None
Delta2kappa2 or delta2lambda2
```
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Classes of immunoglobulins
```
IgG
IgM
IgD
IgE
IgA
```
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What is the IgG structure
Monomer
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Percentage IgG serum antibodies
80%
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Location of IgG
Blood, lymph, intestine
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Half life IgG serum
23 days
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IgG complement fixation
Yes
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IgG placental transfer
Yes
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IgG known functions 3
Enhances phagocytosis
Neutralizes toxins and viruses
Protects fetus and newborn
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IgM structure
Pentamer
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IgM percentage serum antibodies
5-10%
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IgM location
Blood, lymph, B cell surface (monomer)
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IgM half life in serum
5 days
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IgM complement fixation
Yes
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IgM placental transfer
No
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Known functions of IgM 2
First antibodies produced during an infection
| Effective against microbes and agglutination antigens
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IgD structure
Monomer
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IgD percentage serum antibodies
0.2%
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IgD location
B cell surface, blood, and lymoh
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IgD half life in serum
3 days
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IgD complement fixation
No
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IgD placenta transfer
No
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IgD known functions
Function unknown in serum
| On B cell surface, initiate immune response
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IgE structure
Monomer
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IgE percentage serum antibodies
0.002%
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IgE location
Bound to mast cells and basophils throughout body. Blood
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IgE half life in serum
2 days
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IgE complement fixation
No
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IgE placenta transfer
No
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Known functions of IgE
Allergic reactions. Possibly lysis of worms
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IgA structure
Dimer
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IgA placental transfer
No
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IgA known functions
Localized protection of mucosal surfaces
| Provides immunity to infant digestive tract
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IgA percentage serum antibodies
10-15%
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IgA location
Secretions (tears, saliva, intestine, milk) blood and lymph
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IgA half life in serum
6 days
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IgA complement fixation
No
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Where is J chain of secretory IgA
Right in middle of dimer.
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How is secretory IgA formed
Plasma cell in su mucosa
Secretes dimeric IgA
Dimeric IgA binds with poly-Ig receptor on epithelial cell
Travels in vesicle to other side of cell
Secreted by cell into lumen via enzymatic cleavage
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Functional properties of Ig
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Agglutination
Opsonized ion
Phagocytosis facilitation
Neutralization
Immobilization of bacteria
Complement activation
Mucosal protection
```
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Agglutination
When antigen is mixed with its corresponding antibody. IgM particularly suitable for this.
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Opsonizatiom
Coating of bacteria for which the anti body's Fab region has specificity (esp IgG)
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Phagocytosis facilitation
Cells possess Fc receptor, eg, neutrophil Polymorphonuclear Leukocytes (Polymorphs). Both the Fab and Fc portions of the immunoglobulin molecule are involved.
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Neutralization
Of toxins and blocking attachment. This applies particularly to IgG. Here, only Fab is involved
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Immobilization of bacteria
Antibodies against bacterial ciliate or flagellate eill hinder bacteria movement /ability to escape phagocytic cells. Only Fab is involved.
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Complement activation
(Classical pathway) especially by Fc region of IgM and IgG, leads to bacteria death by MAC; complement components also facilitate phagocytosis by cells possessing a receptor for C3b, eg, Polymorphs
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Mucosal protection
Provided mainly by IgA and to lesser degree IgM. IgA acts chiefly by inhibiting pathogens from gaining attachment to mucosal surfaces. This is a Fab function.
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Polyclonal antibody
A population of antibodies against one antigen, but against multiple epitopes of that antigen.
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Monoclonal antibody
An antibody which is directed against one epitope of one antigen
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Plasmacytomas
Cancer of a single colon of plasma cell, the end stage of B cell differentiation normally located in bone marrow
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Myeloma
Plasmacytomas once it metastasizes into multiple bone marrow sites
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Plasmacytomas tumor arises from
A single antibody producing cell, therefore the tumor produces a large amount of a single kind of Ig-myeloma protein
149
Bence-Jones Protein
Patients with multiple myeloma excrete BJ proteins in the urine. It is a homogenous light chain of one or two classes of L chains (kappa or lambda)
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How are polyclonal antibodies different from monoclonal antibodies?
- p antibodies recognize multiple epitopes, making rhem more tolerant of small changes in nature of antigen
- p antibodies target multiple epitopes, so they provide more robust detection
- monoclonal antibodies react with one epitope on antigen so are more specific
- reproducible results???
