Nature of Antigens and the Major Histocompatibility Complex Flashcards
Immune system that is characterized by specific recognition of individual pathogens
Adaptive Immune System
The key cells that are responsible for the specificity, diversity, and memory that characterize adaptive immunity
Lymphocytes
Materials that trigger the immune response of lymphocytes
Immunogens
Macromolecules capable of triggering an adaptive immune response by inducing the formation of antibodies or sensitized T cells in an immunocompetent host
Immunogens
Substance that reacts with an antibody or sensitized T cells but may not be able to evoke an immune response in the first place
Antigens
All immunogens are antigens, but the converse is not true. True or False?
True
Factors Influencing the Immune Response
Unique biological properties of the individual
Nature of the immunogen
Genetic coding of major histocompatibility complex (MHC) molecules
Immunogen processing and presentation
Biological properties of the individual that influence the nature of the immune response
Age
Overall health
Dose
Route of inoculation
Genetic capacity
How does age influence immune response?
In general, older individuals are more likely to have a decreased response to antigenic stimulation. At the other end of the age scale, neonates do not fully respond to immunogens because their immune systems are not completely developed
How does overall health influence immune response?
Individuals who are malnourished, fatigued, or stressed are less likely to mount a successful immune response
How does dose influence immune response?
Generally, the larger the amount of an immunogen one is exposed to, the greater the immune response
It determines the actual amount of immunogen needed to generate an immune response
How we are exposed to pathogens and where they get into our bodies
Different routes of inoculation
Intravenous (into a vein)
Intradermal (into the skin)
Subcutaneous (beneath the skin)
Oral contact
How does route of inoculation influence immune response?
The route where the immunogen enters the body determines which cell populations will be involved in the response
A system of genes that code for cell-surface molecules that play an important role in antigen recognition
Major histocompatibility complex (MHC)
The ability of an immunogen to stimulate a host response
Immunogenicity
Factors influencing the immunogenicity of immunogens
Macromolecular size
Foreignness
Chemical composition and molecular complexity
Ability to be processed and presented with MHC molecules
Usually, an immunogen must have a molecular weight of at least _____ to be recognized by the immune system and the most active immunogens typically have a molecular weight of over _____ daltons
10,000; 100,000
“The greater the molecular weight, the more potent the molecule is as an immunogen”. True or False?
True
How does lymphocytes acquire their ability to distinguish between self and nonself?
Thru maturity in primary lymphoid organs
“The more distant taxonomically the source of the immunogen is from the host, the more successful it is as a stimulus”. True or False?
True; more foreign, more effective as immunogen
The most effective immunogens
Proteins and polysaccharides
Why do we consider proteins as powerful immunogens?
Because they are made up of a variety of units known as amino acids
Nonimmunogenic synthetic polymers made up of a few simple repeating units with no bending or folding within the molecule
Nylon or Teflon
Why carbohydrates are less immunogenic than proteins?
Because they are smaller than proteins and have a limited number of sugars available to create their structures
As immunogens, carbohydrates most often occur in the form of
Glycolipids or Glycoproteins
Does pure nucleic acids and lipids perform as immunogens?
No; unless attached to suitable carrier molecule
If a macromolecule cannot be degraded and presented with MHC molecules, then it would be an excellent immunogen. True or False?
False; poor immunogen
The key portion of the immunogen
Determinant site or epitope
Molecular shapes or configurations that are recognized by B or T cells
Epitopes
Number of amino acids in protein epitopes recognized by B cells
As few as 6 to 15 amino acids
This type of epitope consists of amino acids following one another on a single chain
Sequential/Linear epitopes
Type of epitope that results from the folding of one chain or multiple chains
Conformational epitope
This type of epitope brings certain amino acids from different segments of a linear sequence or sequences into close proximity with each other so they can be recognized together
Conformational epitope
Epitopes recognized by B cells may differ from those recognized by T cells. True or False?
True
Characteristics of B cells in the recognition of immunogens:
Reacts with both linear and conformational epitopes of immunogens
Anything that is capable of cross-linking surface immunoglobulin molecules is able to trigger B-cell activation
The immunogen does not necessarily have to be degraded first.
How does T cells recognize immunogens?
For T cells to be able to recognize an immunogen it must first be degraded into small peptides by an antigen-presenting cell (APC). Then the peptides form a complex with MHC proteins and are carried to the surface of the APC
Nonimmunogenic materials that, when combined with a carrier, create new antigenic determinants
Haptens
Haptens by themselves are considered:
Antigen but not immunogen
Once antibody production is initiated, the hapten is capable of reaction with antibody even when the hapten is not complexed to a carrier molecule. True or False?
True
Are haptens capable enough to facilitate precipitation or agglutination? Why?
Precipitation or agglutination reactions will not occur because a hapten has a single determinant site and cannot form the cross-links with more than one antibody molecule that are necessary for precipitation or agglutination.
Hapten produced by poison ivy
Catechols
How does poison ivy give rise to contact dermatitis?
Poison ivy (Rhus radicans) contains chemical substances called catechols, which are haptens. Once in contact with the skin, these can couple with tissue proteins to form the immunogens that give rise to contact dermatitis
The best known drug (haptens) that combines with normal proteins in the body to provoke an immune response
Penicillin
Australian scientist who conducted the most famous study of haptens
Karl Landsteiner
This book provides detailed results of an exhaustive study of haptens; which contributed greatly to our knowledge of antigen–antibody reactions
The Specificity of Serological Reactions, published in 1917
A substance administered with an immunogen that increases the immune response in order to provide immunity to a particular disease
Adjuvants
Clinical function of adjuvants
Addition of an adjuvant to a substance used for an immunization helps to make the immunization more effective
How does adjuvants work?
Adjuvants actually work by targeting APCs, which are key to the adaptive immune response. Substances used as adjuvants protect immunogens from degradation and allow a longer response time that attracts a large number of immune system cells to the injection site, which helps to boost the strength of the response
The only adjuvant approved for clinical use
Aluminum salts
How does aluminum salts perform as adjuvants?
They complex with the immunogen to increase its size and to prevent a rapid escape from the tissues
Ideal route of inoculation for adjuvants to work
Intramuscular
Advantage of incorporating adjuvants in immunization:
Adjuvants are used to accelerate the immune response and increase the duration of protection, thus reducing the need for booster immunizations
Categories according to their relationship to the host
Autoantigens
Alloantigens
Heteroantigens
Heterophile antigens
Antigens that belong to the host
Autoantigens
Characteristics of autoantigens
Does not evoke immune response under normal circumstances. However, if an immune response does occur to autoantigens, it may result in an autoimmune disease
Antigens from other members of the host’s species and are capable of eliciting an immune response
Alloantigens
Type of antigen in concern in tissue transplantation and in blood transfusions
Alloantigens
Antigens from other species, such as other animals, plants, or microorganisms
Heteroantigens
Heteroantigens that exist in unrelated plants or animals but are either identical or closely related in structure so that antibody to one will cross-react with antigen of the other
Heterophile antigens
Screening test for Infectious Mononucleosis (IM)
Paul-Bunnell screening test
Principle of Paul-Bunnell test
Detection of heterophile antibody
This account for differences in how individuals respond to particular immunogens
Major Histocompatibility Complex
The genetic capability to mount an immune response is linked to a group of molecules originally referred to as
Human leukocyte antigens (HLA)
Etiology of the term human leukocyte antigens (HLA)
They were first defined by discovering an antibody response to circulating white blood cells (WBCs)
Human leukocyte antigens (HLA) are now known as:
Major Histocompatibility Complex (MHC) Molecules
Etiology of the term MHC molecules
They determine whether transplanted tissue is histocompatible and thus accepted or recognized as foreign and rejected
MHC molecules are found in:
All nucleated cells in the body
The main function of MHC
To bring antigen in the body to the surface of cells for recognition by T cells
When does T-cell activation occur?
T-cell activation will occur only when antigen is combined with MHC molecules on the surface of other cells
System of genes that encodes cell-surface molecules
MHC
MHC molecules play a pivotal role in the development of cellular immunity only. True or False?
False; both humoral and cellular immunity
The most polymorphic system found in humans
MHC system
Genes that code for proteins that play a pivotal role in immune recognition
MHC genes
Importance of the polymorphism of MHC system
It is essential to our survival because it allows for an immune response to diverse immunogens
Location of the genes coding for the MHC molecules in humans
Short arm of chromosome 6
3 categories/classes of MHC genes:
Class I genes
Class II genes
Class III genes
Three different locations or loci where class I genes are found:
A, B, C
Class II genes are situated in what region?
D region
Different loci where class II genes are found:
DR, DQ, DP
How many genes are coding for class I molecules?
For class I molecules, there is only one gene coding for each particular molecule
How many genes are coding for class II molecules?
Class II molecules have one gene that codes for the α chain and one or more genes that code for the β chain
Location of class III genes
Class III genes lies between the class I and class II regions on chromosome 6
Proteins coded by class III genes:
C4A
C4B
C2
B complement proteins
Cytokines such as tumor necrosis factor (TNF)
Function of class I and II molecules
They are involved in antigen recognition; in this role, they influence the repertoire of antigens to which T cells can respond
Function of class III molecules
They are secreted proteins that have an immune function, but they are not expressed on cell surfaces
Alternate forms of a gene that code for slightly different varieties of the same product
Alleles
Why do we describe MHC system as polymorphic?
Because there are so many possible alleles at each location
When all alleles that an individual inherits code for products that are expressed on cells
Codominant
Because the MHC genes are closely linked, they are inherited together as a package called a:
Haplotype
This accounts for the uniqueness of an individuals MHC type.
Polymorphism; there are numerous alleles or variant forms at each locus
How do we serologically define HLA nomenclature?
Through the use of a battery of antibodies
Where can we find class I MHC (HLA) molecules?
They are expressed on all nucleated cells
Where can we find class II MHC (HLA) molecules?
They are found primarily on APCs
Body distribution and concentration of class I MHC molecules
Highest:
Lymphocytes
Myeloid cells
Low or undetected:
Liver hepatocytes
Neural cells
Muscle cells
Sperm
HLA-C antigens are expressed at a much higher level than HLA-A and HLA-B antigens. True or False?
False, lower levels
Clinical correlation of the concentration of HLA-A, HLA-B, HLA-C antigens
Since HLA-C is expressed at a much lower level than the other two, HLA-A and HLA-B antigens are the most important to match for transplantation
Chemical and structural composition of class I antigen
Class I antigen is a glycoprotein dimer made up of two noncovalently linked polypeptide chains (α chain; β2–microglobulin)
Gene coding for β2–microglobulin of class I MHC
Single gene on chromosome 15 that is not polymorphic
What do we mean by “β2–microglobulin is encoded by a single gene on chromosome 15 that is not polymorphic”?
This means that every class I molecule contains the same β2–microglobulin
Describe the sructure of the α chain of class I antigen
The α chain is folded into three domains—α1, α2, and α3—and it is inserted into the cell membrane via a transmembrane segment that is hydrophobic
Describe the structure and function of β2–microglobulin
β2–microglobulin does not penetrate the cell membrane, but it is essential for proper folding of the α chain
Function of α1 and α2 domains
They serve as the walls of a deep groove at the top of the molecule that functions as the peptide-binding site in antigen recognition
Holding capacity of the peptide-binding site of class I MHC
This binding site is able to hold peptides that are between 8 and 11 amino acids long
In class I MHC, most of the polymorphism resides in the α1 and α2 regions, whereas the α3 and β2 regions are relatively constant. True or False?
True
In class I MHC, the CD8 on cytotoxic T cells reacts with:
α3 region
Designation for nonclassical class I antigens
E, F, and G
Function of nonclassical class I antigens
This group of molecules, except for G, are not expressed on cell surfaces and do not function in antigen recognition but may play other roles in the immune response
Function of G antigens
Expressed on fetal trophoblast cells during the first trimester of pregnancy. G antigens are thought to help ensure tolerance for the fetus by protecting placental tissue from the action of NK cells
How does G antigens ensure the tolerance of fetus from the action of NK cells?
G antigens bind to NK inhibitory receptors and turn off the NK cytotoxic response
Function of E antigens
Similar role as G antigen
Function of F antigens
Unknown
Where can we find class II MHC molecules?
They are found on the APCs that include:
B lymphocytes
Monocytes
Macrophages
Dendritic cells
Thymic epithelium
Most effective antigen-presenting cell
Dendritic cells
Cells with the highest levels of class II molecules on their surface
Dendritic cells
Chemical and structural composition of the major class II molecules —DP, DQ, and DR
Consist of two noncovalently bound polypeptide chains that are encoded by separate genes in the MHC complex. These molecules are called heterodimers because they contain two different chains
Class II MCH molecule with the highest level of expression. Why?
DR is expressed at the highest level because it accounts for about one-half of all the class II molecules on a particular cell
Most highly polymorphic class II MHC molecule
DRβ gene
Class II MCH molecule with the lowest level of expression
DP
Both the α chain and the β chain of class II MHC are anchored to the cell membrane. True or False?
True
Each chain of class II MHC has how many domains?
Each chain has two domains
This forms the peptide-binding site of class II MHC
α1 and β1 domains
Why does class II molecules to capture longer peptides than class I molecules?
Because both ends of the peptide-binding cleft are open
Designation for nonclassical class II genes
DM, DN, and DO
Function of nonclassical class II genes
Products of these genes play a regulatory role in antigen processing
Function of DM gene
Helps to load peptides onto class II molecules
Function of DO gene
Modulates antigen binding
Function of DN gene
Unknown
In class II MHC, the CD4 on helper T cells reacts with:
β2 region
The main role of the class I and II MHC molecules
Antigen presentation
Describe antigen presentation
A process by which degraded peptides within cells are transported to the plasma membrane where T cells can then recognize them
T cells can only “see” and respond to antigens when they are combined with MHC molecules. True or False?
True
Function of class I molecules
mainly present peptides synthesized within the cell to CD8 (cytotoxic) T cells
Function of class II molecules
Present exogenous antigen to CD4 (helper) T cells
Where does the exogenous proteins presented by class II molecules come from?
They are those taken into the cell from the outside and degraded
The watchdogs of viral, tumor, and certain parasitic antigens that are synthesized within the cell
Class I molecules
They mount immune response to bacterial infections or other pathogens found outside cells
Class II molecules
Minimum requirements to trigger T-cell response:
Peptides must be available in adequate supply for MHC molecules to bind
Must be able to be bound effectively
Must be recognized by a TCR
Functional difference/s between class I and II molecules
The mechanisms by which processed antigen is transported to the surface
It is where class I molecules are synthesized
Rough endoplasmic reticulum
And for a time they remain anchored in the endoplasmic reticulum membrane
Why is it called endogenous pathway of antigen presentation?
Because antigens that bind to class I proteins are actually synthesized in the same cell as the class I molecules
Binding of the newly synthesized proteins helps to stabilize the association of the α chain of class I with the β2–microglobulin. True or False?
True
88-kd membrane-bound molecule in the endoplasmic reticulum
Calnexin
Function of calnexin
Keeps the α chain in a partially folded state while it awaits binding to β2–microglobulin
What happens when β2–microglobulin binds to α chain of class I MHC?
When β2–microglobulin binds, calnexin and ERp57 are released and two other chaperone molecules—calreticulin and tapasin— associate with the complex and help to stabilize it for peptide binding
Intracellular peptides/materials processed by class I molecule:
Virus
Tumor
Bacterial antigen
Defective proteins (fail to fold correctly)
Enzyme responsible for the digestion of defective intracellular proteins
Proteases
Proteases that reside in large cytoplasmic complexes called
Proteasomes
What is proteosome?
Packets of enzymes formed into a cylindrical shape through which peptides pass and are cleaved
These are responsible for the adenosine triphosphate-dependent transport of peptides suitable for binding to class I molecules
Transporters associated with antigen processing (TAP1 and TAP2)
TAP1 and TAP2 are most efficient at transporting peptides that are between
8 to 16 amino acids in size
Of the thousands of peptides that may be processed by class I MHC, only a small fraction of them (1% or less) actually induce a T-cell response. True or False?
True
Explain the exogenous pathway of antigen presentation
Antigen is taken into the cell from the outside by means of either phagocytosis or endocytosis
Describe phagocytosis or endocytosis
processes by which cells ingest extracellular molecules by enclosing them in a small portion of the plasma membrane
Characteristics of dendritic cells
Most potent activators of T cells, are excellent at capturing and digesting exogenous antigens such as bacteria
Hydrolytic enzymes within the endosomes digest antigen into peptides of
13 to 18 amino acids in length
It is where class II molecules are synthesized
Endoplasmic reticulum
Protein that associates with class II molecules
Invariant chain (Ii)
Molecular weight of invariant chain (Ii)
31-kd
Function of invariant chain (Ii)
Ii may be responsible for helping to bring α and β chains together in the ER lumen and then moving them out through the Golgi complex to the endocytic vesicles where digested antigen is found
Class II molecules must be transported from the endoplasmic reticulum (ER) to an endosomal compartment where they can then bind peptides. True or False?
True
The remaining small fragment after the degradation of invariant chain is called
class II invariant chain peptide (CLIP)
Why does the binding groove of MHC class II can accommodate more amino acids than the binding groove of MHC class I?
Because in class II molecules, the groove is open on both ends, unlike class I molecules, which have a closed end
Responsible for forming a trimolecular complex that occurs between antigen, class II molecule, and an appropriate TCR
Class II molecules
Clinical significance of MHC
Testing for MHC antigens has typically been carried out before tissue transplant procedures
Why is it important to test for MHC antigens before tissue transplant procedures?
Because both class I and class II molecules can induce a response that leads to graft rejection
How does MHC antigens play a role in the development of autoimmune diseases?
Inheritance of certain HLA antigens appears to predispose a person to certain autoimmune diseases
A progressive chronic inflammatory disorder affecting the vertebrae of the spine caused by the inheritance of HLA B27
Ankylosing spondylitis
Class I and class II molecules determine the types of peptides to which an individual can mount an immune response. True or False?
True
HLA that can increase resistance to HIV infection
HLA B8
