Lecture 2: Antigens, MHC, and Adaptive Immunity

________ immunity centers on T-cells.

Cell-mediated

_________ immunity centers on B-cells and antibody.

Humoral

Larger molecules are ____ likely to be immunogenic, or trigger an immune response.

more

_______ are usually stronger immunogens than simple repeating structures.

Proteins

What is the difference between an antigen and immunogen?

An antigen is a substance recognized by the immune system, while an immunogen is a substance capable of stimulating an adaptive immune response.

*Some antigens will not be able to trigger an immune response

Which two age populations may have weaker immune systems?

Neonates and older adults.

Why is it bad to administer either a low or high dose of a vaccine?

A low dose can lead to insufficient protection while a high dose can promote tolerance.

What are 5 factors that can affect the strength of an immune response?

1. Age

2. Health

3. Genetics

4. Portal of Entry/Route

5. Dose of Vaccine

What are 2 kinds of epitopes B-cells are capable of recognizing and what are the differences?

A linear epitope is a continuous amino acid sequence (a peptide). A conformational epitope is a 3D surface formed by protein folding.

What kind of antigen does a T-cell recognize?

A linear epitope (a processed peptide) shown by MHC.

What happens if a hapten is found alone?

A hapten can bind to a B-cell receptor, but no cross-linking (and therefore no immune response) will occur. Additionally, a hapten can bind to floating antibodies, but no agglutination will take place.

What happens if a hapten is bound to a carrier?

A hapten + carrier can bind to a B-cell receptor and allow cross-linking to occur. An immune response should take place.

Additionally, a hapten + carrier can bind to floating antibodies allowing agglutination to take place.

Define autoantigen.

Antigens that belong to the host and don’t trigger an immune response.

Define alloantigen.

An antigen that is found in another member of the host’s species (e.g., another human) and that is capable of triggering an immune response. This is relevant when it comes to transfusions and transplants.

Define heteroantigen.

An antigen that is found in a species different from the host (e.g., zebra) and that is capable of triggering an immune response.

Define heterophile antigen.

An antigen from the host that is either identical or closely related to an antigen from a different species so that antibody to one will cross-react with antibody to the other.

What does MHC stand for?

Major Histocompatibility Complex.

What does HLA stand for?

Human Leukocyte Antigen.

The MHC is a gene region found on chromosome number ___.

6

Within the MHC gene region, which HLAs are encoded in the MHC Class I subregion?

A, B, and C.

Within the MHC gene region, which HLAs are encoded in the MHC Class II subregion?

DP, DQ, DR

The antigen presented by MHC Class I comes from ______/_______ pathogens.

endogenous/intracellular

The antigen presented by MHC Class II comes from _____/_____ pathogens.

exogenous/extracellular

On which cells can MHC Class I be found?

Every nucleated cell.

On which cells can MHC Class II be found?

APCs.

MHC Class I presents antigens to ___ T-cells.

CD8 cytotoxic

MHC Class II presents antigens to ____ T-cells.

CD4 helper

Describe the membrane-distal and membrane-proximal domains of the MHC Class II molecule.

The α2 and β2 domains (L → R) are the membrane-proximal domains, and α1 and β1 (L → R) are the membrane-distal domains. The epitope binds to domains α1 and β1, while CD4 binds to β2.

Describe the membrane-distal and membrane-proximal domains of the MHC Class I molecule.

The α2 and α1 domains (L → R) are the membrane-proximal domains, and α3 and β-2 (L → R) are the membrane-proximal domains. The epitope binds to the α2 and α1 domains, while CD8 binds to the α3 domain

How does the MHC Class I cell show an internal protein from an intracellular pathogen?

1. A proteasome will degrade protein → peptides

2. Peptides will be moved into the ER via TAP

3. The MHC molecule is being constructed in the ER. β-2 microglobulin binds to the alpha chain

4. The peptide will bind to the alpha chain of MHC Class I

5. The peptide-bound MHC Class I is transported → Golgi → cell surface

6. Peptide binds to CD8 T-Cell

How does the MHC Class II cell show an internal protein from an extracellular pathogen?

1. The invariant chain will bind to MHC Class II in the ER to prevent an endogenous antigen from binding

2. MHC Class II-invariant chain complex will pass through Golgi

3. Once it passes through Golgi, the invariant chain is degraded, leaving behind a bound fragment called CLIP

4. An exogenous antigen will enter the cell in a vesicle and will be degraded into peptides

5. The peptide from the exogenous antigen will replace the CLIP fragment so that it will be bound to MHC Class II

6. The peptide-bound MHC Class II will travel to the cell surface to be presented to a helper CD4 T-cell

What 2 conditions need to be met for a T-cell to recognize a peptide?

1. The peptide needs to be bound to MHC

2. The MHC needs to match with the T-cell (i.e., MHC Class I with CD8 T-cell and MHC Class II with CD4 T-cell)

Haplotype

A linked set of HLA alleles inherited together from one parent.

Closer HLA matching generally _______ risk of immune recognition and rejection when it comes to transplants.

lowers

Explain the double negative (DN), double positive (DP), and single positive (SP) stages in T-cell development.

1. A T-cell precursor will enter the thymus as a thymocyte

2. It starts off as DN because it is neither CD8 nor CD4

3. Once the cell develops alpha-beta chains, it becomes DP with both CD8 and CD4

4. The DP thymocyte will undergo positive selection where it will INTERMEDIATLEY bind to either MHC Class II or MHC Class I on a thymic stromal cell. If it binds to MHC Class II, it will become a SP CD4 cell. If it binds to MHC Class I, it will become a SP CD8 cell. If the binding never happens or if it happens too strongly, the cell is eliminated

5. The SP thymocyte will undergo negative selection where it will encounter a thymic stromal cell. It will present the thymocyte with a self-antigen. If the CD8 or CD4 cell binds to the self-antigen, it will die via apoptosis. If it does not bind, it will exit the thymus as a mature T-cell.

Describe the structure of the T-cell receptor/CD3 complex

The T-cell receptor is made of alpha and beta chains. They bind to the peptide presented by MHC Class I or II. On the left side there is a delta-epsilon chain, and on the right side there is a gamma-epsilon chain. There is a zeta-zeta chain on the inside of the cell. The chains on either side and below the receptor are collectively known as CD3.

What is the purposes of the T-cell receptor and CD3.

The T-cell receptor (alpha and beta chains) recognizes peptides while CD3 are responsible for intracellular signaling once the peptide binds to the receptor.

Th1

Important for macrophage activation; supports cytotoxic response against intracellular pathogens.

Th2

Activates mast cells, B cells, and eosinophiles, so this means it plays a role in dealing with EC parasites and allergic reactions.

Th17

Recruits granulocytes in response to EC bacterial and fungal infections. It enhances inflammation in autoimmune responses.

Tfh

These reside in the lymph node and help B-cells with antibody production, B-cell activation, memory, and immunoglobulin class switching.

Treg

These cells can detect self-antigens and prevent other T-cells from responding to/attacking self and other harmless agents.

Since both NK cells and CD8 cytotoxic T-cells both release granzymes and perforins to kill harmed host cells, what differentiates the two leukocytes?

NK cells are non-specific and part of the innate immune response while CD8 cells are antigen-specific and part of the adaptive immune response.

Explain the steps of B-cell development.

1. Heavy chain rearrangement occurs to transition from a stem cell to a Pro-B cell

2. Bone marrow stromal cells will send developmental signals to the Pro-B cell so it can mature into a Pre-B cell.

3. The Pre-B cell will synthesize heavy chains in the cytoplasm and then display them on the surface of the cell with surrogate (temporary) light chain to form the Pre-BCR.

4. Once light chain rearrangement is complete, a function IgM will be on the surface of the now immature B-cell.

5. If the immature B-cell encounters a self-antigen, it will undergo apoptosis (negative selection).

6. Immature B-cells become mature when they survive negative selection and leave the bone marrow. They can either migrate to the spleen or travel through the lymph nodes and enter circulation (IgM and IgD)

What does the B-cell that stays in the spleen look like?

IgM is bound and it has a CD1 marker.

What does the B-cell that travel to the lymph nodes and ends up in circulation look like?

IgM and IgD are bound. It has a CD23 marker.

How do Tfh (follicular helper T cells) help B cells grow, divide, and differentiate into plasma cells?

1. An antigen will bind to the B cell receptor, and the B cell will process it into a peptide that will be presented to the Tfh cell on an MHC Class II molecule.

2. Additionally, CD40 on the B cell will bind to CD40L on the Tfh cell.

3. This allows the Tfh cell to release cytokines to promote B cell growth, division, and differentation.

How can B cells grow, differentiate, and divide in a T cell-independent manner?

microbial polysaccharides that have identical subunits can bind to multiple B cell receptors, resulting in cross-linkage. Also, antigen can bind to innate immune receptors like TLRs.

What is the disadvantage of T cell-independent B cell cell activation?

Limited class switching (stays as IgM) and weaker memory.

What happens after a B cell finds an antigen that it can bind to.

Only that B cell, not the other naive and different B cells, will be cloned and later turned into plasma cells and memory cells.

_______ is the first immunoglobulin to appear in the primary immune response, and then ____.

IgM; IgG

How does immunoglobulin diversity compare between the primary versus the secondary immune response?

The primary immune response mainly includes IgM and IgG while the second has more class-switched antibodies.

Put the immune response together, starting with barrier breach and ending with memory.

barrier breach → pattern recognition → inflammation + phagocytosis → APC processes antigen → MHC displays it → T cell activation → B cell help/antibody → memory

Central Tolerance

Self-reactive lymphocytes are eliminated or tightly controlled during development.