Dr. Zeff Lectures Flashcards
Natural killer cells are especially good at dealing with _______ pathogens
Intracellular
What are the 3 types of phagocytic cells?
Macrophages
Dendritic Cells
Neutrophils
Which type of phagocyte cannot present MHC?
Neutrophils
____ cells are responsible for mediating humoral immunity.
B cells
____ cells are responsible for mediating cell-mediated immunity.
T cells
Treg cells are generated through negative selection. A small subset of T cells that recognize self-peptide too strongly become Treg cells instead of undergoing apoptosis. Treg cells are only CD____+ cells.
4
Define inflammation
Recruitment of circulating blood leukocytes and various plasma proteins to sites of infection where they function to destroy the microbes and repair damged tissue.
Describe the process of antigen presentation via MHC II.
Antigen / microbe binds to receptor on surface of APC. Ag is endocytosed. Endosome fuses with lysosome that contains cathepsins, which are proteases. pH decreases in phagosome –> activates cathepsins, which degrade Ag.
Simultaneously, MHC II resides embedded in ER membrane. It is bound by invariant protein, which covers it so that it does’t bind to any peptides in the ER. An endosome from ER buds off and travels to fuse with phagosome. After fusion, proteases in the phagosome remove a small tail portion of invariant chain to produce CLIP. HLA-DM then non-enzymatically removes CLIP so that the Ag peptide (10-30AAs) can bind to MHC II. The phago-edosome then moves to the membrane where it fuses with the membrane and expresses MHC II with bound Ag on its surface.
For MHC II, what loci will individuals have in the HLA2 region of their chromosome?
P Q R
They will inherit one allele from mom and one from dad at each location. These genes are co-dominant so if the have P7 (M) and P8 (D) then their APCs can express both a P7 and P8 MHC II protein. These differ slighltly in the peptides they can bind.
MHC II is expressed on _____ cells, whereas MHC I is expressed on ______ cells.
APCs
Has the potential to be expressed on all cells
Describe the general structure of MHC II.
Describe the general structure of MHC I.
- For MHC I, what conditions must be present in order for MHC I to be present on a cell’s surface?
- If no foreign peptides are present, what does MHC I load onto its surface?
- It must be bound to peptide and Beta_2_microglobin must be present.
- Self peptide
How do cancer cells manipulate MHC I to evade the immune system?
They inactivate beta_2_microglobin so that without a functional Beta_2_microglobin MHC I cannot be presented and the cancer will not be detected inside the cell.
- For MHC I, what alleles do we inherit from our parents?
- What does each allele code for?
- How are these alleles inherited?
- B#, C#, A# –> # represents subtype of that allele
- A complete alpha chain
- Co-dominant
Describe the process of presentation on MHC I.
Virus binds to receptors on cell surface –> nucleic acid enters cell and virus replicates in the cell producing a lot of viral protein. Viral protein made in excess is recognized by the cell as aberrant and misfolded so it is tagged by Ub for degradation in the proteasome. This produces smaller viral fragments ~ 9AA in length. These fragments then enter the ER via TAP (transporter associated protein) where they are loaded onto MHC I. A vesicle buds off from the ER and fuses with the membrane, expressing MHC I with bound viral peptide on the surface.
Does each MHC molecule display only 1 peptide?
Each MHC can display only 1 peptide at a time, but each MHC is capable of displaying many different peptides. There are specific positions within the binding pocket of the MHC peptide binding domain that are called anchor locations, and as long as the peptide has the complementary residues at the anchor locations then it can bind to the MHC.
Describe cross-presentation.
A virus infects a cell in a tissue and that cell is not a type of cell that migrates to the lymph nodes. The infected cell presents viral Ag on MHC I. A dendritic cell recognizes the Ag and phagocytizes the infected cell and Ag. Inside the dendritic cell, the viral Ag is transported from the phagosome to the cytosol, where it will be degraded by the proteasome and enter the ER to be loaded on MHC I. Once loaded on MHC I on the surface of the dendritic cell, the dendritic cell can express MHC I + co-stimulator to activate CD8+ cells in lymph nodes.
The TCR is similar in structure to the ______ region of Abs.
Variable (FAB)
Which Abs contain an extra constant domain (CH4)
IgM and IgE
This Ab is the first Ab made by a B cell.
IgM
This Ab is a monomeric receptor on B cells. Very little of it will ever be found in the blood.
IgD
This Ab is an opsonin, a complement activator, can cross the placenta during the 3rd trimester and mediates Ab dependent cellular cytotoxicity of NK cells.
IgG
This Ab exists as a dimer and is released into the GI lumen where it binds to bacteria and antigen to prevent colonization of the gut and damge to gut mucosa.
IgA
This Ab mediates hypersensitivity reactions of mast cells, B cells and eosinophils and also responds to extracellular parasites.
IgE
The ____ chain in Ab and the ____ chain in TCR are more diverse.
Heavy
Beta
Which of the hypervariable regions has the most diveristy and why?
HV3 has the most diveristy because it contains the DJ gene segments which undergo rearrangement so they are subject to high levels of diversity that is not reliant on mutation but rather a programmed mechanism of introducing diversity.
The alpha chain of the TCR is homologous to the ____ chain of Ab.
Light
The beta chain of the TCR is homologous to the ______ chain of Ab.
Heavy
What sources contribute to diversity in the TCR?
1) The # of VDJ gene segments
2) Combinatorial diveristy - total possible combinations based off # of gene segments due to action of VDJ recombinase
3) Combinatorial association - at the protein level, any alpha portion can combine with any beta portion
4) Junctional diversity - action of TDT adding random nucleotides to sites that undergo recombination
CD8 binds to ______ on the MHC I molecule.
alpha 3
CD4 binds to _________ on the MHC II receptor.
Beta 2
What part of the Ab heavy chain gene is unique to the heavy chain?
The d section
Heavy Chain
How many V genes are there?
How many D genes are there?
How many J genes are there?
How many mu genes are there?
45
23
6
4
Describe the action of VDJ recombinase.
VDJ recombinase is responsible for recombining the heavy chain genes to generate diversity. It consists of RAG1 and RAG2 that are nucleases that cleave dsDNA. Any DNA that is “spliced” out is lost as an episome, so mature lymphocytes actually don’t have an identical genome compared to other cells in the body. The first recombination is between D&J, then between V & DJ. The mRNA that is produced still contains extra V & J genes which are spliced out during post-transcriptional processing of the mRNA to produce the mature mRNA.
What part of the heavy chain genome corresponds to the constant regions?
The mu
VDJ recombination occurs during the Pro-B cell stage.
True/False.
True
What is allelic exclusion and at what point during B cell maturation does it occur?
Allelic exclusion occurs when heavy chain that is produced is bound to surrogate light chain and moves to the membrane of the Pre-B cell. This signals to the B cell to stop making heavy chain and start making light chain.
What Ab is expressed on immature B cell?
What about on mature B cell?
IgM
IgM and IgD
IgM and IgD are the same isotype.
True/False
False - they are the same idiotype. They bind to the same antigen, but IgM has 4 constant domains whereas IgD only has 3.
What 5 elements lead to diversity in B cell Abs?
1) The # of VDJ genes alone
2) Combinatorial diversity: the many ways in which V, D and J can combine as a result of VDJ recombination
3) Combinatorial association: the many combinations of heavy and light chain that can occur
4) Junctional diversity: the action of TDT at splice sites during VDJ recombination that adds random nucleotides to create further diversity
5) Somatic hypermutation: association of CD40 ligand on an activated T cell and CD40 receptor on a mature naive b cell leads to activation of activation induced cytidine deaminase (AID). AID is highly error prone so it results in a high degree of mutation called somatic hypermutation. These mutations occur so frequently that they are likely to eventually result in a mutation that confers a higher degree of affinity for antigen (hyper variable regions). Higher affinity results in better binding and better signaling so B cells that produce Ab with this affinity matured Abs will be selected for further proliferation (memory B cells and plasma cells) while B cells that bind less well will die off.
