Foundations 2 week 2-3
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What are the basic steps that begin T cell maturation?
- CD34+ progenitors enter the thymus through the bloodstream.
- Stem cell markers CD34 and CD44 are then downregulated while T cell-specific markers are upregulated.
- IL-7 in the thymus induces T cell differentiation.
What happens if a patient has a IL-7 defect?
- IL-7 defects result in an absence of T cells (T cells do not differentiate).
- B cell development is dependent on T cells, so it results in a complete lack of T and B cells.
- This causes severe combined immunodeficiency syndrome, or SCID
What cell surface markers are present in uncommitted progenitor cells?
- CD34: Stem-cell surface marker
- CD44: Adhesion
What cell surface markers are present in committed double negative T cells?
- CD2, CD5: Adhesion and signaling
- CD127: IL-7 receptor
- CD1A: MHC class-I-like molecule
What does double negative mean?
An absence of CD4 and CD8.
What cells are responsible for positive selection?
Cortical epithelial cells. They present antigens and send survival signals to cells that bind.
What does the HIV env gene code?
Gp120 and gp41
What does the HIV GAG gene encode?
- P24 (forms the capsid around the RNA)
What do the HIV PRO-POL genes encode?
- Ribonuclease H: Separates the RNA from the newly made DNA
- HIV protease: cleaves the polyprotein produced from the GAG gene into individual proteins
- Integrase: splices double stranded DNA into the host DNA
What are the spliced/non-contiguous HIV genes?
- TAT/TAR: Stimulate the synthesis of viral proteins.
- VIF: helps the virus survive in the cytosol
- VPU: helps the virus bud from the cell.
How does Zidovudine (AZT) work?
- Zidovudine (AZT) acts like a thymine, but prevents the RT from completing the DNA.
- It is a RT inhibitor.
Describe the kinetics of a B cell antibody response.
- Around day 6 or 7, antibody production begins and then increases until the body limits the production.
- On a second exposure, it only takes 1 or 2 days.
- The initial response will produce more IgM than IgG.
- The secondary response will produce more IgG than IgM ( [IgG] > [IgM] ).
How do CD2 cells mature and change?
- A double negative T cell (CD2 cell) will undergo gene rearrangement of ß+γ+δ and express either γ+δ, or ß+γ+δ. If ß+γ+δ, it will express CD4 and CD8
- If ß+γ+δ, it will then undergo further gene rearrangement for α+γ+δ, expressing either γ+δ (1%-5%) or α+ß (95%-99%). α+ß T cells become standard T cells with α:ß chains.
- γ:δ T cells do not require MHC presentation, and are less diverse. Their function is relatively unknown, but they act similar to innate immune cells.
Name 2 anti-inflammatory cytokines that suppress inflammatory cells.
How long does it take for the initial adaptive immune response to really kick in?
About 7 days
An 8 month old infant suffering from severe recurrent infections is found to have
undetectable T cell numbers in the blood.
Which receptor is most likely to contain a mutation?
IL-7, which induces T cell differentiation.
Know the order and timing of immune response events in a “typical” viral infection.Note: the time frame varies with each virus.
- Day 0: Infection and viral genome enters the host cell nucleus, causing type 1 interferons to be released (IFNß and IFNα).Dendritic cells and macrophages engulf the virus. Dentritic cells express CD80/86 and produce cytokines (IL-1, IL-6, IL-12, TNFα). Macrophages produce cytokines and chemokines (IL-1, IL-6, IL-12, TNFα, IL-8 aka CXCL8)
- Day 1: Viral gene transcription and translation
- Day 2: Viral particles formed and shed. NK cells attack infected tissues (peaking around days 3-4). Lecting-binding pathway of the complement system begins.
- Day 4: T cells upregulate IL-2Rα and IL-2 to promote T cell proliferation.
- Day 6: T cells activate B cells and migrate to the site of infection.
- Day 12-15: Inflammation subsides. CTLA-4 is produced to stop proliferation and cytokine expression.
- Day 15-25: Memory B and T cells develop.
Describe how Toll-like receptor signaling affects antigen presenting cells and infected cells.
- TLRs on dendritic cells and macrophages recognize pathogens, causing a strong increase in the number of CD80/CD86 surface proteins and MHC II proteins, both signal for T cell activation and survival.
- Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs), like double stranded RNA
How does V(D)J recombination work?
- Light chains have Variable molecules (V) and joining sections (J)
- Heavy chains have Variable molecules (V), Diversity segments (D), and joining sections (J)
- Rearrangement occurs first on the heavy chain and then on the light chain.
- Early pro-B cell stage - Late pro-B cell stage: D-J rearrangment (heavy chains).
What enzyme is critical for gene rearrangement to occur and how does it works?
- RAG (recombination activating genes) enzymes sit at the end of VDJ genes to separate, shuffle, and then rejoin the VDJ genes.
- They produce a covalently closed hairpin at the coding end and then wait for other enzymes to repair the DNA breaks.
What is Isotype switching?
Recombination between specific switch regions. The variable region does not change, so antigen affinity does not change. Only the constant region of the heavy chain changes, thereby changing the type of immunoglobulin (eg, IgM -> IgG), but not the affinity.
What is somatic hypermutation?
Activated B cells become centroblasts in the lymph nodes to proliferate, differentiate, and gather in orbs of cells called Germinal Centers where they mutate their antibodies. These mutations allow the immune system to adapt to new foreign elements.
What is Affinity maturation?
- The process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response.
- Affinity maturation includes somatic hypermutation followed by clonal selection (a process where mutated B cells compete for limited growth resources. The B cells with the greatest affinity survive).
What is Hyper-IgM syndrome?
Hyper-IgM syndrome occurs when a mutation in CD40L prevents cells from producing high affinity IgG or IgA, resulting in more IgM.
How is a T-dependent antibody response initiated?
- To create antibodies, a BCR must be cross linked -> activation of tyrosine kinase -> phosphorylation of ITAM -> phosphorylation of CD19 which sends the signal. CD19 must be bound to the complement molecules (C3d, CR2, CD81).
- Then, the BCR and antigen are endocytosed. The endosome fuses with a lysosome for antigen processing. Peptides of the antigen are then loaded on MHC class II molecules for presentation to CD4+ T cells.
What molecules allow for the rolling interaction of T cells and endothelium?
Binding of L-selectin (T cell) to GlyCAM-1 and CD34 (endothelium).
What causes a T cell to stop and pass through the endothelium when a chemokine is detected?
LFA-1 (T cell) binds to ICAM-1 (endothelium).
T cell activation requires signal 2. What is signal 2?
- Binding of CD28 (T cell) to B7 (CD80/86, on the APC).
- Note: Signal 1 is the attachment to the MHC molecule. Signal 2 is also known as costimulation. CD4 and CD8 cells to do require costimulation.
What is CTLA-4?
A surface protein that is upregulated in active T cells. It sends a negative signal to dampen T cell proliferation, which prevents lymphoproliferative disease and autoimmunity.
What signals activate macrophages?
What is the signature cytokine produced by TH1 cells?
What is the signature cytokine produced by TH2 cells?
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