MHC/Central Tolerance

What is the “marker for self” for all of a person’s cells?

Major histocompatibility complex

What type of protein is MHC?

Glycoprotein

What is the important distinction for cells that contain MHC?

All NUCLEATED cells

Which specific class of MHC is present in all nucleated cells?

MHC Class I

How do infected cells use MHC Class I to signal infection?

Digest foreign antigens, present on cell surface with MHC Class I, cytotoxic T-cells recognize as foreign

Which cells DO NOT contain MHC Class I?

Red blood cells

What does viral infection do overall to MHC Class I levels?

Downregulates production, leading to “missing self” induced killing

What is upregulated by viral infection to result in NK killing?

Stimulatory ligand production

Can antibodies activate NK cells?

Yes, by marking cancer cells or virus-infected cells

Where is MHC Class II present?

Antigen-presenting cells

Which cells can present antigens?

Conventional dendritic cells, basophils, macrophages, B-cells

Do antigen-presenting cells have MHC Class I?

Yes, because they have a nucleus

How do cells use MHC Class II to present antigens?

Digest foreign microbes, use MHC Class II to present antigens to helper T-cells

How do antigen-presenting cells specify the type of pathogen to helper T-cells?

By secreting specific cytokines

TH1 infection

Viral

TH2 infection

Eukaryotic

THA infection

Bacterial

TH17 infection

Gut

TH22 infection

Skin

How can dendritic cells present via MHCII?

Break down invading pathogen, present epitope on MHCII to helper T-cell

How can dendritic cells do “cross presentation”?

Dendritic cell engulfs virus, presents on MHCI directly to cytotoxic T-cell

When does cross-presentation occur?

During viral infections (intracellular - activates cytotoxic T-cells)

Which MHC presentation occurs 100% of the time during bacterial infections?

MHCII

Which cells are individually designed to handle different pathogens?

B-cells and cytotoxic T-cells

What is central tolerance?

Immune cells must recognize foreign pathogens without recognizing proteins on the surface of the organism’s own cells

What are the three regions that commonly recombine in the genome of pre-B-cells?

V, D, and J

Where does VDJ recombination occur in pre-B-cells?

Bone marrow

How many choices are there for the V, D, and J regions, respectively?

65, 27, 6

Describe negative selection among B-cells

Cells recognizing ‘self’ antigens are eliminated by apoptosis

What percentage of B-cells are eliminated through negative selection?

55-75%

Where to B-cells migrate to mature?

Peyer’s patches and spleen

Describe clonal expansion

Division, differentiation when exposed to specific antigen

What is the name for a mature B-cell that has migrated but not yet been selected for clonal expansion?

Naive mature B-cell

When does somatic hypermutation occur?

During clonal selection

What is somatic hypermutation?

Mutations that occur at the antigen-recognizing site of antibodies or T-cell receptors that improve affinity for the antigen

When does somatic hypermutation occur in terms of the proliferation of B-cells or T-cells?

During cell division

Where does VDJ recombination occur for cytotoxic T-cells?

Thymus

If VDJ recombination for B-cells creates different antibodies, what does it create in cytotoxic T-cells?

T-cell receptors

What percentage of cytotoxic T-cells fail the ‘self-check’?

98%

What mechanism prevents autoimmune disease under normal conditions?

PD-1/PD-L1 binding

What protein is present on cytotoxic T-cells that helps with preventing autoimmune disease?

PD-1

What protein is present on somatic cells that helps with preventing autoimmune disease?

PD-L1

How does the PD-1/PD-L1 mechanism change during viral infections?

Downregulation of PD-L1, which activates cytotoxic T-cells

What is a typical characteristic of autoimmune diseases with regard to PD-1/PD-L1?

Decreased somatic synthesis of PD-L1

What is an important characteristic of some anti-cancer drugs?

Bind to PD-1 and PD-L1 to increase activity of cytotoxic T-cells