Lecture 9 Flashcards
Describe the 2 components of the BCR.
1. Describe the naive mature forms found and the activated mature forms found.
- How many are found. What is its function. How is it linked?
Transmembrane receptor in the form of membrane-bound antibody
- Naïve mature B cells= IgM, IgD, Activated/Memory B= IgA, IgE, IgG
- Contains the transmembrane piece still
2) Transmembrane signaling component (Ig-alpha/beta)
- Contains 2 ITAM (…Activation motifs)
- Does all of the intracellular signaling
- Noncovalently linked to Receptor
Describe the B cell co-receptors:
CD19 CD21 CD22 CD32 CD81
CD19: Dominant Signaling component containing ITAMs
CD21: aka Complement Receptor 2 (CR2)- Helps to lower the activation threshold
CD22: Inhibitory and B cell-specific (lacking can cause autoimmunity)
CD32: aka FcyRIIB, inhibitory and contains ITIM
CD81: Stabilizer for CD19
*Collectively known as TAPA-1
Describe B cell activation. How many signals does it require and from where. Describe the 2 signals and what they cause.
Requires 2 signals, one from the BCR and once from the coreceptors
1) Antigen binds to B cell receptor, providing signal 1
- Causes conformational changes in BCR-Igalpha/Igbeta
- Not enough to cause a cascade event
2) Costimulatory molecules will bind to the coreceptors, providing signal 2
- Activation= phosphorylation of ITAMs, dephosphorylation of ITIMs
- Deactivation= phosphorylation of ITIMs, dephosphorylation of ITAMs
What are the 6 steps involved in B cell activation?
1) Ag binds and crosslinks the BCR receptor
2) Conformational change in alpha/beta allows access to ITAMs
3) Src family kinases phosphorylates the ITAMs and Syk kinases (activates)
4) Syk kinase is able to bind to phosphotyrosine residues via SH2 domains
5) Syk kinase phosphorylates BLNK, activating Ras, Rac, PLCy2, and Btk
6) Leads to downstream effects of transcription and activation of the B cell: NFAT, NFkB, AP-1
Describe the 5 steps involved in Complement Receptor 2 Activation.
1) C3b on bacteria cleaved into C3d
2) C3d binds to the CR2 (CD21) receptor, as well as the Ag
- This dual binding lowers the threshold of B cell activation
3) CR2-C3d binding brings CD19 close to the BCR associated kinases; CD19 has to be stabilized with CD81
4) CD19 ITAMs are phosphorylated, allowing recruitment of Lyn and PI3-kinase
5) Further enhances phosphorylation of ITAMs and overall effect of binding
What are the 3 steps for BCR inhibition? What is an example of this?
1) Binding of the inhibitory signal –> Phosphorylation of ITIMs by Src family
2) P-ITIMs recruit SH2 domain phosphatases (SHP and SHIP)
3) Removes phosphate group from the ITAMs and the other enzymatic compounds (PIP3 and inhibits PI3 kinase)
Example: Binding via the CD32 (FcyRIIB) and CD22
How do T cells help B cell activation? List the 4 steps involved in how CD4+ T cells help activate B cells.
T cells will help to activate and dictate which type of antibody to make
1) MHC class 2 on B cells will present Ag to T cell CD3:CD4:TCR complex
2) CD80/86 of B cell binds to CD28 on the T cell to provide co-stimulation for the release of cytokines (IL-4 in particular)
3) T cell will induce expression of CD40L [CD154] to bind to CD40 on B cell
4) B cell upregulate IL-4R and increases the signaling cascade leading to activation
What are the 4 cytokine receptor families?
Type I
Type II
TNF
IL-1/TLR’s
Describe the cytokine receptor family Type I. Which cytokines are found in this family?
Most cytokines (IL-2**, 4, 7, 9, 15, 21) -Both Type I and Type II use JALK/STAT pathway
Describe the cytokine receptor family Type II. Which cytokines are found in this family?
aka interferon pathway (IFN alpha/beta/gamma, and IL-10)
-Both Type I and Type II use JAK/STAT pathway
Describe the cytokine receptor family TNF. Describe the pathway.
Apoptosis (TNF alpha/beta, CD40, FasL)
-TRADD –> TRAF –> NFkB and MAP kinase pathway
Describe the cytokine receptor family IL-1/TLR’s. Which adaptor protein do they use.
use the IRAK adaptor
Chemokine ____ uses a GPCR.
IL-8**
