B Cell Activation And Regulation

Question 1

T or F: B cell signalling can occur through the BCR, similar to signalling in T cells

Answer 1

TRUE; B cell signalling can occur through the BCR, similar to signalling in T cells
- tyrosine phosphorylation cascade is initiated
- co-receptors are involved to amplify signal

NOTE: BUT B cells proliferate and differentiate into plasma cells

Question 2

BCR structure

Answer 2

1. membrane-bound immunoglobulin (m-Ig)
2. Ig-α and Ig-β accessory proteins ; necessary for m-Ig to reach surface after synthesis AND are responsible for signal transduction (ITAM are phosphorylated)

Question 3

Outline B cell activation cascade

Answer 3

• antigen induces BCR conformational change
• BCR translocated to lipid rafts = BCRs cross-link with antigen = brings Ig-α and Ig-β near Lyn (tyrosine kinase)
• CD45 dephosphorylates Lyn = partially active
• Lyn auto-trans-phosphorylates in the kinase domain = fully active
• Activated Lyn phosphorylates ITAMs on Ig-α and Ig-β = brings Syk to membrane, which binds ITAMs on SH2 domains
• Lyn phosphorylates Syk = active
• Activated Syk brings and phosphorylates BLNK = brings Btk and PLCy2
• Lyn phosphorylates Btk = active Btk phosphorylates PLCy2
• PLCy2 cleaves PIP2 = IP3 + DAG

Question 4

Which tyrosine kinases in the B cells are related to T cells ?

Answer 4

• Lyn (B cells) and Lck (T cells)
• Syk (B cells) and ZAP-70 (T cells)

Question 5

How are tyrosine kinases (Lyn, Fyn, Blk) activated ?

Answer 5

• CD45 removes phosphate group from tyrosine = partial activation
• auto-trans-phosphorylation = active

Question 6

Describe how the B Cell Co-receptor functions

Answer 6

• When foreign antigen is tagged by complement (C3d), it binds both CD21 and BCR
• CD21 brings CD19 and TAPA-1 (CD81) = forms B cell co-receptor
• Activated Syk phosphorylates CD19 = amplifies BCR signal

NOTE: co-receptor does NOT constitute signal 2

Question 7

Describe how the inhibitory B cell co-receptor functions

Answer 7

• phosphorylation of ITIM on CD22 delivers negative signal to B cell
• SHP-1 and SHIP (phosphatases) remove phosphates from ITAMs on BCR
• negative signals predominates only without antigen*

*NOTE: this occurs simultaneously with positive signals; as long as antigen is present, positive signal predominates

Question 8

Differentiate TI vs TD antigens, and identify Signal 2 in B cells

Answer 8

Thymus-independent antigens (TI):
- LPS on bacteria cannot be processed through MHC I or II
- no memory B cells after activation

Thymus-dependent antigens (TD):
- B cell internalize antigen, and present via MHC II to T helper cells

Signal 2; CD40 (B cell) and CD40L (activated T cell) binding:
= proliferation and differentiation of B cells in response to TD antigens

Question 9

What causes class switching in B cells ?

Answer 9

• cytokines from ie. T helper
  = switching from IgM > IgA (mucosal) or IgE (parasites)
• Blimp-1 (transcriptional repressor) down-regulates genes involved in BCR signalling, antigen presentation and proliferation
• B cells mature into plasma cells = ONLY produce antigen-specific antibodies