tolerance LB

B Cell Tolerance
Wendy Davidson Ph.D.
May 3, 2011
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Factors that contribute to the increased threshold
of activation in anergic B cells
HEL and Ars/A1 models:
1. Continuous signaling via self
Ag/BCR
2. Decreasd surface IgM
3. Chronic ERK and NFAT signaling
4. Increased intracellular Ca++
5. Constitutive activation of SHIP-1
and DOK-1
6. Inhibition of activation of Syk and
Akt survival pathway
Ferry et.al. 2006. Transplantation 81:308-315

B cell signaling in response to acute and chronic
stimulation
Cambier JC, Nature Reviews, 2007
Dual
phosphorylation
of ITAMS
Mono phosphorylation of ITAMS
SHIP1 and DOK activated
by LYN, modulate signaling
•Chronic BCR signaling required to maintain anergic state
•Anergy reversible by removal of Ag
•Most relevant to MD4XMD5 and Ars/A1 Tg models

Anergic B cells can be rescued from death if sufficient
BAFF is available
Fas/FasL and CD40/CD40L interactions
also may contribute to the death of
anergic B cells Ferry et.al. 2006.
Transplantation 81:308-315

Other mechanisms for rescuing autoreactive anergic B
cells
•signaling threshold, negative signaling
CD22-/-, SHIP1-/-, FcRIIb-/- mice
•exposure to auto Ag
Transfer autoreactive Tg B cells to auto Ag-free environment
•Cross anti-DNA and anti-Sm Tg mice to autoimmune MRL-lpr
or B6-lpr mice
•Reduce the affinity of the BCR
•Defects in cell death pathways (Fas, Bim)